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Introduction. The Child Behavior Checklist (CBCL/ 6-18) is the most commonly used parent-completed instrument that assesses child and adolescent psychopathology. It has been used in epidemiology and clinical studies. The last version contains DSM-oriented subscales. Objective. Investigate the psychometric properties of the CBCL/6-18 and develops a valid and reliable Mexican version. Method. Psychologists and child psychiatrists adapted the Spanish version of CBCL/6-18, and a back translation was done by a native English speaker. Discrepancies in the adaptation were solved by consensus. The checklist was applied to children in the community and to outpatients from a psychiatric children hospital. Reliability was evaluated by estimating internal consistency (Cronbach's alpha) on all scales: retest at one week was evaluated with intraclass correlation coefficients (ICC). A receiver operating characteristic (ROC) curve was performed to estimate a cut-off which correctly identified children from the clinically referred patients and children recruited in the community (non-referred). Mean differences for the groups were calculated with the Student's t test. Results. The Mexican version of the CBCL/6-18 showed that the Cronbach's alpha coefficient was 0.90 for internalizing problems, 0.94 for externalizing problems and 0.97 for the total problem scale. The ICC was 0.97 for the total problem scale. Significant differences were found between the mean score in broad band, narrow and the new DSM/oriented scales. Conclusions. The Mexican version of CBCL/6-18 is a reliable and valid screening instrument for clinical and epidemiologic use. [ABSTRACT FROM AUTHOR]

Human African trypanosomiasis is a neglected tropical disease that is usually fatal without treatment. WHO has revised its rhodesiense human African trypanosomiasis treatment guidelines on the basis of an independent systematic literature review and following the GRADE methodology. This Review reports on the decision-making process and summarises the new recommendations and their potential implications for health-care professionals and policy makers. Due to data scarcity, all recommendations are conditional and based on very low certainty of evidence. Fexinidazole replaces suramin and melarsoprol as the first-line therapy in individuals aged 6 years and older with a bodyweight of 20 kg or more. As fexinidazole is effective in both stages of rhodesiense human African trypanosomiasis, a lumbar puncture for staging is no longer required. In settings in which first-choice drugs are not readily available, immediate interim treatment with pentamidine is suggested. The introduction of oral fexinidazole represents an advancement in the management of rhodesiense human African trypanosomiasis considering the life-threatening adverse reactions individuals can have to melarsoprol. However, children below the age or weight limits remain ineligible for treatment with fexinidazole., Competing Interests: Declaration of interests JS reports that the Instituto de Higiene e Medicina Tropical–Lisbon was a partner in the European & Developing Countries Clinical Trials Partnership (EDCTP2) HAT-r-ACC project (for a clinical trial on fexinidazole in rhodesiense human African trypanosomiasis [HAT]; NCT03974178), coordinated by the Drugs for Neglected Diseases initiative (DNDi), and funded by the EDCTP. JS had a non-remunerated role in training the clinical investigators of the field teams. LB was a member of the data and safety monitoring board for the clinical trial on fexinidazole in rhodesiense HAT. PPS was employed as an advisor at the DNDi until 2021. MPB participated in the scientific advisory committee of the DNDi that dealt with the fexinidazole trials, among other projects. VL reports that the Institut de Recherche pour le Développement was a partner in the HAT-r-ACC project (for a clinical trial on fexinidazole in rhodesiense HAT [NCT03974178]), coordinated by the DNDi. VL was responsible for training project health staff in the diagnosis of HAT (two trainings, one in Malawi and one in Uganda, in 2019). AE chaired the data and safety monitoring board for the clinical trial on fexinidazole in rhodesiense HAT. AE also participated in the scientific advisory committee of the DNDi. All other authors declare no competing interests., (Copyright © 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Pancreatic cancer (PanCa) is one of the deadliest cancers, with limited therapeutic response. Various molecular oncogenic events, including dysregulation of ribosome biogenesis, are linked to the induction, progression, and metastasis of PanCa. Thus, the discovery of new therapies suppressing these oncogenic events and ribosome biogenesis could be a novel therapeutic approach for the prevention and treatment of PanCa. The current study was designed to investigate the anti-cancer effect of honey against PanCa. Our results indicated that honey markedly inhibited the growth and invasive characteristics of pancreatic cancer cells by suppressing the mRNA expression and protein levels of key components of ribosome biogenesis, including RNA Pol-I subunits (RPA194 and RPA135) along with its transcriptional regulators, i.e., UBTF and c-Myc. Honey also induced nucleolar stress in PanCa cells by reducing the expression of various nucleolar proteins (NCL, FBL, and NPM). Honey-mediated regulation on ribosome biogenesis components and nucleolar organization-associated proteins significantly arrested the cell cycle in the G2M phase and induced apoptosis in PanCa cells. These results, for the first time, demonstrated that honey, being a natural remedy, has the potential to induce apoptosis and inhibit the growth and metastatic phenotypes of PanCa by targeting ribosome biogenesis.

Objective: To compare the accuracy of Kane, Barrett Universal II, Haigis, and SRK-T formulas in eyes with average keratometry greater than 46 diopters (D)., Methods: A retrospective analysis was conducted on 101 eyes of 101 patients with average keratometry greater than 46 D. The absolute prediction error (EA) was obtained for each patient one month after surgery. The mean absolute prediction error (MEA), median absolute prediction error (MedEA) and the percentage of patients with absolute refractive error less than 0.25 D, 0.50 D, and 1.00 D were calculated for each formula analyzed., Results: The Kane formula achieved the lowest MEA (0.53 ± 0.43) and the lowest MedEA (0.41), followed by Barrett Universal II (MEA: 0.56 ± 0.42, MedEA: 0.49), SRK-T (MEA: 0.59 ± 0.44, MedEA: 0.54), and Haigis (MEA: 0.77 ± 0.47, MedEA: 0.69), showing a significant difference in the results. It was also observed that the Kane formula was the most accurate, with the highest percentage of patients, with EA less than 0.25 D, 0.50 D, and 1.00 D (30.7%, 54.4%, and 86.1%, respectively), while the Haigis formula was the least accurate (12.9%, 33.7%, and 69.3%, respectively)., Conclusion: In eyes with corneas having average keratometry greater than 46 D, the Kane formula proves to be a useful tool in intraocular lens (IOL) power calculation and demonstrates higher precision compared to the Barrett Universal II, SRK-T, and Haigis formulas., (Copyright © 2024 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction: High-dose methotrexate (HDMTX) use can be limited by the development of acute kidney injury (AKI). Early AKI detection is paramount to prevent further renal injury and irreversible toxicities. This study sought to determine whether early elimination patterns of MTX would be useful as a biomarker of AKI in HDMTX treatment., Methods: This retrospective cohort study included two sites that collected ≥2 MTX levels within 16 h from completion of MTX infusion. Early levels were tagged and MTX elimination half-life (t ½ ) were calculated from combinations of two of three different early time periods. Receiver operating characteristic (ROC) curves were synthesized for each elimination t ½ (biomarker) with respect to AKI and delayed methotrexate elimination (DME); the biomarker with the highest area under the ROC curve (AUC) was tested in a multiple variable logistic regression model., Results: Data from 169 patients who received a total of 556 courses of HDMTX were analyzed. ROC analysis revealed MTX elimination t ½ calculated from the second and third time periods had the highest AUC for AKI at 0.62 (interquartile range [IQR] 0.56-0.69) and DME at 0.86 (IQR 0.73-1.00). After adjusting for age, sex, dose (mg/m 2 ), infusion duration, HDMTX course, and baseline estimated glomerular filtration rate, it remained significant for AKI with an OR of 1.29 and 95% confidence interval of 1.03-1.65., Conclusion: Early MTX elimination t ½ measured within 16 h of infusion completion was significantly associated with the development of AKI and serves as an early clearance biomarker that may identify patients who benefit from increased hydration, augmented leucovorin rescue, and glucarpidase administration., (© 2024 Resonance, Inc and The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

An enduring question in evolutionary biology concerns the degree to which episodes of convergent trait evolution depend on the same genetic programs, particularly over long timescales. In this work, we genetically dissected repeated origins and losses of prickles-sharp epidermal projections-that convergently evolved in numerous plant lineages. Mutations in a cytokinin hormone biosynthetic gene caused at least 16 independent losses of prickles in eggplants and wild relatives in the genus Solanum . Homologs underlie prickle formation across angiosperms that collectively diverged more than 150 million years ago, including rice and roses. By developing new Solanum genetic systems, we leveraged this discovery to eliminate prickles in a wild species and an indigenously foraged berry. Our findings implicate a shared hormone activation genetic program underlying evolutionarily widespread and recurrent instances of plant morphological innovation.

Background: Arteriovenous grafts (AVGs) are used for patients deemed unsuitable for the creation of an autogenous arteriovenous fistula (AVF) or unable to await maturation of the AVF before starting hemodialysis. However, AVGs are prone to infection and thrombosis resulting in low long-term patency rates. The novel aXess Hemodialysis Graft consists of porous polymeric biomaterial allowing the infiltration by cells and the growth of neotissue, while the graft itself is gradually absorbed, ultimately resulting in a fully functional natural blood vessel. The Pivotal Study will examine the long-term effectiveness and safety of the aXess Hemodialysis Graft., Methods: The Pivotal Study is a prospective, single-arm, multicenter study that will be conducted in 110 subjects with end-stage renal disease who are not deemed suitable for the creation of an autogenous vascular access. The primary efficacy endpoint will be the primary patency rate at 6 months. The primary safety endpoint will be the freedom from device-related serious adverse events at 6 months. The secondary endpoints will include the procedural success rate, time to first cannulation, patency rates, the rate of access-related interventions to maintain patency, the freedom from device-related serious adverse events and the rate of access site infections. Patients will be followed for 60 months. An exploratory Health Economic and Outcomes Research sub-study will determine potential additional benefits of the aXess graft to patients, health care institutions, and reimbursement programs., Discussion: The Pivotal study will examine the long-term performance and safety of the aXess Hemodialysis Graft and compare the outcome measures with historical data obtained with other graft types and autogenous AVFs. Potential advantages may include superior long-term patency rates and lower infection rates versus currently available AVGs and a shorter time to first cannulation compared to an autologous AVF. As such, the aXess Hemodialysis Graft may fulfill an unmet clinical need in the field of hemodialysis access., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Frans Moll is a consultant to Xeltis B.V. All other authors declare no conflict of interest.

Background: This update of the guideline on the management of amyotrophic lateral sclerosis (ALS) was commissioned by the European Academy of Neurology (EAN) and prepared in collaboration with the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD) and the support of the European Network for the Cure ALS (ENCALS) and the European Organization for Professionals and Patients with ALS (EUpALS)., Methods: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the effectiveness of interventions for ALS. Two systematic reviewers from Cochrane Response supported the guideline panel. The working group identified a total of 26 research questions, performed systematic reviews, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available., Results: A guideline mapping effort revealed only one other ALS guideline that used GRADE methodology (a National Institute for Health and Care Excellence [NICE] guideline). The available evidence was scarce for many research questions. Of the 26 research questions evaluated, the NICE recommendations could be adapted for 8 questions. Other recommendations required updates of existing systematic reviews or de novo reviews. Recommendations were made on currently available disease-modifying treatments, multidisciplinary care, nutritional and respiratory support, communication aids, psychological support, treatments for common ALS symptoms (e.g., muscle cramps, spasticity, pseudobulbar affect, thick mucus, sialorrhea, pain), and end-of-life management., Conclusions: This update of the guideline using GRADE methodology provides a framework for the management of ALS. The treatment landscape is changing rapidly, and further updates will be prepared when additional evidence becomes available., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Primary objective was to determine if a patient informational brochure describing potentially useful strategies could help manage specific taste changes. Secondary objective was to describe the specific strategies used and whether the strategies were perceived as being helpful., Procedure: This single-center study included pediatric patients with cancer or hematopoietic cell transplant recipients receiving active treatment who experienced bothersome taste changes in the last month. Participants participated in baseline and follow-up interviews conducted 14-21 days apart. A brochure that listed 16 potentially helpful strategies was provided at baseline. At follow-up, we asked about brochure use and whether it helped. At both interviews, we asked about experienced taste changes, strategies used, and whether strategy helped., Results: Of 100 enrolled participants, different (87%) and bad (72%) taste were most common at baseline. Following the brochure intervention, statistically significant reductions were observed in food tasting different, bad, bland, bitter, sour, and metallic. For most strategies, the proportion of patients who used specific strategies or found them helpful was not significantly different between baseline and follow-up. However, "eating foods you like" was considered helpful in significantly more participants who used the strategy in follow-up (72 out of 89, 80.9%) compared with baseline (55 out of 95, 57.9%; p = .008). Between visits, 81.2% looked at the brochure. Among participants, 53.1% found the brochure helpful, very helpful, or extremely helpful., Conclusions: A brochure that offered strategies to manage changes in taste helped participants cope with them. Further research should evaluate the brochure using randomized and multicenter trials., (© 2024 Wiley Periodicals LLC.)

Background: Dengue is a global health problem of high significance, with 3.9 billion people at risk of infection. The geographic expansion of dengue virus (DENV) infection has resulted in increased frequency and severity of the disease, and the number of deaths has increased in recent years. Wolbachia,an intracellular bacterial endosymbiont, has been under investigation for several years as a novel dengue-control strategy. Some dengue vectors (Aedes mosquitoes) can be transinfected with specific strains of Wolbachia, which decreases their fitness (ability to survive and mate) and their ability to reproduce, inhibiting the replication of dengue. Both laboratory and field studies have demonstrated the potential effect of Wolbachia deployments on reducing dengue transmission, and modelling studies have suggested that this may be a self-sustaining strategy for dengue prevention, although long-term effects are yet to be elucidated., Objectives: To assess the efficacy of Wolbachia-carrying Aedes speciesdeployments (specifically wMel-, wMelPop-, and wAlbB- strains of Wolbachia) for preventing dengue virus infection., Search Methods: We searched CENTRAL, MEDLINE, Embase, four other databases, and two trial registries up to 24 January 2024., Selection Criteria: Randomized controlled trials (RCTs), including cluster-randomized controlled trials (cRCTs), conducted in dengue endemic or epidemic-prone settings were eligible. We sought studies that investigated the impact of Wolbachia-carrying Aedes deployments on epidemiological or entomological dengue-related outcomes, utilizing either the population replacement or population suppression strategy., Data Collection and Analysis: Two review authors independently selected eligible studies, extracted data, and assessed the risk of bias using the Cochrane RoB 2 tool. We used odds ratios (OR) with the corresponding 95% confidence intervals (CI) as the effect measure for dichotomous outcomes. For count/rate outcomes, we planned to use the rate ratio with 95% CI as the effect measure. We used adjusted measures of effect for cRCTs. We assessed the certainty of evidence using GRADE., Main Results: One completed cRCT met our inclusion criteria, and we identified two further ongoing cRCTs. The included trial was conducted in an urban setting in Yogyakarta, Indonesia. It utilized a nested test-negative study design, whereby all participants aged three to 45 years who presented at healthcare centres with a fever were enrolled in the study provided they had resided in the study area for the previous 10 nights. The trial showed that wMel-Wolbachia infected Ae aegypti deployments probably reduce the odds of contracting virologically confirmed dengue by 77% (OR 0.23, 95% CI 0.15 to 0.35; 1 trial, 6306 participants; moderate-certainty evidence). The cluster-level prevalence of wMel Wolbachia-carrying mosquitoes remained high over two years in the intervention arm of the trial, reported as 95.8% (interquartile range 91.5 to 97.8) across 27 months in clusters receiving wMel-Wolbachia Ae aegypti deployments, but there were no reliable comparative data for this outcome. Other primary outcomes were the incidence of virologically confirmed dengue, the prevalence of dengue ribonucleic acid in the mosquito population, and mosquito density, but there were no data for these outcomes. Additionally, there were no data on adverse events., Authors' Conclusions: The included trial demonstrates the potential significant impact of wMel-Wolbachia-carrying Ae aegypti mosquitoes on preventing dengue infection in an endemic setting, and supports evidence reported in non-randomized and uncontrolled studies. Further trials across a greater diversity of settings are required to confirm whether these findings apply to other locations and country settings, and greater reporting of acceptability and cost are important., (Copyright © 2024 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Eggplant ( Solanum melongena L.) breeding for fruit quality has mostly focused on visual traits and nutritional and bioactive compounds, including chlorogenic acid. However, higher contents of chlorogenic acid may lead to more pronounced fruit flesh browning. We examined a diverse collection of 59 eggplant accessions across five varietal types ('black oval', 'striped', 'anthocyanin-free', 'purple', and 'black elongated') to evaluate the degree of browning, polyphenol oxidase (PPO) activity, and chlorogenic acid (CGA) content. The results reveal moderate correlations among these traits, with no clear differences among the varietal types, suggesting that other factors, including genetic variation, might significantly influence these traits. Notably, 'black oval' accessions demonstrated higher browning and PPO activity, whereas 'striped' accessions showed low variability. The identification of genotypes with lower browning and higher CGA content highlights opportunities for targeted genotype selection to improve eggplant chlorogenic acid content while maintaining low or moderate browning, pointing towards the importance of genetic considerations in breeding strategies to reduce browning and enhance nutritional value.

Objective: Mobile Health (mHealth) refers to using mobile devices to support health. This study aimed to identify specific methodological challenges in systematic reviews (SRs) of mHealth interventions and to develop guidance for addressing selected challenges., Study Design and Setting: Two-phase participatory research project. First, we sent an online survey to corresponding authors of SRs of mHealth interventions. On a five-category scale, survey respondents rated how challenging they found 24 methodological aspects in SRs of mHealth interventions compared to non-mHealth intervention SRs. Second, a subset of survey respondents participated in an online workshop to discuss recommendations to address the most challenging methodological aspects identified in the survey. Finally, consensus-based recommendations were developed based on the workshop discussion and subsequent interaction via email with the workshop participants and two external mHealth SR authors., Results: We contacted 953 corresponding authors of mHealth intervention SRs, of whom 50 (5 %) completed the survey. All the respondents identified at least one methodological aspect as more or much more challenging in mHealth intervention SRs than in non-mHealth SRs. A median of 11 (IQR 7.25-15) out of 24 aspects (46 %) were rated as more or much more challenging. Those most frequently reported were: defining intervention intensity and components (85 %), extracting mHealth intervention details (71 %), dealing with dynamic research with evolving interventions (70 %), assessing intervention integrity (69 %), defining the intervention (66 %) and maintaining an updated review (65 %). Eleven survey respondents participated in the workshop (five had authored more than three mHealth SRs). Eighteen consensus-based recommendations were developed to address issues related to mHealth intervention integrity and to keep mHealth SRs up to date., Conclusion: mHealth SRs present specific methodological challenges compared to non-mHealth interventions, particularly related to intervention integrity and keeping SRs current. Our recommendations for addressing these challenges can improve mHealth SRs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Identification of novel genotypes with enhanced nitrogen use efficiency (NUE) is a key challenge for a sustainable tomato production. In this respect, the performance of a panel of thirty tomato accessions were evaluated under high (HN; 5 mM N) and low (LN; 0.5 mM N) nitrogen irrigation solutions. For each treatment, when 50% of plants reached the first flower bud stage, plant growth and biomass traits, chlorophyll, flavonol and anthocyanin indexes, nitrogen balance index (NBI), C:N ratio in leaves, stems, and roots, and NUE were evaluated. Significant (p < 0.05) effects were observed for accession, N treatment, and their interaction across all the traits. Under LN, plants showed a delayed development (40 days for HN vs. 65 days for LN) and reduced growth and biomass. On average, LN condition led to 41.8% decrease in nitrogen uptake efficiency (NUpE) but also 189.0% increase in NUtE, resulting in 62.2% overall increase in NUE. A broad range of variation among accessions was observed under both HN and LN conditions. Under LN conditions, chlorophyll index and NBI decreased, while flavonol and anthocyanin indexes increased. Leaf C:N ratio was positively correlated with nitrogen utilisation efficiency (NUtE) in both N treatments. Multi-trait analyses identified top-performing accessions under each condition, allowing to identify one accession among top performers under both conditions. Correlation analysis revealed that high root biomass and leaf C:N ratio are useful markers for selecting high NUE accessions. These findings offer valuable insights for improving tomato NUE under varying nitrogen fertilization conditions and for breeding high-NUE cultivars., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

High-dose methotrexate (HDMTX) is used to treat a broad spectrum of cancers. Methotrexate (MTX) monitoring and adequate supportive care are critical for safe drug administration; however, MTX level timing is not always possible in low- and middle-income countries. The aim of this study was to evaluate HDMTX supportive care capacity and MTX monitoring practices in Latin America (LATAM) to identify gaps and opportunities for improvement. A multicenter survey was conducted among LATAM pediatric oncologists. Twenty healthcare providers from 20 institutions answered the online questionnaire. HDMTX was used to treat acute lymphoblastic leukemia (ALL; 100%), non-Hodgkin lymphoma (84.2%), diffuse large B-cell lymphoma (47.4%), osteosarcoma (78.9%), and medulloblastoma (31.6%). Delays in starting HDMTX infusion were related to bed shortages (47.4%) and MTX shortages (21.1%). MTX monitoring was performed at an in-hospital laboratory in 52%, at an external/nearby laboratory in 31.6%, and was not available in 10.5%. Median interval between sampling and obtaining MTX levels was ≤ 2 h in 45% and ≥ 6 h in 30%, related to laboratory location. Sites without access to MTX monitoring reduced the MTX dose for patients with high-risk ALL or did not include MTX in the treatment of patients with osteosarcoma. Respondents reported that implementation of point-of-care testing of MTX levels is feasible. In LATAM, highly variable supportive care capacity may affect the safe administration of MTX doses. Improving accessibility of MTX monitoring and the speed of obtaining results should be prioritized to allow delivery of full doses of MTX required by the current protocols.

Giant cell arteritis (GCA) is a systemic vasculitis mediated by an aberrant immunological response against the blood vessel wall. Although the pathogenic mechanisms that drive GCA have not yet been elucidated, there is strong evidence that CD4 + T cells are key drivers of the inflammatory process occurring in this vasculitis. The aim of this study was to further delineate the role of CD4 + T cells in GCA by applying single-cell RNA sequencing and T cell receptor (TCR) repertoire profiling to 114.799 circulating CD4 + T cells from eight GCA patients in two different clinical states, active and in remission, and eight healthy controls. Our results revealed an expansion of cytotoxic CD4 + T lymphocytes (CTLs) in active GCA patients, which expressed higher levels of cytotoxic and chemotactic genes when compared to patients in remission and controls. Accordingly, differentially expressed genes in CTLs of active patients were enriched in pathways related to granzyme-mediated apoptosis, inflammation, and the recruitment of different immune cells, suggesting a role of this cell type in the inflammatory and vascular remodelling processes occurring in GCA. CTLs also exhibited a higher clonal expansion in active patients with respect to those in remission. Drug repurposing analysis prioritized maraviroc, which targeted CTLs, as potentially repositionable for this vasculitis. In addition, effector regulatory T cells (Tregs) were decreased in GCA and showed lower expression of genes involved in their suppressive activity. These findings provide further insights into the pathogenic role of CD4 + T cells in GCA and suggest targeting CTLs as a potential therapeutic option., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Here we describe the novel, multi-point Comet Interceptor mission. It is dedicated to the exploration of a little-processed long-period comet, possibly entering the inner Solar System for the first time, or to encounter an interstellar object originating at another star. The objectives of the mission are to address the following questions: What are the surface composition, shape, morphology, and structure of the target object? What is the composition of the gas and dust in the coma, its connection to the nucleus, and the nature of its interaction with the solar wind? The mission was proposed to the European Space Agency in 2018, and formally adopted by the agency in June 2022, for launch in 2029 together with the Ariel mission. Comet Interceptor will take advantage of the opportunity presented by ESA's F-Class call for fast, flexible, low-cost missions to which it was proposed. The call required a launch to a halo orbit around the Sun-Earth L2 point. The mission can take advantage of this placement to wait for the discovery of a suitable comet reachable with its minimum Δ V capability of 600  ms - 1 . Comet Interceptor will be unique in encountering and studying, at a nominal closest approach distance of 1000 km, a comet that represents a near-pristine sample of material from the formation of the Solar System. It will also add a capability that no previous cometary mission has had, which is to deploy two sub-probes - B1, provided by the Japanese space agency, JAXA, and B2 - that will follow different trajectories through the coma. While the main probe passes at a nominal 1000 km distance, probes B1 and B2 will follow different chords through the coma at distances of 850 km and 400 km, respectively. The result will be unique, simultaneous, spatially resolved information of the 3-dimensional properties of the target comet and its interaction with the space environment. We present the mission's science background leading to these objectives, as well as an overview of the scientific instruments, mission design, and schedule., Competing Interests: Competing InterestsThe authors declare no competing interests., (© The Author(s) 2024.)

Systemic sclerosis (SSc) is a complex disease that affects the connective tissue, causing fibrosis. SSc patients show altered immune cell composition and activation in the peripheral blood (PB). PB monocytes (Mos) are recruited into tissues where they differentiate into macrophages, which are directly involved in fibrosis. To understand the role of CD14 + PB Mos in SSc, a single-cell transcriptome analysis (scRNA-seq) was conducted on 8 SSc patients and 8 controls. Using unsupervised clustering methods, CD14 + cells were assigned to 11 clusters, which added granularity to the known monocyte subsets: classical (cMos), intermediate (iMos) and non-classical Mos (ncMos) or type 2 dendritic cells. NcMos were significantly overrepresented in SSc patients and showed an active IFN-signature and increased expression levels of PTGES, in addition to monocyte motility and adhesion markers. We identified a SSc-related cluster of IRF7+ STAT1+ iMos with an aberrant IFN-response. Finally, a depletion of M2 polarised cMos in SSc was observed. Our results highlighted the potential of PB Mos as biomarkers for SSc and provided new possibilities for putative drug targets for modulating the innate immune response in SSc., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To develop evidence-based expert-consensus recommendations for the management of non-infectious, non-neoplastic, non-demyelinating disease associated uveitis., Methods: Clinical research questions relevant to the objective of the document were identified, and reformulated into PICO format (patient, intervention, comparison, outcome) by a panel of experts selected based on their experience in the field. A systematic review of the available evidence was conducted, and evidence was graded according to GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. Subsequently, recommendations were developed., Results: Three PICO questions were constructed referring to uveitis anterior, non-anterior and complicated with macular edema. A total of 19 recommendations were formulated, based on the evidence found and/or expert consensus., Conclusions: Here we present the first official recommendations of the Spanish Society of Rheumatology for the treatment of non-infectious and non-demyelinating disease associated uveitis. They can be directly applied to the Spanish healthcare system as a tool for assistance and therapeutic homogenisation., (Copyright © 2023 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Eggplant (Solanum melongena) is a major vegetable crop with great potential for genetic improvement owing to its large and mostly untapped genetic diversity. It is closely related to over 500 species of Solanum subgenus Leptostemonum that belong to its primary, secondary, and tertiary genepools and exhibit a wide range of characteristics useful for eggplant breeding, including traits adaptive to climate change. Germplasm banks worldwide hold more than 19 000 accessions of eggplant and related species, most of which have yet to be evaluated. Nonetheless, eggplant breeding using the cultivated S. melongena genepool has yielded significantly improved varieties. To overcome current breeding challenges and for adaptation to climate change, a qualitative leap forward in eggplant breeding is necessary. The initial findings from introgression breeding in eggplant indicate that unleashing the diversity present in its relatives can greatly contribute to eggplant breeding. The recent creation of new genetic resources such as mutant libraries, core collections, recombinant inbred lines, and sets of introgression lines will be another crucial element and will require the support of new genomics tools and biotechnological developments. The systematic utilization of eggplant genetic resources supported by international initiatives will be critical for a much-needed eggplant breeding revolution to address the challenges posed by climate change., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Although previous studies have suggested a relationship between telomere shortening and systemic sclerosis (SSc), the association between these two traits remains poorly understood. The objective of this study was to assess the causal relationship between telomere length in leukocytes (LTL) and SSc using the two-sample Mendelian randomization approach, with the genome-wide association study data for both LTL and SSc. The results of inverse-variance weighted regression (OR = 0.716 [95% CI 0.528-0.970], p = 0.031) and the Mendelian randomization pleiotropy residual sum and outlier method (OR = 0.716 [95% CI 0.563-0.911], p = 0.035) indicate an association between telomere length and SSc. Specifically, longer genetically predicted LTL is associated with a reduced risk of SSc. Sensitivity tests highlight the significant roles of the variants rs10936599 and rs2736100 annotated to the TERC and TERT genes, respectively. Our findings suggest an influence of telomere length in leukocytes on the development of SSc., Competing Interests: The authors declare no conflicts of interest.

Background: Fibromyalgia (FM) and major depression disorder (MDD) frequently co-occur. Both disorders may share common serotonergic alterations, although there is less evidence of such alterations in FM. It is also unclear as to whether these alterations are persistent over time or transient. The objectives of this study were to (i) examine the changes in mRNA expression of serotonin transporter (SERT) on the surface of peripheral blood mononuclear cells (PBMCs) in FM, MDD, and the FM + MDD subjects compared to healthy controls, and to (ii) evaluate the effect of drug treatment on SERT expression., Methods: PBMCs were isolated from FM, MDD, FM + MDD, and control subjects. SERT expression was analyzed at the mRNA level via quantitative real-time polymerase chain reaction. Statistical analyses were performed using analyses of variance and linear mixed-effects models., Results: SERT mRNA expression was significantly reduced in MDD subjects compared to controls ( p < 0.001), but not in FM nor in FM + MDD subjects. Although the drug treatments improved symptoms in FM, MDD, and FM + MDD subjects, they had no significant effect on SERT mRNA expression., Conclusions: These results corroborate the role of the SERT in the pathophysiology of MDD, but not in FM, and show that the decreased mRNA expression of SERT is a persistent, rather than transient, phenomenon.

Background: The objective is to examine and synthesise the best available experimental evidence about the effect of ambulatory consultation duration on quality of healthcare., Methods: We included experimental studies manipulating the length of outpatient clinical encounters between adult patients and clinicians (ie, therapists, pharmacists, nurses, physicians) to determine their effect on quality of care (ie, effectiveness, efficiency, timeliness, safety, equity, patient-centredness and patient satisfaction)., Information Sources: Using controlled vocabulary and keywords, without restriction by language or year of publication, we searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews and Scopus from inception until 15 May 2023., Risk of Bias: Cochrane Risk of Bias instrument., Data Synthesis: Narrative synthesis., Results: 11 publications of 10 studies explored the relationship between encounter duration and quality. Most took place in the UK's general practice over two decades ago. Study findings based on very sparse and outdated evidence-which suggested that longer consultations improved indicators of patient-centred care, education about prevention and clinical referrals; and that consultation duration was inconsistently related to patient satisfaction and clinical outcomes-warrant low confidence due to limited protections against bias and indirect applicability to current practice., Conclusion: Experimental evidence for a minimal or optimal duration of an outpatient consultation is sparse and outdated. To develop evidence-based policies and practices about encounter length, randomised trials of different consultation lengths-in person and virtually, and with electronic health records-are needed., Trial Registration Number: OSF Registration DOI:10.17605/OSF.IO/EUDK8., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Donor site wounds of split-thickness skin grafts can be a major cause of morbidity. Choosing the appropriate dressing for these wounds is crucial to successful healing. Various types of dressing are available, including hydrogel dressings. A review of current evidence is required to guide clinical decision-making on the choice of dressing for the treatment of donor sites of split-thickness skin grafts., Objectives: To assess the effects of hydrogel dressings on donor site wounds following split-thickness skin grafts for wound healing., Search Methods: In July 2022 we searched the Cochrane Wounds Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL EBSCO Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies as well as reviews, meta-analyses, and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication, or study setting., Selection Criteria: Randomised controlled trials (RCTs) comparing hydrogel dressings with other types of dressing, topical treatments or no dressing, or with different types of hydrogel dressings in managing donor site wounds irrespective of language and publication status., Data Collection and Analysis: Two review authors independently carried out data extraction, risk of bias assessment using the Cochrane risk of bias tool, RoB 1, and quality assessment according to GRADE methodology., Main Results: We included two studies (162 participants) in this review. One study with three arms and 101 participants (15 months' duration) was conducted in a children's hospital, and compared hydrogel dressings in the form of Sorbact with Algisite, an alginate dressing and Cuticerin, a smooth acetate gauze impregnated with water-repellent ointment. Another study with two arms and 61 participants (19 months' duration) was conducted in three surgery departments and compared an octenidine-containing hydrogel dressing with an identical non-antimicrobial hydrogel dressing. We identified no studies that compared hydrogel dressings with another therapy such as a topical agent (a topical agent is a cream, an ointment or a solution that is applied directly to the wound), or no dressing, or a combination of hydrogel dressings and another therapy versus another therapy alone. Both studies were at high risk of attrition bias and the second study was also at unclear risk of selection bias. Amorphous hydrogel dressings versus other types of dressings Amorphous hydrogel dressings may increase time to wound healing when compared with alginate (mean difference (MD) 1.67 days, 95% confidence interval (CI) 0.56 to 2.78; 1 study, 69 participants; low-certainty evidence) or Cuticerin dressings (MD 1.67 days, 95% CI 0.55 to 2.79; 1 study, 68 participants; low-certainty evidence). The effect of amorphous hydrogel dressings compared with other types of dressings is uncertain for pain at the donor site and wound complications, including scarring and itching (very low-certainty evidence). No adverse events were reported in any of the groups. The study did not report health-related quality of life or wound infection. Octenidine-based hydrogel dressing versus octenidine-free hydrogel dressing The effect of octenidine-based hydrogel dressings versus octenidine-free hydrogel dressings is uncertain for time to wound healing (MD 0.40, 95% CI 0.28 to 0.52; 1 study, 41 participants) and wound infection, as the certainty of the evidence is very low. The certainty of the evidence is also very low for adverse events, with two participants in the intervention group and one participant in the comparison group reporting adverse events (risk ratio (RR) 0.58, 95% CI 0.06 to 5.89; 1 study, 41 participants). The study did not report donor site pain, health-related quality of life, or wound complications., Authors' Conclusions: There is insufficient evidence to determine the effect of hydrogel dressings on donor site wounds of split thickness skin grafts compared with other types of dressings. There is a need for adequately powered and well-designed RCTs, with adequate sample sizes, types of populations and subgroups, types of interventions, and outcomes, that compare hydrogel dressings with other treatment options in the treatment of donor site wounds of split-thickness skin grafts., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

The development of new cultivars with improved nitrogen use efficiency (NUE) is key for implementing sustainable agriculture practices. Crop wild relatives (CWRs) provide valuable genetic resources for breeding programs aimed at achieving this goal. In this study, three eggplant ( Solanum melongena ) accessions together with their advanced backcrosses (ABs; BC3 to BC5 generations) were evaluated for 22 morpho-agronomic, physiological, and NUE traits under low nitrogen (LN) fertilization conditions. The ABs were developed with introgressions from the wild relatives Solanum insanum , Solanum dasyphyllum , and Solanum elaeagnifolium . The AB population comprised a total of 25, 59, and 59 genotypes, respectively, with overall donor wild relative genome coverage percentages of 58.8%, 46.3%, and 99.2%. The three S. melongena recurrent parents were also evaluated under control (normal) N fertilization. Reduction of N fertilization in the parents resulted in decreased chlorophyll content-related traits, aerial biomass, stem diameter, and yield and increased NUE, nitrogen uptake efficiency (NUpE), and nitrogen utilization efficiency (NUtE). However, the decrease in yield was moderate, ranging between 62.6% and 72.6%. A high phenotypic variation was observed within each of the three sets of ABs under LN conditions, with some individuals displaying improved transgressive characteristics over the recurrent parents. Using the single primer enrichment technology 5 k probes platform for high-throughput genotyping, we observed a variable but high degree of recurrent parent genome recovery in the ABs attributable to the lines recombination, allowing the successful identification of 16 quantitative trait loci (QTL). Different allelic effects were observed for the introgressed QTL alleles. Several candidate genes were identified in the QTL regions associated with plant growth, yield, fruit size, and NUE-related parameters. Our results show that eggplant materials with introgressions from CWRs can result in a dramatic impact in eggplant breeding for a more sustainable agriculture., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nanjing Agricultural University.)

Objective: Systemic sclerosis (SSc) is a complex autoimmune disease with a strong genetic component. However, most of the genes associated with the disease are still unknown because associated variants affect mostly noncoding intergenic elements of the genome. We used functional genomics to translate the genetic findings into a better understanding of the disease., Methods: Promoter capture Hi-C and RNA-sequencing experiments were performed in CD4+ T cells and CD14+ monocytes from 10 SSc patients and 5 healthy controls to link SSc-associated variants with their target genes, followed by differential expression and differential interaction analyses between cell types., Results: We linked SSc-associated loci to 39 new potential target genes and confirmed 7 previously known SSc-associated genes. We highlight novel causal genes, such as CXCR5, as the most probable candidate gene for the DDX6 locus. Some previously known SSc-associated genes, such as IRF8, STAT4, and CD247, showed cell type-specific interactions. We also identified 15 potential drug targets already in use in other similar immune-mediated diseases that could be repurposed for SSc treatment. Furthermore, we observed that interactions were directly correlated with the expression of important genes implicated in cell type-specific pathways and found evidence that chromatin conformation is associated with genotype., Conclusion: Our study revealed potential causal genes for SSc-associated loci, some of them acting in a cell type-specific manner, suggesting novel biologic mechanisms that might mediate SSc pathogenesis., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

We present the complete chloroplast genome sequence of an endophytic Ostreobium sp. isolated from a 19th-century coralline red algal specimen from St. Croix, U.S. Virgin Islands. The chloroplast genome is 84,848 bp in length, contains 114 genes, and has a high level of gene synteny to other Ostreobiaceae., Competing Interests: The authors declare no conflict of interest.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma that is confined within the CNS. Due to its ability to cross the blood-brain barrier, high-dose methotrexate (HDMTX) is the backbone for induction chemotherapy. This systematic review was conducted to observe outcomes among different HDMTX doses (low, <3 g/m 2 ; intermediate, 3-4.9 g/m 2 ; high, ≥5 g/m 2 ) and regimens used in the treatment of PCNSL. A PubMed search resulted in 26 articles reporting clinical trials using HDMTX for PCNSL, from which 35 treatment cohorts were identified for analysis. The median dose of HDMTX used for induction was 3.5 g/m 2 (interquartile range IQR, 3-3.5); the intermediate dose was most frequently used in the studies examined (24 cohorts, 69%). Five cohorts used HDMTX monotherapy, 19 cohorts used HDMTX + polychemotherapy, and 11 cohorts used HDMTX + rituximab ± polychemotherapy. Pooled overall response rate (ORR) estimates for low, intermediate, and high dose HDMTX cohorts were 71%, 76%, and 76%, respectively. Pooled 2-year progression-free survival (PFS) estimates for low, intermediate, and high HDMTX dose cohorts were 50%, 51%, and 55%, respectively. Regimens that included rituximab showed a tendency to have higher ORR and 2-year PFS than those that did not include rituximab. These findings indicate that current protocols utilizing 3-4 g/m 2 of HDMTX in combination with rituximab provide therapeutic efficacy in PCNSL.

Purpose: To examine the associations of current electronic cigarette and cannabis use patterns with depression symptoms and suicidal ideation and behavior overall and stratified by sex among U.S. high school students., Design: Quantitative, cross-sectional study., Setting: The 2019 National Youth Risk Behavior Survey., Subjects: 12,401 high school students in 9th-12th grade., Measures: Dependent variables were depression symptoms, suicidal ideation, suicide plan, suicide attempt, and suicide attempt-related injury. Independent variables were past 30 day e-cigarette and cannabis use patterns. Covariates included demographics, grade level, and other tobacco product use., Analysis: Multivariable logistic regression models., Results: Approximately 15.7% of students were exclusive e-cigarette users, 4.5% were exclusive cannabis users, and 16.4% were concurrent e-cigarette and cannabis users. Exclusive e-cigarette and cannabis users, and concurrent users were at increased odds ( P < .05) of having depression symptoms, seriously considered attempting suicide, planning suicide, suicide attempt, and having suicide attempt-related injury compared to non-users. Female users, especially concurrent users, had higher odds of reporting depression symptoms ( P < .01) and all suicidal ideation and behavior outcomes ( P < .01) than female non-users, but results varied for male students., Conclusion: E-cigarette and cannabis use patterns significantly predicted depression symptomatology and suicidal ideation and behavior, with female students having higher odds. Results suggest the need for tailored interventions to address mental health and suicidality among U.S. adolescents, and especially female students.

Background: Different forms of vaccines have been developed to prevent the SARS-CoV-2 virus and subsequent COVID-19 disease. Several are in widespread use globally.  OBJECTIVES: To assess the efficacy and safety of COVID-19 vaccines (as a full primary vaccination series or a booster dose) against SARS-CoV-2., Search Methods: We searched the Cochrane COVID-19 Study Register and the COVID-19 L·OVE platform (last search date 5 November 2021). We also searched the WHO International Clinical Trials Registry Platform, regulatory agency websites, and Retraction Watch., Selection Criteria: We included randomized controlled trials (RCTs) comparing COVID-19 vaccines to placebo, no vaccine, other active vaccines, or other vaccine schedules., Data Collection and Analysis: We used standard Cochrane methods. We used GRADE to assess the certainty of evidence for all except immunogenicity outcomes.  We synthesized data for each vaccine separately and presented summary effect estimates with 95% confidence intervals (CIs).  MAIN RESULTS: We included and analyzed 41 RCTs assessing 12 different vaccines, including homologous and heterologous vaccine schedules and the effect of booster doses. Thirty-two RCTs were multicentre and five were multinational. The sample sizes of RCTs were 60 to 44,325 participants. Participants were aged: 18 years or older in 36 RCTs; 12 years or older in one RCT; 12 to 17 years in two RCTs; and three to 17 years in two RCTs. Twenty-nine RCTs provided results for individuals aged over 60 years, and three RCTs included immunocompromized patients. No trials included pregnant women. Sixteen RCTs had two-month follow-up or less, 20 RCTs had two to six months, and five RCTs had greater than six to 12 months or less. Eighteen reports were based on preplanned interim analyses. Overall risk of bias was low for all outcomes in eight RCTs, while 33 had concerns for at least one outcome. We identified 343 registered RCTs with results not yet available.  This abstract reports results for the critical outcomes of confirmed symptomatic COVID-19, severe and critical COVID-19, and serious adverse events only for the 10 WHO-approved vaccines. For remaining outcomes and vaccines, see main text. The evidence for mortality was generally sparse and of low or very low certainty for all WHO-approved vaccines, except AD26.COV2.S (Janssen), which probably reduces the risk of all-cause mortality (risk ratio (RR) 0.25, 95% CI 0.09 to 0.67; 1 RCT, 43,783 participants; high-certainty evidence). Confirmed symptomatic COVID-19 High-certainty evidence found that BNT162b2 (BioNtech/Fosun Pharma/Pfizer), mRNA-1273 (ModernaTx), ChAdOx1 (Oxford/AstraZeneca), Ad26.COV2.S, BBIBP-CorV (Sinopharm-Beijing), and BBV152 (Bharat Biotect) reduce the incidence of symptomatic COVID-19 compared to placebo (vaccine efficacy (VE): BNT162b2: 97.84%, 95% CI 44.25% to 99.92%; 2 RCTs, 44,077 participants; mRNA-1273: 93.20%, 95% CI 91.06% to 94.83%; 2 RCTs, 31,632 participants; ChAdOx1: 70.23%, 95% CI 62.10% to 76.62%; 2 RCTs, 43,390 participants; Ad26.COV2.S: 66.90%, 95% CI 59.10% to 73.40%; 1 RCT, 39,058 participants; BBIBP-CorV: 78.10%, 95% CI 64.80% to 86.30%; 1 RCT, 25,463 participants; BBV152: 77.80%, 95% CI 65.20% to 86.40%; 1 RCT, 16,973 participants). Moderate-certainty evidence found that NVX-CoV2373 (Novavax) probably reduces the incidence of symptomatic COVID-19 compared to placebo (VE 82.91%, 95% CI 50.49% to 94.10%; 3 RCTs, 42,175 participants). There is low-certainty evidence for CoronaVac (Sinovac) for this outcome (VE 69.81%, 95% CI 12.27% to 89.61%; 2 RCTs, 19,852 participants). Severe or critical COVID-19 High-certainty evidence found that BNT162b2, mRNA-1273, Ad26.COV2.S, and BBV152 result in a large reduction in incidence of severe or critical disease due to COVID-19 compared to placebo (VE: BNT162b2: 95.70%, 95% CI 73.90% to 99.90%; 1 RCT, 46,077 participants; mRNA-1273: 98.20%, 95% CI 92.80% to 99.60%; 1 RCT, 28,451 participants; AD26.COV2.S: 76.30%, 95% CI 57.90% to 87.50%; 1 RCT, 39,058 participants; BBV152: 93.40%, 95% CI 57.10% to 99.80%; 1 RCT, 16,976 participants). Moderate-certainty evidence found that NVX-CoV2373 probably reduces the incidence of severe or critical COVID-19 (VE 100.00%, 95% CI 86.99% to 100.00%; 1 RCT, 25,452 participants). Two trials reported high efficacy of CoronaVac for severe or critical disease with wide CIs, but these results could not be pooled. Serious adverse events (SAEs) mRNA-1273, ChAdOx1 (Oxford-AstraZeneca)/SII-ChAdOx1 (Serum Institute of India), Ad26.COV2.S, and BBV152 probably result in little or no difference in SAEs compared to placebo (RR: mRNA-1273: 0.92, 95% CI 0.78 to 1.08; 2 RCTs, 34,072 participants; ChAdOx1/SII-ChAdOx1: 0.88, 95% CI 0.72 to 1.07; 7 RCTs, 58,182 participants; Ad26.COV2.S: 0.92, 95% CI 0.69 to 1.22; 1 RCT, 43,783 participants); BBV152: 0.65, 95% CI 0.43 to 0.97; 1 RCT, 25,928 participants). In each of these, the likely absolute difference in effects was fewer than 5/1000 participants. Evidence for SAEs is uncertain for BNT162b2, CoronaVac, BBIBP-CorV, and NVX-CoV2373 compared to placebo (RR: BNT162b2: 1.30, 95% CI 0.55 to 3.07; 2 RCTs, 46,107 participants; CoronaVac: 0.97, 95% CI 0.62 to 1.51; 4 RCTs, 23,139 participants; BBIBP-CorV: 0.76, 95% CI 0.54 to 1.06; 1 RCT, 26,924 participants; NVX-CoV2373: 0.92, 95% CI 0.74 to 1.14; 4 RCTs, 38,802 participants). For the evaluation of heterologous schedules, booster doses, and efficacy against variants of concern, see main text of review., Authors' Conclusions: Compared to placebo, most vaccines reduce, or likely reduce, the proportion of participants with confirmed symptomatic COVID-19, and for some, there is high-certainty evidence that they reduce severe or critical disease. There is probably little or no difference between most vaccines and placebo for serious adverse events. Over 300 registered RCTs are evaluating the efficacy of COVID-19 vaccines, and this review is updated regularly on the COVID-NMA platform (covid-nma.com). Implications for practice Due to the trial exclusions, these results cannot be generalized to pregnant women, individuals with a history of SARS-CoV-2 infection, or immunocompromized people. Most trials had a short follow-up and were conducted before the emergence of variants of concern. Implications for research Future research should evaluate the long-term effect of vaccines, compare different vaccines and vaccine schedules, assess vaccine efficacy and safety in specific populations, and include outcomes such as preventing long COVID-19. Ongoing evaluation of vaccine efficacy and effectiveness against emerging variants of concern is also vital., (Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Purpose of Review: Systemic sclerosis (SSc) is a complex autoimmune disorder that affects the connective tissue and causes severe vascular damage and fibrosis of the skin and internal organs. There are recent advances in the field that apply novel methods to high throughput genotype information of thousands of patients with SSc and provide promising results towards the use of genomic data to help SSc diagnosis and clinical care., Recent Findings: This review addresses the development of the first SSc genomic risk score, which can contribute to differentiating SSc patients from healthy controls and other immune-mediated diseases. Moreover, we explore the implementation of data mining strategies on the results of genome-wide association studies to highlight subtype-specific HLA class II associations and a strong association of the HLA class I locus with SSc for the first time. Finally, the combination of genomic data with transcriptomics informed drug repurposing and genetic association studies in well characterized SSc patient cohorts identified markers of severe complications of the disease., Summary: Early diagnosis and clinical management of SSc and SSc-related complications are still challenging for rheumatologists. The development of predictive models and tools using genotype data may help to finally deliver personalized clinical care and treatment for patients with SSc in the near future., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Obesity contributes to a chronic proinflammatory state, which is a known risk factor to develop immune-mediated diseases. However, its role in systemic sclerosis (SSc) remains to be elucidated. Therefore, we conducted a two-sample mendelian randomization (2SMR) study to analyze the effect of three body fat distribution parameters in SSc. As instrumental variables, we used the allele effects described for single nucleotide polymorphisms (SNPs) in different genome-wide association studies (GWAS) for SSc, body mass index (BMI), waist-to-hip ratio (WHR) and WHR adjusted for BMI (WHRadjBMI). We performed local (pHESS) and genome-wide (LDSC) genetic correlation analyses between each of the traits and SSc and we applied several Mendelian randomization (MR) methods (i.e., random effects inverse-variance weight, MR-Egger regression, MR pleiotropy residual sum and outlier method and a multivariable model). Our results show no genetic correlation or causal relationship between any of these traits and SSc. Nevertheless, we observed a negative causal association between WHRadjBMI and SSc, which might be due to the effect of gastrointestinal complications suffered by the majority of SSc patients. In conclusion, reverse causality might be an especially difficult confounding factor to define the effect of obesity in the onset of SSc.

Background: The ongoing coronavirus 2019 disease (COVID-19) pandemic strained medical systems worldwide. We report on the impact on pediatric oncology care in Latin American (LATAM) during its first year., Method: Four cross-sectional surveys were electronically distributed among pediatric onco-hematologists in April/June/October 2020, and April/2021 through the Latin American Society of Pediatric Oncology (SLAOP) email list and St Jude Global regional partners., Results: Four hundred fifty-three pediatric onco-hematologists from 20 countries responded to the first survey, with subsequent surveys response rates above 85%. More than 95% of participants reported that treatment continued without interruption for new and active ongoing patients, though with disruptions in treatment availability. During the first three surveys, respondents reported suspensions of outpatient procedures (54.2%), a decrease in oncologic surgeries (43.6%), radiotherapy (28.4%), stem cell transplants (SCT) (69.3%), and surveillance consultations (81.2%). Logistic regression analysis showed that at the beginning of the first wave, participants from countries with healthcare expenditure below 7% were more likely to report a decrease in outpatient procedures (odds ratio [OR]: 1.84, 95% CI: 1.19-2.8), surgeries (OR: 3, 95% CI: 1.9-4.6) and radiotherapy (OR: 6, 95% CI: 3.5-10.4). Suspension of surveillance consultations was higher in countries with COVID-19 case fatality rates above 2% (OR: 3, 95% CI: 1.4-6.2) and SCT suspensions in countries with COVID-19 incidence rate above 100 cases per 100,000 (OR: 3.48, 95% CI: 1.6-7.45). Paradoxically, at the beginning of the second wave with COVID-19 cases rising exponentially, most participants reported improvements in cancer services availability., Conclusion: Our data show the medium-term collateral effects of the pandemic on pediatric oncology care in LATAM, which might help delineate oncology care delivery amid current and future challenges posed by the pandemic., (© 2022 Wiley Periodicals LLC.)

Background and Purpose: This update of the treatment guidelines was commissioned by the European Academy of Neurology and the European section of the Movement Disorder Society. Although these treatments are initiated usually in specialized centers, the general neurologist and general practitioners taking care of PD patients should know the therapies and their place in the treatment pathway., Methods: Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the spectrum of approved interventions including deep brain stimulation (DBS) or brain lesioning with different techniques (radiofrequency thermocoagulation, radiosurgery, magnetic resonance imaging-guided focused ultrasound surgery [MRgFUS] of the following targets: subthalamic nucleus [STN], ventrolateral thalamus, and pallidum internum [GPi]). Continuous delivery of medication subcutaneously (apomorphine pump) or through percutaneous ileostomy (intrajejunal levodopa/carbidopa pump [LCIG]) was also included. Changes in motor features, health-related quality of life (QoL), adverse effects, and further outcome parameters were evaluated. Recommendations were based on high-class evidence and graded in three gradations. If only lower class evidence was available but the topic was felt to be of high importance, clinical consensus of the guideline task force was gathered., Results: Two research questions have been answered with eight recommendations and five clinical consensus statements. Invasive therapies are reserved for specific patient groups and clinical situations mostly in the advanced stage of Parkinson's disease (PD). Interventions may be considered only for special patient profiles, which are mentioned in the text. Therapy effects are reported as change compared with current medical treatment. STN-DBS is the best-studied intervention for advanced PD with fluctuations not satisfactorily controlled with oral medications; it improves motor symptoms and QoL, and treatment should be offered to eligible patients. GPi-DBS can also be offered. For early PD with early fluctuations, STN-DBS is likely to improve motor symptoms, and QoL and can be offered. DBS should not be offered to people with early PD without fluctuations. LCIG and an apomorphine pump can be considered for advanced PD with fluctuations not sufficiently managed with oral treatments. Unilateral MRgFUS of the STN can be considered for distinctly unilateral PD within registries. Clinical consensus was reached for the following statements: Radiosurgery with gamma radiation cannot be recommended, unilateral radiofrequency thermocoagulation of the pallidum for advanced PD with treatment-resistant fluctuations and unilateral radiofrequency thermocoagulation of the thalamus for resistant tremor can be recommended if other options are not available, unilateral MRgFUS of the thalamus for medication-resistant tremor of PD can be considered only within registries, and unilateral MRgFUS of the pallidum is not recommended., Conclusions: Evidence for invasive therapies in PD is heterogeneous. Only some of these therapies have a strong scientific basis. They differ in their profile of effects and have been tested only for specific patient groups., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Retinoblastoma survivors in low- and middle-income countries are exposed to high-intensity treatments that potentially place them at higher risk of early subsequent malignant neoplasms (SMNs)., Methods: We followed 714 (403 [56.4%] nonhereditary and 311 [43.5%] hereditary) retinoblastoma survivors diagnosed from August 1987 to December 2016, up to the age of 16 years. We quantified risk of SMNs with cumulative incidence (CI) and standardized incidence ratios (SIR) analysis. Multivariate regression Cox model was used to determine the association of treatments and risk of SMNs., Results: Median follow-up was of 9 years (range: 0.18-16.9) and 24 survivors (3.36%) developed 25 SMNs (n = 22 hereditary, n = 2 nonhereditary). SMNs included sarcomas (osteosarcomas, Ewing sarcomas, rhabdomyosarcomas; n = 12), leukemias (n = 5), and central nervous system tumors (CNS; n = 3). All cases of acute myeloid leukemia (AML) and most of Ewing sarcomas occurred within 5 years of retinoblastoma diagnosis. The type of SMN was the main indicator of mortality (five of five patients with leukemias, six of 12 with sarcomas, and zero of three with CNS tumors died). Compared to the general population, radiation increased the risk of Ewing sarcoma in hereditary survivors by 700-fold (95% CI = 252-2422.6) and chemotherapy increased the risk of AML by 140-fold (95% CI = 45.3-436). The CI of SMNs for hereditary survivors was 13.7% (95% CI = 8.4-22.1) at 15 years., Conclusion: Retinoblastoma survivors from Argentina are at higher risk of developing SMNs early in life compared to the general Argentinean population, especially those treated with radiation plus chemotherapy. AML and Ewing sarcoma presented within 5 years of retinoblastoma diagnosis are associated with chemotherapy and radiation exposure., (© 2022 Wiley Periodicals LLC.)

Background: Good patient adherence to antiretroviral (ART) medication determines effective HIV viral suppression, and thus reduces the risk of progression and transmission of HIV. With accurate methods to monitor treatment adherence, we could use simple triage to target adherence support interventions that could help in the community or at health centres in resource-limited settings., Objectives: To determine the accuracy of simple measures of ART adherence (including patient self-report, tablet counts, pharmacy records, electronic monitoring, or composite methods) for detecting non-suppressed viral load in people living with HIV and receiving ART treatment., Search Methods: The Cochrane Infectious Diseases Group Information Specialists searched CENTRAL, MEDLINE, Embase, LILACS, CINAHL, African-Wide information, and Web of Science up to 22 April 2021. They also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing studies. No restrictions were placed on the language or date of publication when searching the electronic databases., Selection Criteria: We included studies of all designs that evaluated a simple measure of adherence (index test) such as self-report, tablet counts, pharmacy records or secondary database analysis, or both, electronic monitoring or composite measures of any of those tests, in people living with HIV and receiving ART treatment. We used a viral load assay with a limit of detection ranging from 10 copies/mL to 400 copies/mL as the reference standard. We created 2 × 2 tables to calculate sensitivity and specificity., Data Collection and Analysis: We screened studies, extracted data, and assessed risk of bias using QUADAS-2 independently and in duplicate. We assessed the certainty of evidence using the GRADE method. The results of estimated sensitivity and specificity were presented using paired forest plots and tabulated summaries. We encountered a high level of variation among studies which precluded a meaningful meta-analysis or comparison of adherence measures. We explored heterogeneity using pre-defined subgroup analysis., Main Results: We included 51 studies involving children and adults with HIV, mostly living in low- and middle-income settings, conducted between 2003 and 2021. Several studies assessed more than one index test, and the most common measure of adherence to ART was self-report. - Self-report questionnaires (25 studies, 9211 participants; very low-certainty): sensitivity ranged from 10% to 85% and specificity ranged from 10% to 99%. - Self-report using a visual analogue scale (VAS) (11 studies, 4235 participants; very low-certainty): sensitivity ranged from 0% to 58% and specificity ranged from 55% to 100%. - Tablet counts (12 studies, 3466 participants; very low-certainty): sensitivity ranged from 0% to 100% and specificity ranged from 5% to 99%. - Electronic monitoring devices (3 studies, 186 participants; very low-certainty): sensitivity ranged from 60% to 88% and the specificity ranged from 27% to 67%. - Pharmacy records or secondary databases (6 studies, 2254 participants; very low-certainty): sensitivity ranged from 17% to 88% and the specificity ranged from 9% to 95%. - Composite measures (9 studies, 1513 participants; very low-certainty): sensitivity ranged from 10% to 100% and specificity ranged from 49% to 100%. Across all included studies, the ability of adherence measures to detect viral non-suppression showed a large variation in both sensitivity and specificity that could not be explained by subgroup analysis. We assessed the overall certainty of the evidence as very low due to risk of bias, indirectness, inconsistency, and imprecision. The risk of bias and the applicability concerns for patient selection, index test, and reference standard domains were generally low or unclear due to unclear reporting. The main methodological issues identified were related to flow and timing due to high numbers of missing data. For all index tests, we assessed the certainty of the evidence as very low due to limitations in the design and conduct of the studies, applicability concerns and inconsistency of results., Authors' Conclusions: We encountered high variability for all index tests, and the overall certainty of evidence in all areas was very low. No measure consistently offered either a sufficiently high sensitivity or specificity to detect viral non-suppression. These concerns limit their value in triaging patients for viral load monitoring or enhanced adherence support interventions., (Copyright © 2022 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: Refugees, and other forcibly displaced people, face mental distress and may be disproportionately affected by risk factors for suicide. Little is known about suicidal behaviour in these highly mobile populations because collecting timely, relevant, and reliable data is challenging., Methods and Findings: A systematic review was performed to identify studies of any design reporting on suicide, suicide attempts, or suicidal ideation among populations of displaced people. A sensitive electronic database search was performed in August 2020, and all retrieved studies were screened for relevance by two authors. Studies were categorised by the population being evaluated: refugees granted asylum, refugees living in temporary camps, asylum seekers, or internally displaced people. We distinguished between whether the sampling procedure in the studies was likely to be representative, or the sample examined a specific non-representative subgroup of displaced people (such as those already diagnosed with mental illness). Data on the rates of suicide or the prevalence of suicide attempts or suicidal ideation were extracted by one reviewer and verified by a second reviewer from each study and converted to common metrics. After screening 4347 articles, 87 reports of 77 unique studies were included. Of these, 53 were studies in representative samples, and 24 were based on samples of specific target populations. Most studies were conducted in high-income countries, and the most studied population subgroup was refugees granted asylum. There was substantial heterogeneity across data sources and measurement instruments utilised. Sample sizes of displaced people ranged from 33 to 196,941 in studies using general samples. Suicide rates varied considerably, from 4 to 290 per 100,000 person-years across studies. Only 8 studies were identified that compared suicide rates with the host population. The prevalence of suicide attempts ranged from 0.14% to 15.1% across all studies and varied according to the prevalence period evaluated. Suicidal ideation prevalence varied from 0.17% to 70.6% across studies. Among refugees granted asylum, there was evidence of a lower risk of suicide compared with the host population in 4 of 5 studies. In contrast, in asylum seekers there was evidence of a higher suicide risk in 2 of 3 studies, and of a higher risk of suicidal ideation among refugees living in camps in 2 of 3 studies compared to host populations., Conclusion: While multiple studies overall have been published in the literature on this topic, the evidence base is still sparse for refugees in camps, asylum seekers, and internally displaced people. Less than half of the included studies reported on suicide or suicide attempt outcomes, with most reporting on suicidal ideation. International research networks could usefully define criteria, definitions, and study designs to help standardise and facilitate more research in this important area., Registration: PROSPERO CRD42019137242., Competing Interests: The authors declare no financial or non-financial competing interests regarding this manuscript.

Background: Interleukin-1 (IL-1) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19), on the premise that their immunomodulatory effect might be beneficial in people with COVID-19., Objectives: To assess the effects of IL-1 blocking agents compared with standard care alone or with placebo on effectiveness and safety outcomes in people with COVID-19. We will update this assessment regularly., Search Methods: We searched the Cochrane COVID-19 Study Register and the COVID-19 L-OVE Platform (search date 5 November 2021). These sources are maintained through regular searches of MEDLINE, Embase, CENTRAL, trial registers and other sources. We also checked the World Health Organization International Clinical Trials Registry Platform, regulatory agency websites, Retraction Watch (search date 3 November 2021)., Selection Criteria: We included randomised controlled trials (RCTs) evaluating IL-1 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity., Data Collection and Analysis: We followed Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two researchers independently screened and extracted data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence using the GRADE approach for the critical outcomes of clinical improvement (Day 28; ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28; ≥ D60); all-cause mortality (D28; ≥ D60); incidence of any adverse events; and incidence of serious adverse events., Main Results: We identified four RCTs of anakinra (three published in peer-reviewed journals, one reported as a preprint) and two RCTs of canakinumab (published in peer-reviewed journals). All trials were multicentre (2 to 133 centres). Two trials stopped early (one due to futility and one as the trigger for inferiority was met). The median/mean age range varied from 58 to 68 years; the proportion of men varied from 58% to 77%. All participants were hospitalised; 67% to 100% were on oxygen at baseline but not intubated; between 0% and 33% were intubated at baseline. We identified a further 16 registered trials with no results available, of which 15 assessed anakinra (four completed, four terminated, five ongoing, three not recruiting) and one (completed) trial assessed canakinumab. Effectiveness of anakinra for people with COVID-19 Anakinra probably results in little or no increase in clinical improvement at D28 (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.97 to 1.20; 3 RCTs, 837 participants; absolute effect: 59 more per 1000 (from 22 fewer to 147 more); moderate-certainty evidence. The evidence is uncertain about an effect of anakinra on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.67, 95% CI 0.36 to 1.22; 2 RCTs, 722 participants; absolute effect: 55 fewer per 1000 (from 107 fewer to 37 more); low-certainty evidence) and ≥ D60 (RR 0.54, 95% CI 0.30 to 0.96; 1 RCT, 606 participants; absolute effect: 47 fewer per 1000 (from 72 fewer to 4 fewer) low-certainty evidence); and 2) all-cause mortality at D28 (RR 0.69, 95% CI 0.34 to 1.39; 2 RCTs, 722 participants; absolute effect: 32 fewer per 1000 (from 68 fewer to 40 more); low-certainty evidence).  The evidence is very uncertain about an effect of anakinra on 1) the proportion of participants with clinical improvement at ≥ D60 (RR 0.93, 95% CI 0.78 to 1.12; 1 RCT, 115 participants; absolute effect: 59 fewer per 1000 (from 186 fewer to 102 more); very low-certainty evidence); and 2) all-cause mortality at ≥ D60 (RR 1.03, 95% CI 0.68 to 1.56; 4 RCTs, 1633 participants; absolute effect: 8 more per 1000 (from 84 fewer to 147 more); very low-certainty evidence). Safety of anakinra for people with COVID-19 Anakinra probably results in little or no increase in adverse events (RR 1.02, 95% CI 0.94 to 1.11; 2 RCTs, 722 participants; absolute effect: 14 more per 1000 (from 43 fewer to 78 more); moderate-certainty evidence).  The evidence is uncertain regarding an effect of anakinra on serious adverse events (RR 0.95, 95% CI 0.58 to 1.56; 2 RCTs, 722 participants; absolute effect: 12 fewer per 1000 (from 104 fewer to 138 more); low-certainty evidence). Effectiveness of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in clinical improvement at D28 (RR 1.05, 95% CI 0.96 to 1.14; 2 RCTs, 499 participants; absolute effect: 42 more per 1000 (from 33 fewer to 116 more); moderate-certainty evidence).  The evidence of an effect of canakinumab is uncertain on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.72, 95% CI 0.44 to 1.20; 2 RCTs, 499 participants; absolute effect: 35 fewer per 1000 (from 69 fewer to 25 more); low-certainty evidence); and 2) all-cause mortality at D28 (RR:0.75; 95% CI 0.39 to 1.42); 2 RCTs, 499 participants; absolute effect: 20 fewer per 1000 (from 48 fewer to 33 more); low-certainty evidence).  The evidence is very uncertain about an effect of canakinumab on all-cause mortality at ≥ D60 (RR 0.55, 95% CI 0.16 to 1.91; 1 RCT, 45 participants; absolute effect: 112 fewer per 1000 (from 210 fewer to 227 more); very low-certainty evidence). Safety of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in adverse events (RR 1.02; 95% CI 0.86 to 1.21; 1 RCT, 454 participants; absolute effect: 11 more per 1000 (from 74 fewer to 111 more); moderate-certainty evidence). The evidence of an effect of canakinumab on serious adverse events is uncertain (RR 0.80, 95% CI 0.57 to 1.13; 2 RCTs, 499 participants; absolute effect: 44 fewer per 1000 (from 94 fewer to 28 more); low-certainty evidence)., Authors' Conclusions: Overall, we did not find evidence for an important beneficial effect of IL-1 blocking agents. The evidence is uncertain or very uncertain for several outcomes. Sixteen trials of anakinra and canakinumab with no results are currently registered, of which four are completed, and four terminated. The findings of this review are updated on the COVID-NMA platform (covid-nma.com)., (Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Abstract: Chronic pain in childhood is an international public health problem. We conducted a systematic review and meta-analysis to provide a summary of the published evidence of pharmacological, physical, and psychological therapies for children with chronic pain conditions. We searched CENTRAL, MEDLINE, EMBASE, and PsycINFO from inception to April 2020; clinical trial registries; and other sources for randomised controlled trials or comparative observational trials. We extracted critical outcomes of pain intensity, quality of life, physical functioning, role functioning, emotional functioning, sleep, and adverse events. We assessed studies for risk of bias and certainty of the evidence using GRADE. We included 34 pharmacological (4091 participants), 25 physical therapy (1470 participants), and 63 psychological trials (5025 participants). Participants reported a range of chronic pain conditions. Most studies were assessed to have unclear or high risk of bias across multiple domains. Pharmacological, physical, and psychological therapies showed some benefit for reducing pain, posttreatment, but only physical and psychological therapies improved physical functioning. We found no benefit of any treatment modality for health-related quality of life, role functioning, emotional functioning, or sleep. Adverse events were poorly reported, particularly for psychological and physical interventions. The largest evidence base for the management of chronic pain in children supports the use of psychological therapies, followed by pharmacological and physical therapies. However, we rated most outcomes as low or very low certainty, meaning further evidence is likely to change our confidence in the estimates of effects. This protocol was registered on PROSPERO (CRD42020172451)., (Copyright © 2021 International Association for the Study of Pain.)

Background: Human African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without treatment. Conventional treatments require days of intravenous infusion, but a recently developed drug, fexinidazole, can be given orally. Another oral drug candidate, acoziborole, is undergoing clinical development and will be considered in subsequent editions.   OBJECTIVES: To evaluate the effectiveness and safety of currently used drugs for treating second-stage Trypanosoma brucei gambiense trypanosomiasis (gambiense human African trypanosomiasis, g-HAT)., Search Methods: On 14 May 2021, we searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, BIOSIS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We also searched reference lists of included studies, contacted researchers working in the field, and contacted relevant organizations., Selection Criteria: Eligible studies were randomized controlled trials that included adults and children with second-stage g-HAT, treated with anti-trypanosomal drugs currently in use., Data Collection and Analysis: Two review authors extracted data and assessed risk of bias; a third review author acted as an arbitrator if needed. The included trial only reported dichotomous outcomes, which we presented as risk ratio (RR) or risk difference (RD) with 95% confidence intervals (CI).   MAIN RESULTS: We included one trial comparing fexinidazole to nifurtimox combined with eflornithine (NECT). This trial was conducted between October 2012 and November 2016 in the Democratic Republic of the Congo and the Central African Republic, and included 394 participants. The study reported on efficacy and safety, with up to 24 months' follow-up.  We judged the study to be at low risk of bias in all domains except blinding;  as the route of administration and dosing regimens differed between treatment groups,  participants and personnel were not blinded, resulting in a high risk of performance bias.   Mortality with fexinidazole may be higher at 24 months compared to NECT. There were 9/264 deaths in the fexinidazole group and 2/130 deaths in the NECT group (RR 2.22, 95% CI 0.49 to 10.11; 394 participants; low-certainty evidence). None of the deaths were related to treatment. Fexinidazole likely results in an increase in the number of people relapsing during follow-up, with 14 participants in the fexinidazole group (14/264) and none in the NECT group (0/130) relapsing at 24 months (RD 0.05, 95% CI 0.02 to 0.08; 394 participants; moderate-certainty evidence).   We are uncertain whether there is any difference between the drugs regarding the incidence of serious adverse events at 24 months. (31/264 with fexinidazole and 13/130 with NECT group at 24 months). Adverse events were common with both drugs (247/264 with fexinidazole versus 121/130 with NECT), with no difference between groups (RR 1.01, 95% CI 0.95 to 1.06; 394 participants; moderate-certainty evidence).  AUTHORS' CONCLUSIONS: Oral treatment with fexinidazole is much easier to administer than conventional treatment, but deaths and relapse appear to be more common. However, the advantages or an oral option are considerable, in terms of convenience, avoiding hospitalisation and multiple intravenous infusions, thus increasing adherence., (Copyright © 2021 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Psoriatic arthritis is a chronic systemic inflammatory disease that affects the skin, musculoskeletal structures and other organs and systems compromising functionality, quality of life and reducing the life expectancy of patients. It is a complex disease that requires specialist and timely care and management. The alternatives for treating the manifestations of psoriatic arthritis have increased and the effect of the different agents on specific manifestations has been clarified in recent studies. Therefore, we should incorporate the available evidence to build a strategy for the treatment of these patients. The Mexican College of Rheumatology selected a committee to evaluate these different alternatives and make recommendations., Methods: The study group included 16 rheumatologists and 3 certified dermatologists, selected from different health institutions and regions of the country. An executive committee was formed to coordinate the meetings and a committee of experts selected the literature search criteria, prepared the research questions, rated the quality of the evidence, and produced the recommendations in the different disease domains based on the GRADE methodology., Results: 24 updated recommendations were generated for the treatment of patients with psoriatic arthritis. The recommendations establish the role of the drugs currently available in our country. The importance of adequate disease control is emphasized, individualizing the level of involvement of each patient in each of the six domains potentially affected by the disease. In addition, the sequence in the choice of treatments available for each domain is established, based on their efficacy, safety profile and accessibility., Conclusions: With this consensus document, it will be possible to improve the care of patients with psoriatic arthritis. The recommendations were generated based on the best available information and in consideration of the Mexican health system., (Copyright © 2021 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Nevoid acanthosis nigricans is a rare, benign form of acanthosis nigricans. Of the 24 cases documented in the literature, only two are exclusively localized to the umbilicus. We present four cases of nevoid acanthosis nigricans localized to the umbilicus; in patients less than 25 years of age, with no known co-morbidities, three of whom were females. Two of the cases received, with good response, treatment based on topical calcipotriol, a medication not previously reported to be used for this indication. Contrary to other types of acanthosis nigricans, the nevoid acanthosis nigricans is not associated with any syndrome, endocrinopathy, obesity, medication, or neoplasia and it can be confused with other pathologies such as epidermal nevus or dermatosis neglecta.

Background/objective: Psoriatic arthritis (PsA) is a chronic inflammatory illness. Approximately, 15% of psoriasis patients have undiagnosed PsA. In Mexico, we found no related studies. Our objective was to investigate the clinical-epidemiological characteristics of PsA in psoriasis patients in western Mexico., Methods: A cross-sectional study including Mexican patients with clinical and histopathological diagnosis of psoriasis. Physical examination, rheumatoid factor analysis and radiographies of axial and peripheral skeleton were performed. The prevalence of PsA using the CASPAR criteria, age, sex; clinical variants of PsA, psoriasis type and the Psoriasis Area and Severity Index (PASI), were assessed. Descriptive and inferential statistics were used., Results: Of 90 patients with psoriasis, 48 met the criteria for PsA, with a prevalence of 53%, and average age of 50 ± 15 years. Predominating were, the female sex in 29 (60%), the axial variant of PsA in 24 (50%), and psoriasis plaques in 40 (83%). The average PASI was 12 ± 11. All cases were rheumatoid factor negative. These variables were not significantly different when comparing subjects with and without PsA, except for the female sex (60% vs. 7%; P < 0.001)., Conclusions: Patients with psoriasis should intentionally be evaluated jointly Dermatologists and Rheumatologists searching joint involvement given the high prevalence of PsA previously undiagnosed., (© 2021 The Australasian College of Dermatologists.)

Objectives: Genomic Risk Scores (GRS) successfully demonstrated the ability of genetics to identify those individuals at high risk for complex traits including immune-mediated inflammatory diseases (IMIDs). We aimed to test the performance of GRS in the prediction of risk for systemic sclerosis (SSc) for the first time., Methods: Allelic effects were obtained from the largest SSc Genome-Wide Association Study (GWAS) to date (9 095 SSc and 17 584 healthy controls with European ancestry). The best-fitting GRS was identified under the additive model in an independent cohort that comprised 400 patients with SSc and 571 controls. Additionally, GRS for clinical subtypes (limited cutaneous SSc and diffuse cutaneous SSc) and serological subtypes (anti-topoisomerase positive (ATA+) and anti-centromere positive (ACA+)) were generated. We combined the estimated GRS with demographic and immunological parameters in a multivariate generalised linear model., Results: The best-fitting SSc GRS included 33 single nucleotide polymorphisms (SNPs) and discriminated between patients with SSc and controls (area under the receiver operating characteristic (ROC) curve (AUC)=0.673). Moreover, the GRS differentiated between SSc and other IMIDs, such as rheumatoid arthritis and Sjögren's syndrome. Finally, the combination of GRS with age and immune cell counts significantly increased the performance of the model (AUC=0.787). While the SSc GRS was not able to discriminate between ATA+ and ACA+ patients (AUC<0.5), the serological subtype GRS, which was based on the allelic effects observed for the comparison between ACA+ and ATA+ patients, reached an AUC=0.693., Conclusions: GRS was successfully implemented in SSc. The model discriminated between patients with SSc and controls or other IMIDs, confirming the potential of GRS to support early and differential diagnosis for SSc., Competing Interests: Competing interests: LB-C: none; GV-M: none; MK: none; MA-H: none; ELI: none; International SSc Group: none; PRECISESADS Consortium: none; MEAl-R: none; LB: none; JM: none., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune-mediated diseases (IMDs) are complex pathologies that are strongly influenced by environmental and genetic factors. Associations between genetic loci and susceptibility to these diseases have been widely studied, and hundreds of risk variants have emerged during the last two decades, with researchers observing a shared genetic pattern among them. Nevertheless, the pathological mechanism behind these associations remains a challenge that has just started to be understood thanks to functional genomic approaches. Transcriptomics, regulatory elements, chromatin interactome, as well as the experimental characterization of genomic findings, constitute key elements in the emerging understandings of how genetics affects the etiopathogenesis of IMDs. In this review, we will focus on the latest advances in the field of functional genomics, centering our attention on systemic rheumatic IMDs.

Background: Plasmodium vivax liver stages (hypnozoites) may cause relapses, prolonging morbidity, and impeding malaria control and elimination. The World Health Organization (WHO) recommends three schedules for primaquine: 0.25 mg/kg/day (standard), or 0.5 mg/kg/day (high standard) for 14 days, or 0.75 mg/kg once weekly for eight weeks, all of which can be difficult to complete. Since primaquine can cause haemolysis in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, clinicians may be reluctant to prescribe primaquine without G6PD testing, and recommendations when G6PD status is unknown must be based on an assessment of the risks and benefits of prescribing primaquine. Alternative safe and efficacious regimens are needed., Objectives: To assess the efficacy and safety of alternative primaquine regimens for radical cure of P vivax malaria compared to the standard or high-standard 14-day courses., Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); LILACS (BIREME); WHO International Clinical Trials Registry Platform and ClinicalTrials.gov up to 2 September 2019, and checked the reference lists of all identified studies., Selection Criteria: Randomized controlled trials (RCTs) of adults and children with P vivax malaria using either chloroquine or artemisinin-based combination therapy plus primaquine at a total adult dose of at least 210 mg, compared with the WHO-recommended regimens of 0.25 or 0.5 mg/kg/day for 14 days., Data Collection and Analysis: Two review authors independently assessed trial eligibility and quality, and extracted data. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data. We grouped efficacy data according to length of follow-up, partner drug, and trial location. We analysed safety data where included., Main Results: 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days There may be little or no difference in P vivax recurrences at six to seven months when using the same total dose (210 mg adult dose) over seven days compared to 14 days (RR 0.96, 95% CI 0.66 to 1.39; 4 RCTs, 1211 participants; low-certainty evidence). No serious adverse events were reported. We do not know if there is any difference in the number of adverse events resulting in discontinuation of primaquine (RR 1.04, 95% CI 0.15 to 7.38; 5 RCTs, 1427 participants) or in the frequency of anaemia (RR 3.00, 95% CI 0.12 to 72.91, 1 RCT, 240 participants) between the shorter and longer regimens (very low-certainty evidence). Three trials excluded people with G6PD deficiency; two did not provide this information. Pregnant and lactating women were either excluded or no details were provided. High-standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days There may be little or no difference in P vivax recurrences at six months with 0.5 mg/kg/day primaquine for 14 days compared to 0.25 mg/kg/day for 14 days (RR 0.84 (95% CI 0.49 to 1.43; 2 RCTs, 677 participants, low-certainty evidence). No serious adverse events were reported. We do not know whether there is a difference in adverse events resulting in discontinuation of treatment with the high-standard dosage (RR 4.19, 95% CI 0.90 to 19.60; 1 RCT, 778 participants, very low-certainty evidence). People with G6PD deficiency and pregnant or lactating women were excluded. 0.75 mg/kg/week for eight weeks versus high-standard 0.5 mg/kg/day for 14 days We do not know whether weekly primaquine increases or decreases recurrences of P vivax compared to high-standard 0.5 mg/kg/day for 14 days, at 11 months' follow-up (RR 3.18, 95% CI 0.37 to 27.60; 1 RCT, 122 participants; very low-certainty evidence). No serious adverse events and no episodes of anaemia were reported. G6PD-deficient patients were not randomized but included in the weekly primaquine group (only one patient detected). 1 mg/kg/day for seven days versus high standard 0.5 mg/kg/day for 14 days There is probably little or no difference in P vivax recurrences at 12 months between 1.0 mg/kg/day primaquine for seven days and the high-standard 0.5 mg/kg/day for 14 days (RR 1.03, 95% CI 0.82 to 1.30; 2 RCTs, 2526 participants; moderate-certainty evidence). There may be moderate to large increase in serious adverse events in the 1.0 mg/kg/day primaquine for seven days compared with the high-standard 0.5 mg/kg/day for 14 days, during 42 days follow-up (RR 12.03, 95% CI 1.57 to 92.30; 1 RCT, 1872 participants, low-certainty evidence). We do not know if there is a difference between 1.0 mg/kg/day primaquine for seven days and high-standard 0.5 mg/kg/day for 14 days in adverse events that resulted in discontinuation of treatment (RR 2.50, 95% CI 0.49 to 12.87; 1 RCT, 2526 participants, very low-certainty evidence), nor if there is difference in frequency of anaemia by 42 days (RR 0.93, 95% CI 0.62 to 1.41; 2 RCTs, 2440 participants, very low-certainty evidence). People with G6PD deficiency were excluded. Other regimens Two RCTs evaluated other rarely-used doses of primaquine, one of which had very high loss to follow-up. Adverse events were not reported. People with G6PD deficiency and pregnant or lactating women were excluded., Authors' Conclusions: Trials available to date do not detect a difference in recurrence between the following regimens: 1) 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days; 2) high-standard 0.5 mg/kg/day for 14 days versus standard 0.25 mg/kg/day for 14 days; 3) 0.75 mg/kg/week for eight weeks versus high-standard 0.5 mg/kg/day for 14 days; 4) 1 mg/kg/day for seven days versus high-standard 0.5 mg/kg/day for 14 days. There were no differences detected in adverse events for Comparisons 1, 2 or 3, but there may be more serious adverse events with the high seven-day course in Comparison 4. The shorter regimen of 0.5 mg/kg/day for seven days versus standard 0.25 mg/kg/day for 14 days may suit G6PD-normal patients. Further research will help increase the certainty of the findings and applicability in different settings., (Copyright © 2020 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background: The widespread use of mobile technologies can potentially expand the use of telemedicine approaches to facilitate communication between healthcare providers, this might increase access to specialist advice and improve patient health outcomes., Objectives: To assess the effects of mobile technologies versus usual care for supporting communication and consultations between healthcare providers on healthcare providers' performance, acceptability and satisfaction, healthcare use, patient health outcomes, acceptability and satisfaction, costs, and technical difficulties., Search Methods: We searched CENTRAL, MEDLINE, Embase and three other databases from 1 January 2000 to 22 July 2019. We searched clinical trials registries, checked references of relevant systematic reviews and included studies, and contacted topic experts., Selection Criteria: Randomised trials comparing mobile technologies to support healthcare provider to healthcare provider communication and consultations compared with usual care., Data Collection and Analysis: We followed standard methodological procedures expected by Cochrane and EPOC. We used the GRADE approach to assess the certainty of the evidence., Main Results: We included 19 trials (5766 participants when reported), most were conducted in high-income countries. The most frequently used mobile technology was a mobile phone, often accompanied by training if it was used to transfer digital images. Trials recruited participants with different conditions, and interventions varied in delivery, components, and frequency of contact. We judged most trials to have high risk of performance bias, and approximately half had a high risk of detection, attrition, and reporting biases. Two studies reported data on technical problems, reporting few difficulties. Mobile technologies used by primary care providers to consult with hospital specialists We assessed the certainty of evidence for this group of trials as moderate to low. Mobile technologies: - probably make little or no difference to primary care providers following guidelines for people with chronic kidney disease (CKD; 1 trial, 47 general practices, 3004 participants); - probably reduce the time between presentation and management of individuals with skin conditions, people with symptoms requiring an ultrasound, or being referred for an appointment with a specialist after attending primary care (4 trials, 656 participants); - may reduce referrals and clinic visits among people with some skin conditions, and increase the likelihood of receiving retinopathy screening among people with diabetes, or an ultrasound in those referred with symptoms (9 trials, 4810 participants when reported); - probably make little or no difference to patient-reported quality of life and health-related quality of life (2 trials, 622 participants) or to clinician-assessed clinical recovery (2 trials, 769 participants) among individuals with skin conditions; - may make little or no difference to healthcare provider (2 trials, 378 participants) or participant acceptability and satisfaction (4 trials, 972 participants) when primary care providers consult with dermatologists; - may make little or no difference for total or expected costs per participant for adults with some skin conditions or CKD (6 trials, 5423 participants). Mobile technologies used by emergency physicians to consult with hospital specialists about people attending the emergency department We assessed the certainty of evidence for this group of trials as moderate. Mobile technologies: - probably slightly reduce the consultation time between emergency physicians and hospital specialists (median difference -12 minutes, 95% CI -19 to -7; 1 trial, 345 participants); - probably reduce participants' length of stay in the emergency department by a few minutes (median difference -30 minutes, 95% CI -37 to -25; 1 trial, 345 participants). We did not identify trials that reported on providers' adherence, participants' health status and well-being, healthcare provider and participant acceptability and satisfaction, or costs. Mobile technologies used by community health workers or home-care workers to consult with clinic staff We assessed the certainty of evidence for this group of trials as moderate to low. Mobile technologies: - probably make little or no difference in the number of outpatient clinic and community nurse consultations for participants with diabetes or older individuals treated with home enteral nutrition (2 trials, 370 participants) or hospitalisation of older individuals treated with home enteral nutrition (1 trial, 188 participants); - may lead to little or no difference in mortality among people living with HIV (RR 0.82, 95% CI 0.55 to 1.22) or diabetes (RR 0.94, 95% CI 0.28 to 3.12) (2 trials, 1152 participants); - may make little or no difference to participants' disease activity or health-related quality of life in participants with rheumatoid arthritis (1 trial, 85 participants); - probably make little or no difference for participant acceptability and satisfaction for participants with diabetes and participants with rheumatoid arthritis (2 trials, 178 participants). We did not identify any trials that reported on providers' adherence, time between presentation and management, healthcare provider acceptability and satisfaction, or costs., Authors' Conclusions: Our confidence in the effect estimates is limited. Interventions including a mobile technology component to support healthcare provider to healthcare provider communication and management of care may reduce the time between presentation and management of the health condition when primary care providers or emergency physicians use them to consult with specialists, and may increase the likelihood of receiving a clinical examination among participants with diabetes and those who required an ultrasound. They may decrease the number of people attending primary care who are referred to secondary or tertiary care in some conditions, such as some skin conditions and CKD. There was little evidence of effects on participants' health status and well-being, satisfaction, or costs., (Copyright © 2020 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Ectopic ACTH-secretion causing Cushing's syndrome is unusual and its diagnosis is frequently challenging. The presence of high-molecular-weight precursors throughout pro-opiomelanocortin (POMC) translation by these tumors is often not reported. We present the case of a 49-year-old woman with a 3-month history of proximal muscular weakness, skin pigmentation, and weight loss. Upon initial evaluation, she had a full moon face, hirsutism, and a buffalo hump. Laboratory workup showed hyperglycemia, hypokalemia and metabolic alkalosis. ACTH, plasma cortisol, and urinary free cortisol levels were quite elevated. Serum cortisol levels were not suppressed on dexamethasone suppression testing. An octreo-SPECT scan showed enhanced nucleotide uptake in the liver and pancreas. Transendoscopic ultrasound-guided biopsy confirmed the diagnosis of a pancreatic ACTH-secreting neuroendocrine tumor (NET). Surgical excision of both pancreatic and liver lesions was carried out. Western blot analysis of the tumor and metastases revealed the presence of a high-molecular-weight precursor possibly POMC (at 30 kDa) but not ACTH (normally 4.5 kDa). ACTH-precursor secretion is more frequent in ectopic ACTH-secreting tumors compared with other causes of Cushing's syndrome. Hence, the measurement of such ACTH precursors warrants further evaluation, especially in the context of ACTH-dependent hypercortisolism., (Copyright © 2020 Mehta, Lam-Chung, Hinojosa-Amaya, Roldán-Sarmiento, Guillen-Placencia, Villanueva-Rodriguez, Juarez-Leon, Leon-Domínguez, Grajales-Gómez, Ventura-Gallegos, León-Suárez, Gómez-Pérez and Cuevas-Ramos.)

Background: The global burden of poor maternal, neonatal, and child health (MNCH) accounts for more than a quarter of healthy years of life lost worldwide. Targeted client communication (TCC) via mobile devices (MD) (TCCMD) may be a useful strategy to improve MNCH., Objectives: To assess the effects of TCC via MD on health behaviour, service use, health, and well-being for MNCH., Search Methods: In July/August 2017, we searched five databases including The Cochrane Central Register of Controlled Trials, MEDLINE and Embase. We also searched two trial registries. A search update was carried out in July 2019 and potentially relevant studies are awaiting classification., Selection Criteria: We included randomised controlled trials that assessed TCC via MD to improve MNCH behaviour, service use, health, and well-being. Eligible comparators were usual care/no intervention, non-digital TCC, and digital non-targeted client communication., Data Collection and Analysis: We used standard methodological procedures recommended by Cochrane, although data extraction and risk of bias assessments were carried out by one person only and cross-checked by a second., Main Results: We included 27 trials (17,463 participants). Trial populations were: pregnant and postpartum women (11 trials conducted in low-, middle- or high-income countries (LMHIC); pregnant and postpartum women living with HIV (three trials carried out in one lower middle-income country); and parents of children under the age of five years (13 trials conducted in LMHIC). Most interventions (18) were delivered via text messages alone, one was delivered through voice calls only, and the rest were delivered through combinations of different communication channels, such as multimedia messages and voice calls. Pregnant and postpartum women TCCMD versus standard care For behaviours, TCCMD may increase exclusive breastfeeding in settings where rates of exclusive breastfeeding are less common (risk ratio (RR) 1.30, 95% confidence intervals (CI) 1.06 to 1.59; low-certainty evidence), but have little or no effect in settings where almost all women breastfeed (low-certainty evidence). For use of health services, TCCMD may increase antenatal appointment attendance (odds ratio (OR) 1.54, 95% CI 0.80 to 2.96; low-certainty evidence); however, the CI encompasses both benefit and harm. The intervention may increase skilled attendants at birth in settings where a lack of skilled attendants at birth is common (though this differed by urban/rural residence), but may make no difference in settings where almost all women already have a skilled attendant at birth (OR 1.00, 95% CI 0.34 to 2.94; low-certainty evidence). There were uncertain effects on maternal and neonatal mortality and morbidity because the certainty of the evidence was assessed as very low. TCCMD versus non-digital TCC (e.g. pamphlets) TCCMD may have little or no effect on exclusive breastfeeding (RR 0.92, 95% CI 0.79 to 1.07; low-certainty evidence). TCCMD may reduce 'any maternal health problem' (RR 0.19, 95% CI 0.04 to 0.79) and 'any newborn health problem' (RR 0.52, 95% CI 0.25 to 1.06) reported up to 10 days postpartum (low-certainty evidence), though the CI for the latter includes benefit and harm. The effect on health service use is unknown due to a lack of studies. TCCMD versus digital non-targeted communication No studies reported behavioural, health, or well-being outcomes for this comparison. For use of health services, there are uncertain effects for the presence of a skilled attendant at birth due to very low-certainty evidence, and the intervention may make little or no difference to attendance for antenatal influenza vaccination (RR 1.05, 95% CI 0.71 to 1.58), though the CI encompasses both benefit and harm (low-certainty evidence). Pregnant and postpartum women living with HIV TCCMD versus standard care For behaviours, TCCMD may make little or no difference to maternal and infant adherence to antiretroviral (ARV) therapy (low-certainty evidence). For health service use, TCC mobile telephone reminders may increase use of antenatal care slightly (mean difference (MD) 1.5, 95% CI -0.36 to 3.36; low-certainty evidence). The effect on the proportion of births occurring in a health facility is uncertain due to very low-certainty evidence. For health and well-being outcomes, there was an uncertain intervention effect on neonatal death or stillbirth, and infant HIV due to very low-certainty evidence. No studies reported on maternal mortality or morbidity. TCCMD versus non-digital TCC The effect is unknown due to lack of studies reporting this comparison. TCCMD versus digital non-targeted communication TCCMD may increase infant ARV/prevention of mother-to-child transmission treatment adherence (RR 1.26, 95% CI 1.07 to 1.48; low-certainty evidence). The effect on other outcomes is unknown due to lack of studies. Parents of children aged less than five years No studies reported on correct treatment, nutritional, or health outcomes. TCCMD versus standard care Based on 10 trials, TCCMD may modestly increase health service use (vaccinations and HIV care) (RR 1.21, 95% CI 1.08 to 1.34; low-certainty evidence); however, the effect estimates varied widely between studies. TCCMD versus non-digital TCC TCCMD may increase attendance for vaccinations (RR 1.13, 95% CI 1.00 to 1.28; low-certainty evidence), and may make little or no difference to oral hygiene practices (low-certainty evidence). TCCMD versus digital non-targeted communication TCCMD may reduce attendance for vaccinations, but the CI encompasses both benefit and harm (RR 0.63, 95% CI 0.33 to 1.20; low-certainty evidence). No trials in any population reported data on unintended consequences., Authors' Conclusions: The effect of TCCMD for most outcomes is uncertain. There may be improvements for some outcomes using targeted communication but these findings were of low certainty. High-quality, adequately powered trials and cost-effectiveness analyses are required to reliably ascertain the effects and relative benefits of TCCMD. Future studies should measure potential unintended consequences, such as partner violence or breaches of confidentiality., (Copyright © 2020 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)