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Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (

Abstract The pan-immune-inflammation value (PIV), calculated as (neutrophil × platelet × monocyte)/lymphocyte count, may be useful for estimating survival in breast cancer patients. To determine the prognostic value of PIV for overall survival in breast cancer patients in Lima, Peru. A retrospective cohort study was conducted. 97 breast cancer patients diagnosed between January 2010 and December 2016 had their medical records analyzed. The primary dependent variable was overall survival, and the key independent variable was the PIV, divided into high (≥ 310) and low (

Introduction: In Peru, adherence to antihypertensive treatment ranges from 55.5% to 46.6%. Adherence decreases under adverse socioeconomic conditions. Objective: The aim of this research was to evaluate the socioeconomic inequalities in non-adherence to antihypertensive medication in Peru. Methods: A cross-sectional study was conducted through the analysis of data from the Demographic and Family Health Survey carried out in Peru between 2013 and 2023. We addressed the socioeconomic conditions of hypertensive Peruvian adults, including sex, age group, educational level, area or place of residence, and health insurance. These conditions were evaluated as sources of inequality in non-adherence to antihypertensive medication at a general level using the Concentration Index (CI) or Erreygers’ Concentration Index (ECI) among hypertensive adults over 29 years old. Results: In the 15,624 hypertensive adults older than 29 years included in the study, 86.63% were adherent to their antihypertensive medication. However, the inequality in medication non-adherence was considerable (CI: -0.259; 95%CI: -0.385 to -0.132; p

We present the first reported case in the Middle East of bilateral uveal metastasis from prostate cancer in a 74-year-old man. Initially diagnosed in November 2016 with high-volume metastatic castrate-sensitive prostate cancer (mCSPC), his cancer progressed and was castrate-resistant. In December 2022, the patient presented blurry vision in the left eye and was diagnosed with left uveal metastase. Later his disease progressed to the right eye. This case shows the importance of considering ocular metastasis in patients with advanced prostate cancer, highlights the challenges in managing rare metastatic sites, and provides insights into treatment strategies for bilateral uveal metastasis.

Abstract Background To assess the outcome of previously untreated patients with perihilar cholangiocarcinoma who present to a cancer referral center with or without pre-existing trans-papillary biliary drainage. Methods Consecutive patients with a diagnosis of perihilar cholangiocarcinoma presenting between January 1, 2013, and December 31, 2017, were identified from a prospective surgical database and by a query of the institutional database. Of 237 patients identified, 106 met inclusion criteria and were reviewed. Clinical information was obtained from the Electronic Medical Record and imaging studies were reviewed in the Picture Archiving and Communication System. Results 73 of 106 patients (69%) presenting with a new diagnosis of perihilar cholangiocarcinoma underwent trans-papillary biliary drainage (65 endoscopic and 8 percutaneous) prior to presentation at our institution. 8 of the 73 patients with trans-papillary biliary drainage (11%) presented with and 5 developed cholangitis; all 13 (18%) required subsequent intervention; none of the patients without trans-papillary biliary drainage presented with or required drainage for cholangitis (p = 0.008). Requiring drainage for cholangitis was more likely to delay treatment (p = 0.012) and portended a poorer median overall survival (13.6 months, 95%CI [4.08, not reached)] vs. 20.6 months, 95%CI [18.34, 37.51] p = 0.043). Conclusion Trans-papillary biliary drainage for perihilar cholangiocarcinoma carries a risk of cholangitis and should be avoided when possible. Clinical and imaging findings of perihilar cholangiocarcinoma should prompt evaluation at a cancer referral center before any intervention. This would mitigate development of cholangitis necessitating additional drainage procedures, delaying treatment and potentially compromising survival.

Abstract Background Huntington disease (HD) is a neurodegenerative disorder with complex motor and behavioural manifestations. The Q175 knock-in mouse model of HD has gained recent popularity as a genetically accurate model of the human disease. However, behavioural phenotypes are often subtle and progress slowly in this model. Here, we have implemented machine-learning algorithms to investigate behaviour in the Q175 model and compare differences between sexes and disease stages. We explore distinct behavioural patterns and motor functions in open field, rotarod, water T-maze, and home cage lever-pulling tasks. Results In the open field, we observed habituation deficits in two versions of the Q175 model (zQ175dn and Q175FDN, on two different background strains), and using B-SOiD, an advanced machine learning approach, we found altered performance of rearing in male manifest zQ175dn mice. Notably, we found that weight had a considerable effect on performance of accelerating rotarod and water T-maze tasks and controlled for this by normalizing for weight. Manifest zQ175dn mice displayed a deficit in accelerating rotarod (after weight normalization), as well as changes to paw kinematics specific to males. Our water T-maze experiments revealed response learning deficits in manifest zQ175dn mice and reversal learning deficits in premanifest male zQ175dn mice; further analysis using PyMouseTracks software allowed us to characterize new behavioural features in this task, including time at decision point and number of accelerations. In a home cage-based lever-pulling assessment, we found significant learning deficits in male manifest zQ175dn mice. A subset of mice also underwent electrophysiology slice experiments, revealing a reduced spontaneous excitatory event frequency in male manifest zQ175dn mice. Conclusions Our study uncovered several behavioural changes in Q175 mice that differed by sex, age, and strain. Our results highlight the impact of weight and experimental protocol on behavioural results, and the utility of machine learning tools to examine behaviour in more detailed ways than was previously possible. Specifically, this work provides the field with an updated overview of behavioural impairments in this model of HD, as well as novel techniques for dissecting behaviour in the open field, accelerating rotarod, and T-maze tasks.

Located 30 km inland from Lebanon’s coast, The Beqaa Valley (or Beqaa Plains) is considered the agricultural backbone of the country. The Beqaa’s built geographies were shaped by the political and economic hierarchies established by the Roman and Ottoman Empires and revised by the French Mandate. Local and regional economic hardships in the last six decades have led the Beqaa to cycle through periods of decline and recovery, with quick introductions of infrastructural technologies, spurts of loosely regulated building development, and hasty innovations in industrial activity. In this vein, ‘reflexive realism’ concepts of risk regime, logic of production, topographical fragmentation, and internal connectivity, are useful to examine how towns and cities in the Beqaa developed, deteriorated, and adjusted. However, spatial evidence that would inform such inquiries in Rayak, Beqaa, is far from similar to evidence observed in Beirut. Urban morphology research techniques combined with the concept of vernacular architecture can help decode the layers and uses of the built environment. This article introduces a mapping workflow that typologizes built fabrics using five morphological criteria (streets, density, open space, architectural character, and land use) to construct a spatial narrative that can begin characterizing the nature of the Beqaa’s cities and towns.

Abstract Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant mortality, but the underlying cause(s) are unclear. A subset of SIDS infants has abnormalities in the neurotransmitter, serotonin (5-hydroxytryptamine [5-HT]) and the adaptor molecule, 14–3–3 pathways in regions of the brain involved in gasping, response to hypoxia, and arousal. To evaluate our hypothesis that SIDS is, at least in part, a multi-organ dysregulation of 5-HT, we examined whether blood platelets, which have 5-HT and 14–3–3 signaling pathways similar to brain neurons, are abnormal in SIDS. We also studied platelet surface glycoprotein IX (GPIX), a cell adhesion receptor which is physically linked to 14–3–3. In infants dying of SIDS compared to infants dying of known causes, we found significantly higher intra-platelet 5-HT and 14–3–3 and lower platelet surface GPIX. Serum and plasma 5-HT were also elevated in SIDS compared to controls. The presence in SIDS of both platelet and brainstem 5-HT and 14–3–3 abnormalities suggests a global dysregulation of these pathways and the potential for platelets to be used as a model system to study 5-HT and 14–3–3 interactions in SIDS. Platelet and serum biomarkers may aid in the forensic determination of SIDS and have the potential to be predictive of SIDS risk in living infants.

Abstract Weeds pose a major constraint in lentil cultivation, leading to decrease farmers’ revenues by reducing the yield and increasing the management costs. The development of herbicide tolerant cultivars is essential to increase lentil yield. Even though herbicide tolerant lines have been identified in lentils, breeding efforts are still limited and lack proper validation. Marker assisted selection (MAS) can increase selection accuracy at early generations. Total 292 lentil accessions were evaluated under different dosages of two herbicides, metribuzin and imazethapyr, during two seasons at Marchouch, Morocco and Terbol, Lebanon. Highly significant differences among accessions were observed for days to flowering (DF) and maturity (DM), plant height (PH), biological yield (BY), seed yield (SY), number of pods per plant (NP), as well as the reduction indices (RI) for PH, BY, SY and NP. A total of 10,271 SNPs markers uniformly distributed along the lentil genome were assayed using Multispecies Pulse SNP chip developed at Agriculture Victoria, Melbourne. Meta-GWAS analysis was used to detect marker-trait associations, which detected 125 SNPs markers associated with different traits and clustered in 85 unique quantitative trait loci. These findings provide valuable insights for initiating MAS programs aiming to enhance herbicide tolerance in lentil crop.

Abstract Background Malaria in pregnancy remains a major global public health problem. Intermittent prophylaxis treatment of malaria in pregnancy with Sulphadoxine-pyrimethamine and co-trimoxazole is efficacious for prevention of malaria in pregnancy HIV negative and positive women, respectively. However, uptake of the recommended doses of therapies has remained suboptimal in Uganda, majorly due to inadequate knowledge among pregnant women. Therefore, this study aimed to explore attitudes and perceptions towards developing an educational video for malaria preventive therapy. Methods We conducted an exploratory study with qualitative methods among pregnant women attending antenatal care at Kisenyi Health Center IV (KHCIV), health workers from KHCIV, and officials from the Ministry of Health. The study was conducted at KHCIV from October 2022 to March 2023. Focus group discussions (FGD) were conducted among purposively selected pregnant women and key informant interviews (KII) among health workers and Ministry of Health officials. Data were analyzed using inductive and deductive thematic methods in atlas ti.8. Results A total of five FGDs comprising of 7–10 pregnant women were conducted; and KIIs were conducted among four mid-wives, two obstetricians, and two Ministry of Health officials. Generally, all respondents mentioned a need for interventions to improve malaria preventive knowledge among pregnant women; were positive about developing an educative video for malaria preventive therapy in pregnancy; and suggested a short, concise, and edutaining video focusing both the benefits of taking and risks of not taking malaria preventive therapy. They proposed that women may be encouraged to view the video as soon as they conceive and throughout the pregnancy. It also was suggested that the video may be viewed on television sets in maternal and reproductive health clinics and homes, and on smart phones. Conclusion Pregnant women, health workers, and Ministry of Health officials were positive about the development of a short edutaining video on malaria preventive therapy that focuses on both benefits of taking and risks of not taking the malaria preventive therapy in pregnancy. This information guided the video development and therefore, in the development of health educative videos, client and stakeholder inputs may always be solicited.

Abstract Background Hepatitis B virus (HBV) is associated with several acute and long-term complications and vaccination is the cornerstone of prevention. A recent outbreak in Gulu, Uganda, one of the districts covered by a mass vaccination campaign, suggests low uptake of HBV vaccination. This study aims to determine the uptake and completion of HBV vaccination and associated factors among residents of Gulu, Uganda. Methods A mixed methods cross-sectional study was conducted in Gulu, Northern Uganda, among 434 adult residents. A pretested questionnaire was used to collect data on socio-demographics, perceptions, and knowledge of HBV vaccination. Modified Poisson regression analysis was used in STATA 14 software to obtain prevalence ratios for the association between the independent and dependent variables. For qualitative data, 9 key informant interviews were conducted and thematic analysis was done using Quirkos software. Results Out of the 434 respondents, 41.9% had received at least one dose of the hepatitis B vaccine, 32.5% had received at least 2 doses, and only 20% had completed all 3 doses, with an overall completion rate of 47.8% for participants who had been initiated on the vaccine. Gender, residence, risk perception of Hepatitis B infection, perceived safety of the vaccine, and awareness of mass vaccination were associated with uptake of Hepatitis B vaccination. Residence, knowledge, and perception of being at risk of acquiring Hepatitis B were associated with completion. Qualitative results revealed that the levels of uptake and completion could have been affected by access to vaccination sites; inadequate knowledge about the disease; myths about the vaccine and inadequate community engagement. Conclusion Low Hepatitis B vaccine uptake and completion rates were observed in Gulu. To enhance vaccination coverage, future initiatives should prioritize awareness, education, and dispelling of vaccination myths. Additionally, increased government investment in training health workers can serve as a valuable strategy to improve information dissemination and awareness among the population.

Abstract Introduction Uganda currently hosts an estimated 1.5 million refugees. The refugees have challenges in accessing family planning (FP) services in the host country. The study aimed to investigate factors associated with FP use among host and refugee populations in Adjumani district, Uganda. Methods A comparative cross-sectional study was conducted in May 2021 in three refugee settlements and their host communities in Adjumani district. A total of 1,310 respondents, (664 refugees and 646 host) were randomly selected using multistage cluster sampling and interviewed. Quantitative data were collected using structured questionnaires and analyzed using STATA V.15. Descriptive and Multivariate analysis performed. Results We found that modern Contraceptive Prevalence Rate (mCPR) was 30.2% (32.2% for host and 28.2% for refugees). Multivariate analysis showed that women who live singly (AOR = 2.25, 95%, CI: 1.56 -3.84), completed primary education [AOR = 1.65, 95% CI: 1.27–2.16], acquired skills [AOR = 2.28, 95% CI: 2.11–2.47], have the desire for another child [AOR = 3.73, 95% CI: 1.45- 9.60], have stayed in the study area between 3–5 years [AOR = 2.24, 95% CI: 1.46–3.42] were statistically significantly associated with FP use among both refugee and host populations. The key barrier to FP use by host was harassment of women and separation/divorce for not consulting the family members. Whereas amongst the refugees, they do not want to use FP methods. Conclusion Our findings revealed low FP use amongst both populations in Adjumani district. The main factors associated with FP use amongst refugee populations included marital status, level of education, type of occupation, and duration of stay in the study area whereas amongst the host is the marital status. Main reasons for not using FP methods included fear of side effects by hosts and not wanting to use FP by refugees. There is need to sensitize both communities about the benefits of FP at community level.

Background: Black, Indigenous, and People of Color (BIPOC) communities experience higher prevalence of cardiovascular disease and related chronic conditions compared to White communities due to disparities in tobacco exposure. Smoking can be effectively treated but evidence-based treatments are less likely to be offered to or used by BIPOC patients. We present the study protocol of the Smoking Cessation Outreach for Racial Equity (SCORE) trial that tests the effect of adding longitudinal care coordination to current standard of care for smoking cessation to promote health equity among BIPOC patients. Methods: Longitudinal Proactive Outreach (LPO; 4 culturally tailored outreach call cycles over one year by motivational interviewing trained counselors to connect patients to cessation counseling and medication) will be added to the current standard of care, Ask-Advise-Connect (AAC; primary care providers asking all patients if they smoke, and if smoking, advising to quit and connecting to treatment). We will conduct a hybrid type 1 implementation-effectiveness trial to examine the direct effect of AAC + LPO (a multilevel health system intervention) vs. AAC on population-level combustible tobacco abstinence at 18 months and treatment utilization among 2000 BIPOC adults who smoke across two healthcare systems in Minnesota. Participants will be surveyed at 6, 12, and, 18 months post-enrollment to assess outcomes. The primary outcome is biochemically confirmed combustible cigarette abstinence at 18 months. Discussion: LPO has potential to promote health equity by addressing barriers caused by structural racism, including access to care, care fragmentation, and provider racism, by systematically reaching out to all BIPOC patients who smoke. Clinicaltrialsgov: NCT05671380.

Background Robust risk assessment is crucial for the growing repaired tetralogy of Fallot population at risk of major adverse clinical outcomes; however, current tools are hindered by lack of validation. This study aims to develop and validate a risk prediction model for death in the repaired tetralogy of Fallot population. Methods and Results Patients with repaired tetralogy of Fallot enrolled in the INDICATOR (International Multicenter Tetralogy of Fallot Registry) cohort with clinical, arrhythmia, cardiac magnetic resonance, and outcome data were included. Patients from London, Amsterdam, and Boston sites were placed in the development cohort; patients from the Toronto site were used for external validation. Multivariable Cox regression was used to evaluate factors associated with time from cardiac magnetic resonance until the primary outcome: all‐cause death. Of 1552 eligible patients (n=1221 in development, n=331 in validation; median age at cardiac magnetic resonance 23.4 [interquartile range, 15.6–35.6] years; median follow up 9.5 years), 102 (6.6%) experienced the primary outcome. The multivariable Cox model performed similarly during development (concordance index, 0.83 [95% CI, 0.78–0.88]) and external validation (concordance index, 0.80 [95% CI, 0.71–0.90]) and identified older age at cardiac magnetic resonance, obesity, type of tetralogy of Fallot repair, higher right ventricular end‐systolic volume index, and lower biventricular global function index as independent predictors of death. A risk‐scoring algorithm dividing patients into low‐risk (score ≤4) versus high‐risk (score >4) groups was validated to effectively discriminate risk of death (15‐year survival of 95% versus 74%, respectively; P

Abstract BackgroundDespite restrictive opioid management guidelines, opioid use disorder (OUD) remains a major public health concern. Machine learning (ML) offers a promising avenue for identifying and alerting clinicians about OUD, thus supporting better clinical decision-making regarding treatment. ObjectiveThis study aimed to assess the clinical validity of an ML application designed to identify and alert clinicians of different levels of OUD risk by comparing it to a structured review of medical records by clinicians. MethodsThe ML application generated OUD risk alerts on outpatient data for 649,504 patients from 2 medical centers between 2010 and 2013. A random sample of 60 patients was selected from 3 OUD risk level categories (n=180). An OUD risk classification scheme and standardized data extraction tool were developed to evaluate the validity of the alerts. Clinicians independently conducted a systematic and structured review of medical records and reached a consensus on a patient’s OUD risk level, which was then compared to the ML application’s risk assignments. ResultsA total of 78,587 patients without cancer with at least 1 opioid prescription were identified as follows: not high risk (n=50,405, 64.1%), high risk (n=16,636, 21.2%), and suspected OUD or OUD (n=11,546, 14.7%). The sample of 180 patients was representative of the total population in terms of age, sex, and race. The interrater reliability between the ML application and clinicians had a weighted kappa coefficient of 0.62 (95% CI 0.53-0.71), indicating good agreement. Combining the high risk and suspected OUD or OUD categories and using the review of medical records as a gold standard, the ML application had a corrected sensitivity of 56.6% (95% CI 48.7%-64.5%) and a corrected specificity of 94.2% (95% CI 90.3%-98.1%). The positive and negative predictive values were 93.3% (95% CI 88.2%-96.3%) and 60.0% (95% CI 50.4%-68.9%), respectively. Key themes for disagreements between the ML application and clinician reviews were identified. ConclusionsA systematic comparison was conducted between an ML application and clinicians for identifying OUD risk. The ML application generated clinically valid and useful alerts about patients’ different OUD risk levels. ML applications hold promise for identifying patients at differing levels of OUD risk and will likely complement traditional rule-based approaches to generating alerts about opioid safety issues.

Abstract Background Nicotine replacement therapy (NRT) and short messaging service (SMS)-based tobacco cessation interventions have demonstrated effectiveness in reducing tobacco use in many populations, but evidence is needed on which tailored treatments are most efficacious in meeting the complex medical and psychosocial factors confronting people living with HIV (PLWH) in sub-Saharan Africa (SSA). This paper describes the protocol of a study to test the efficacy of both NRT and a tailored SMS-based tobacco use cessation intervention among PLWH in Uganda and Zambia. Methods In a randomized controlled trial, 800 adult PLWH who use tobacco will be recruited by health care professionals at HIV treatment centers where they are receiving care. Participants will be randomized to one of the four study arms: (1) standard of care [SOC; brief clinician advice to quit combined with HIV education and information aimed at encouraging HIV treatment adherence (with no mention of tobacco) delivered via text messages]; (2) SOC + 12 weeks of NRT; (3) SOC + 6 weeks of SMS text messages to support quitting tobacco use (SMS); or (4) SOC + NRT + SMS. Participants will receive a cell phone and solar panel with power bank for charging the phone. The main outcome is cessation of tobacco use by study participants verified by urinary cotinine (

To compare success rates of trabeculectomy (TE) and Preserflo MicroShunt (PMS) in heterogenous glaucoma cohorts with regards to different pre- and postoperative therapeutic regimens. Data of 187 glaucoma patients who either received TE (73 eyes) or PMS implantation (114 eyes) between January 2018 and December 2022 were retrospectively evaluated. Surgical success and failure rates were analyzed within six months of follow-up. Intraocular pressure (IOP) development over the course of follow-up was compared between both groups. Tertiary outcome measures were best-corrected visual acuity (BCVA), number and type of medications, frequency of postoperative complications and revision surgeries. Outcome measures underwent additional assessment based on subgroup categorizations, and failure time hazard ratios were computed. The success rates were comparable between both procedures (TE: 54.1%, PMS: 60.0%; p = 0.17). Both procedures showed significant IOP reduction (p < 0.01); however, overall IOP reduction was greater in the TE group than in the PMS group (TE: Reduction by 12 mmHg (188.9%), PMS: Reduction by 7 mmHg (51.3%); p = 0.01). The number of topical medications decreased significantly in both groups over the course of follow-up (TE: 4 to 0, PMS: 3 to 0; p < 0.01). While the number of complications and revision surgeries were similar in both groups, the time interval until the first revision surgery within the TE group was significantly shorter (TE: 13.5 d, PMS: 163 d; p = 0.01) than within the PMS group. No difference could be detected between TE and PMS with regard to the follow-up regimen. In particular, there was no significant difference in the need for 5-floururacil injections postoperatively (p = 0.29). Less invasive glaucoma surgery with the PMS appeared comparable to the TE within a heterogenous glaucoma cohort with regards to IOP development and freedom from medication.

Although the transition toward a more sustainable agricultural system is sparking the interest of scientists and farmers around the globe, breeding programs are still focusing on optimizing cultivars intended for the monoculture system, and most cultivars available on the market are not suitable for intercropping. The incorporation of versatile cool-season food legumes (CSFLs) in the intercropping system is a promising way toward more diversified and sustainable cropping systems. However, as the selection of good-performing cultivars under sole cropping does not always lead to a good performance in intercropping, the development of an alternative breeding scheme for intercropping is now a necessity. The case study of faba bean–wheat intercropping was used to select for traits associated with better performance of faba bean, resulting in identifying the combined grain yield, 100-seed weight, number of pods per plant, and canopy height as key traits for faba bean–wheat intercropping suitability. Incorporating these traits in the breeding programs would be the cornerstone of the prospective transition.

Abstract Watershed nutrient management often focuses on actions that reduce the movement of nitrogen (N) and phosphorus (P) from agricultural lands into streams. One area of management focus is the buffer of land adjacent to streams. Wetlands and forests in this buffer can intercept and retain N and P from the landscape. In addition to directly intercepting agricultural nutrients, natural habitats in the buffer can alter stream geomorphology and influence the in‐stream processing and transformation of N and P to less labile and mobile forms. Here, we assess the influence of buffer land cover on in‐stream processing of N and P. We measured nutrient dynamics in the water column and sediments of agricultural streams in the Fox River and Duck Creek watersheds (WI, USA) during the growing season. In these streams, water column processing was low, possibly due to a lack of primary producers in the water column. Water column P processing was weakly associated with wetland land cover in the buffer, but buffer land cover had no clear effect on inorganic N processing. On the other hand, sediments were almost always a source of inorganic P and a sink for inorganic N. Sediment P release was higher in streams with more agricultural land cover in the buffer. Sediments in streams with agricultural land cover in the buffer also removed more nitrate, even after accounting for the greater availability of nitrate in those streams. The buffer land cover conditions we quantified occupy a very small portion of the overall watershed (100 m wide, for 1 km upstream of the study site) but nevertheless appear to influence in‐stream cycling of N and P. For P management, reducing agricultural land cover in buffers is already a priority due to the ability of wetlands and forests to intercept nutrients, but this study suggests there may be some additional benefit due to changes in in‐stream P processing.

Abstract During infection, virus-specific CD8+ T cells undergo rapid bursts of proliferation and differentiate into effector cells that kill virus-infected cells and reduce viral load. This rapid clonal expansion can put T cells at significant risk for replication-induced DNA damage. Here, we find that c-Myc links CD8+ T cell expansion to DNA damage response pathways though the E3 ubiquitin ligase, Cullin 4b (Cul4b). Following activation, c-Myc increases the levels of Cul4b and other members of the Cullin RING Ligase 4 (CRL4) complex. Despite expressing c-Myc at high levels, Cul4b-deficient CD8+ T cells do not expand and clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV) in vivo. Cul4b-deficient CD8+ T cells accrue DNA damage and succumb to proliferative catastrophe early after antigen encounter. Mechanistically, Cul4b knockout induces an accumulation of p21 and Cyclin E2, resulting in replication stress. Our data show that c-Myc supports cell proliferation by maintaining genome stability via Cul4b, thereby directly coupling these two interdependent pathways. These data clarify how CD8+ T cells use c-Myc and Cul4b to sustain their potential for extraordinary population expansion, longevity and antiviral responses.

In the past decade, several species of platygastroid wasps were found to be adventive in North America and Europe while under evaluation in quarantine as biological control agents of invasive pests. The scope and relative risk of this phenomenon is not fully known, but it is clearly a trend with implications for classical biological control. As a means of assessing the issue and to provide a global baseline, we implemented a data-mining approach with DNA sequences in the Barcode of Life Database, yielding 201 platygastroid BINs with intercontinental and island distributions. At least fifty-five BINs displayed exact COI barcode matches across continents, with many more BINs scored as inconclusive due to sequence length variation. These intercontinental and island BINs include biocontrol agents known to be adventive, as well as many species identified only to genus with uncertain geographic origins. We provide 2,500 identifications for platygastroid BOLD BINs, 88% to genus, to encourage additional research on this distributional phenomenon. The intercontinental BOLD BINs were compared to literature records and GBIF occurrences of cosmopolitan species to identify gaps and discordance across data sources. Smaller COI barcode datasets from localities in Florida and Germany, including topotypical specimens, revealed more intercontinental matches. We analyzed COI sequences in BOLD for the entirety of Insecta and Araneae to assess this phenomenon more broadly and because these taxa contain many hosts for platygastroid wasps. This method revealed that the intercontinental distribution phenomenon is widespread with implications for assessing biological diversity, taxonomic methodology and regulatory frameworks.

The safety and efficacy of hepatic artery embolization (HAE) in treating intrahepatic cholangiocarcinoma (IHC) was evaluated. Initial treatment response, local tumor progression-free survival (L-PFS), and overall survival (OS) were evaluated in 34 IHC patients treated with HAE. A univariate survival analysis and a multivariate Cox proportional hazard analysis to identify independent factors were carried out. Objective response (OR) at 1-month was 79.4%. Median OS and L-PFS from the time of HAE was 13 (CI = 95%, 7.4–18.5) and 4 months (CI = 95%, 2.09–5.9), respectively. Tumor burden < 25% and increased tumor vascularity on preprocedure imaging and surgical resection prior to embolization were associated with longer OS (p < 0.05). Multivariate logistic regression analysis demonstrated that tumor burden < 25% and hypervascular tumors were independent risk factors. Mean post-HAE hospital stay was 4 days. Grade 3 complication rate was 8.5%. In heavily treated patients with IHC, after exhausting all chemotherapy and other locoregional options, HAE as a rescue treatment option appeared to be safe with a mean OS of 13 months. Tumor burden < 25%, increased target tumor vascularity on pre-procedure imaging, and OR on 1 month follow-up images were associated with better OS. Further studies with a control group are required to confirm the effectiveness of HAE in IHC.

Abstract The relationship between urinary endothelial growth factor (uEGF) and cardiovascular autonomic neuropathy (CAN) in adults with type 1 diabetes was evaluated. uEGF levels at baseline and standardized CAN measures were collected at baseline and annually for 3 years for type 1 diabetes adults. Linear regression analysis and linear mixed effects model were used for analysis. In this cohort (n = 44, 59% women, mean ± standard deviation age 34 ± 13 years and diabetes duration 14 ± 6 years), lower baseline uEGF levels correlated with lower baseline expiration : inspiration ratios (P = 0.03) and greater annual declines in Valsalva ratios (P = 0.02) in the unadjusted model, and correlated with lower low‐frequency power : high‐frequency power ratios (P = 0.01) and greater annual changes in low‐frequency power : high‐frequency power ratios (P = 0.01) after adjustment for age, sex, body mass index, and hemoglobin A1C. In conclusion, baseline uEGF levels correlate to baseline and longitudinal changes in CAN indices. A large‐scale, long‐term study is needed to validate uEGF as a reliable CAN biomarker.

With over 9 million cows in the United States, Holstein is the dominant breed in the US dairy population; however, the US Jersey population is growing. The objective of this study was to determine the profitability of Holstein and Jersey cows managed similarly on the same farms. Holstein and Jersey economic performance was compared within 3 north central US dairies, each milking more than 500 cows. The herds' average distribution was 21% Jersey (27 ± 0.67 kg/d milk, 4.92% ± 0.24 fat, 3.72% ± 0.03 protein) and 79% Holstein (37 ± 1.98 kg/d milk, 3.85% ± 0.21 fat, 3.17% ± 0.17 protein). A comparative budget approach was used to assess economic factors that differed between the breeds on a per cow annual basis, based on the assumption that an existing farm would be constrained by stalls and parlor to an equal number of Jersey and Holstein cows. Data from 2020 were gathered from farm management software, on-farm evaluations, and producer interviews. Sensitivity analysis was performed to determine which conditions would lead to different conclusions. Factors considered in the analysis included milk and component production, milk bonuses, ration prices, and dry matter (DM) intake. In a 2021 price scenario, Holstein cows ranged from $345 to $601 more profitable than Jersey cows on a per cow annual basis. Although Jersey cows had an advantage in component concentration, Holstein cows produced 13 ± 4.7% more fat and 22 ± 6.6% more protein annually due to greater milk yield. This accounted for most of the profitability advantage for Holsteins; 78% of the revenue advantage for Holstein cows came from increased component production. Few health and reproductive differences were found. The sensitivity analysis revealed, if all other factors remained the same, Jersey profitability would equal that of Holstein if any of the following changes occurred (assuming no change in Holstein metrics): mean Jersey milk production increased to 31 kg/d; milk price adjustments decreased from −$0.008 to −$0.11 per kg fluid milk; lactating cow ration price increased from $0.27 per kg DM to $0.53 per kg DM; or Jersey DM intake decreased from 20 to 15 kg/d. The study did not consider crossbred profitability or new infrastructure investments. In conclusion, Holstein cows were more profitable than Jersey cows on these 3 north central US dairies.

This study aimed to evaluate the safety and tolerability of STP1, a combination of ibudilast and bumetanide, tailored for the treatment of a clinically and biologically defined subgroup of patients with Autism Spectrum Disorder (ASD), namely ASD Phenotype 1 (ASD-Phen1). We conducted a randomized, double-blind, placebo-controlled, parallel-group phase 1b study with two 14-day treatment phases (registered at clinicaltrials.gov as NCT04644003). Nine ASD-Phen1 patients were administered STP1, while three received a placebo. We assessed safety and tolerability, along with electrophysiological markers, such as EEG, Auditory Habituation, and Auditory Chirp Synchronization, to better understand STP1’s mechanism of action. Additionally, we used several clinical scales to measure treatment outcomes. The results showed that STP1 was well-tolerated, with electrophysiological markers indicating a significant and dose-related reduction of gamma power in the whole brain and in brain areas associated with executive function and memory. Treatment with STP1 also increased alpha 2 power in frontal and occipital regions and improved habituation and neural synchronization to auditory chirps. Although numerical improvements were observed in several clinical scales, they did not reach statistical significance. Overall, this study suggests that STP1 is well-tolerated in ASD-Phen1 patients and shows indirect target engagement in ASD brain regions of interest.

Caspase 3 activation is a hallmark of cell death and there is a strong correlation between elevated protease activity and evolving pathology in neurodegenerative disease, such as amyotrophic lateral sclerosis (ALS). At the cellular level, ALS is characterized by protein aggregates and inclusions, comprising the RNA binding protein TDP-43, which are hypothesized to trigger pathogenic activation of caspase 3. However, a growing body of evidence indicates this protease is essential for ensuring cell viability during growth, differentiation and adaptation to stress. Here, we explored whether caspase 3 acts to disperse toxic protein aggregates, a proteostasis activity first ascribed to the distantly related yeast metacaspase ScMCA1. We demonstrate that human caspase 3 can functionally substitute for the ScMCA1 and limit protein aggregation in yeast, including TDP-43 inclusions. Proteomic analysis revealed that disrupting caspase 3 in the same yeast substitution model resulted in detrimental TDP-43/mitochondrial protein associations. Similarly, suppression of caspase 3, in either murine or human skeletal muscle cells, led to accumulation of TDP-43 aggregates and impaired mitochondrial function. These results suggest that caspase 3 is not inherently pathogenic, but may act as a compensatory proteostasis factor, to limit TDP-43 protein inclusions and protect organelle function in aggregation related degenerative disease.

Abstract Background Lymphatic complications are common in patients with Fontan circulation. Three-dimensional balanced steady-state free precession (3D bSSFP) angiography by cardiovascular magnetic resonance (CMR) is widely used for cardiovascular anatomical assessment. We sought to determine the frequency of thoracic duct (TD) visualization using 3D bSSFP images and assess whether TD characteristics are associated with clinical outcomes. Methods This was a retrospective, single-center study of patients with Fontan circulation who underwent CMR. Frequency matching of age at CMR was used to construct a comparison group of patients with repaired tetralogy of Fallot (rTOF). TD characteristics included maximum diameter and a qualitative assessment of tortuosity. Clinical outcomes included protein-losing enteropathy (PLE), plastic bronchitis, listing for heart transplantation, and death. A composite outcome was defined as presence of any of these events. Results The study included 189 Fontan patients (median age 16.1 years, IQR 11.0–23.2 years) and 36 rTOF patients (median age 15.7 years, IQR 11.1–23.7 years). The TD diameter was larger (median 2.50 vs. 1.95 mm, p = 0.002) and more often well visualized (65% vs. 22%, p

ABSTRACT: Background: Identification of risk factors for biventricular (BiV) repair in children with hypoplastic left ventricles (HLV) has been challenging. We sought to identify preoperative cardiovascular magnetic resonance (CMR) predictors of outcome in patients with HLVs who underwent BiV repair, with a focus on the mitral valve (MV). Methods: Single-center retrospective analysis of preoperative CMRs on patients with HLV (≤50 mL/m2) and no endocardial fibroelastosis who underwent BiV repair from 2005–2022. CMR measurements included MV orifice area in diastole. The primary composite outcome included time to death, transplant, BiV takedown, heart failure admission, left atrial decompression, or unexpected reoperation; and the secondary outcome included more than or equal to moderate mitral stenosis and/or regurgitation. Results: Median follow-up was 0.7 (interquartile range 0.1, 2.2) years. Of 122 patients [59 atrioventricular canal (AVC) and 63 non-AVC] age 3 ± 2.8 years at the time of BiV repair, freedom from the primary outcome at 2 years was 53% for AVC and 69% for non-AVC (log rank p = 0.12), and freedom from the secondary outcome at 2 years was 49% for AVC and 79% for non-AVC (log rank p

IntroductionContraceptive use can be lifesaving, empowering and cost-effective for women and girls. Access to contraception is still challenging to female refugees due to several barriers including language, low educational level, lack of information, influence by family members, limited income, cultural and religious norms. This study explored barriers to contraceptive use among South Sudanese refugee women living in Adjumani district, Uganda.MethodsAn exploratory study design using qualitative methods were employed involving women of reproductive age (15-49 years). Purposive sampling was used to select participants for Focus Group Discussions (FGDs) and In-depth Interviews (IDIs) from three settlements in Adjumani district. We conducted four FGDs, each consisting of 8 participants. We also conducted fourteen in-depth interviews (IDIs) with women of reproductive age. The IDI and FGD guides were translated into local languages before they were used to collect data. The interviews were recorded, transcribed verbatim and translated into English. Audio recordings were labeled before being translated back to English. Deductive, team-based coding was implemented, and a codebook developed. Transcripts were entered, and data coded using Atlas ti version 14. Data were analyzed using content analysis to produce the final outputs for the study.ResultsThe study found several challenges to contraceptive use. These included gender dynamics, socially constructed myths on contraceptive use, cultural norms, limited knowledge about contraceptives, men's negative attitudes, antagonism of contraceptive use by leaders and reprisal of women who use contraception.ConclusionThe study concluded that there is need for community strategies to break down the barriers to contraception utilization among refugee women. Such strategies should involve men and women alongside gatekeepers to enhance sustainability.

Abstract The evolution of ice‐phase particles within precipitating clouds depends on the environmental properties of the cloud and on physical characteristics of the particles themselves, which can be modified by airflow over steep terrain. Through employing a unique Lagrangian particle‐based precipitation model, this study investigates the sensitivities in ice‐phase particle growth and transport due to variabilities in riming processes over an orographic barrier. This analysis is applied to two wintertime stratiform cyclones sampled by in situ aircraft over windward slopes during the Olympic Mountains Experiment. For both events, we simulate the ice‐phase particle evolution and trajectory within a two‐dimensional prescribed state representative of median observed cloud properties. Sensitivity simulations were constructed based on observed variabilities in supercooled liquid water (SLW) properties and its vertical extent above the melting level. Perturbations of SLW concentration equivalent to the 85th and 15th percentiles of observed values, which typically amounted to a change of less than 0.05 g m−3, resulted in respective increases or decreases in the ice‐phase contribution to surface precipitation mass by as much as 50% and horizontal particle trajectories differences exceeding 10 km. Similar sensitivities were found in response to varying the vertical extent of SLW above the melting level and to adjustments in mean SLW droplet size. The significant precipitation response to small variations in cloud properties principally arises from changing rates of rime mass accumulation and correspondingly, increases in particle fall speed. Considerations for the numerical representation of the riming process and its complex effects on precipitation are discussed.

Objective: To evaluate the ability of DynaMedex, an evidence-based drug and disease Point of Care Information (POCI) resource, in answering clinical queries using keyword searches. Methods: Real-world disease-related questions compiled from clinicians at an academic medical center, DynaMedex search query data, and medical board review resources were categorized into five clinical categories (complications & prognosis, diagnosis & clinical presentation, epidemiology, prevention & screening/monitoring, and treatment) and six specialties (cardiology, endocrinology, hematology-oncology, infectious disease, internal medicine, and neurology). A total of 265 disease-related questions were evaluated by pharmacist reviewers based on if an answer was found (yes, no), whether the answer was relevant (yes, no), difficulty in finding the answer (easy, not easy), cited best evidence available (yes, no), clinical practice guidelines included (yes, no), and level of detail provided (detailed, limited details). Results: An answer was found for 259/265 questions (98%). Both reviewers found an answer for 241 questions (91%), neither found the answer for 6 questions (2%), and only one reviewer found an answer for 18 questions (7%). Both reviewers found a relevant answer 97% of the time when an answer was found. Of all relevant answers found, 68% were easy to find, 97% cited best quality of evidence available, 72% included clinical guidelines, and 95% were detailed. Recommendations for areas of resource improvement were identified. Conclusions: The resource enabled reviewers to answer most questions easily with the best quality of evidence available, providing detailed answers and clinical guidelines, with a high level of replication of results across users.

Cortical-striatal synaptic dysfunction, including enhanced toxic signaling by extrasynaptic N-methyl-d-aspartate receptors (eNMDARs), precedes neurodegeneration in Huntington disease (HD). A previous study showed Activin A, whose transcription is upregulated by calcium influx via synaptic NMDARs, suppresses eNMDAR signaling. Therefore, we examined the role of Activin A in the YAC128 HD mouse model, comparing it to wild-type controls. We found decreased Activin A secretion in YAC128 cortical-striatal co-cultures, while Activin A overexpression in this model rescued altered eNMDAR expression. Striatal overexpression of Activin A in vivo improved motor learning on the rotarod task, and normalized striatal neuronal eNMDAR-mediated currents, membrane capacitance and spontaneous excitatory postsynaptic current frequency in the YAC128 mice. These results support the therapeutic potential of Activin A signaling and targeting eNMDARs to restore striatal neuronal health and ameliorate behavioral deficits in HD.

Abstract Background Uganda has registered an increased investment in family planning (FP) programs, which has contributed to improvement in knowledge of modern contraceptive methods being nearly universal. However, this has not matched the uptake of modern methods or the reduction in the unmet need for FP. This may be explained by the different influences which include health workers, family, and friends. Due to the limited uptake of contraceptive methods, a program on improving awareness, access to, and uptake of modern contraceptives is being implemented in selected regions in Uganda. We, therefore, conducted a formative study to determine the influences on contraceptive uptake at the onset of this program. Methods Using a qualitative study design, we conducted thirty-two focus group discussions and twenty-one in-depth interviews involving men and women of reproductive age. We also carried out twenty-one key informant interviews with people involved in FP service delivery. Data was collected in four districts where implementation of the program was to take place. Audio recorders were used to collect data and tools were translated into local languages. A codebook was developed, and transcripts were coded in vivo using the computer software Atlas-ti version 7 before analysis. Ethical clearance was obtained from institutional review boards and informed consent was sought from all participants. Results From the study, most married people mentioned health workers as their main influence while adolescents reported their peers and friends. Religious leaders and mothers-in-law were reported to mainly discourage people from taking up modern contraceptive methods. The cultural value attached to having many children influenced the contraceptive use decision among people in rural settings. Other influences included a person’s experience and housing. Conclusions Health workers, religious leaders, and mothers determine the uptake of contraceptive services. The study recommends the consideration of the role of these influences in the design of FP program interventions as well as more involvement of health workers in sensitization of communities about contraceptive methods.

Drug discovery was initially attributed to coincidence or experimental research. Historically, the traditional approaches were complex, lengthy, and expensive, entailing costly random screening of synthesized compounds or natural products coupled with in vivo validation largely depending on the availability of appropriate animal models. Currently, in silico modeling has become a vital tool for drug discovery and repurposing. Molecular docking and dynamic simulations are being used to find the best match between a ligand and a molecule, an approach that could help predict the biomolecular interactions between the drug and the target host. Beauvericin (BEA) is an emerging mycotoxin produced by the entomopathogenic fungus Beauveria bassiana, being originally studied for its potential use as a pesticide. BEA is now considered a molecule of interest for its possible use in diverse biotechnological applications in the pharmaceutical industry and medicine. In this manuscript, we provide an overview of the repurposing of BEA as a potential therapeutic agent for multiple diseases. Furthermore, considerable emphasis is given to the fundamental role of in silico techniques to (i) further investigate the activity spectrum of BEA, a secondary metabolite, and (ii) elucidate its mode of action.

BackgroundIn tuberculosis (TB) control, nonadherence to treatment persists as a barrier. The traditional method of ensuring adherence, that is, directly observed therapy, faces significant challenges that hinder its widespread adoption. Digital adherence technologies such as video directly observed therapy (VDOT) are emerging as promising solutions. However, as these novel technologies gain momentum, a critical gap is the lack of comprehensive studies evaluating their efficacy and the unique experiences of patients in Africa. ObjectiveThe aim of this study was to assess patients’ experiences that affected acceptability, usefulness, and ease of use with an enhanced VDOT system during monitoring of TB treatment. MethodsWe conducted individual open-ended interviews in a cross-sectional exit qualitative study in Kampala, Uganda. Thirty participants aged 18-65 years who had completed the VDOT randomized trial were purposively selected to represent variability in sex, adherence level, and HIV status. We used a hybrid process of deductive and inductive coding to identify content related to the experience of study participation with VDOT. Codes were organized into themes and subthemes, which were used to develop overarching categories guided by constructs adapted from the modified Technology Acceptance Model for Resource-Limited Settings. We explored participants’ experiences regarding the ease of use and usefulness of VDOT, thereby identifying the facilitators and barriers to its acceptability. Perceived usefulness refers to the benefits users expect from the technology, while perceived ease of use refers to how easily users navigate its various features. We adapted by shifting from assessing perceived to experienced constructs. ResultsThe participants’ mean age was 35.3 (SD 12) years. Of the 30 participants, 15 (50%) were females, 13 (43%) had low education levels, and 22 (73%) owned cellphones, of which 10 (45%) had smartphones. Nine (28%) were TB/HIV-coinfected, receiving antiretroviral therapy. Emergent subthemes for facilitators of experienced usefulness and ease of VDOT use were SMS text message reminders, technology training support to patients by health care providers, timely patient-provider communication, family social support, and financial incentives. TB/HIV-coinfected patients reported the added benefit of adherence support for their antiretroviral medication. The external barriers to VDOT’s usefulness and ease of use were unstable electricity, technological malfunctions in the app, and lack of cellular network coverage in rural areas. Concerns about stigma, disease disclosure, and fear of breach in privacy and confidentiality affected the ease of VDOT use. ConclusionsOverall, participants had positive experiences with the enhanced VDOT. They found the enhanced VDOT system user-friendly, beneficial, and acceptable, particularly due to the supportive features such as SMS text message reminders, incentives, technology training by health care providers, and family support. However, it is crucial to address the barriers related to technological infrastructure as well as the privacy, confidentiality, and stigma concerns related to VDOT.

Background This paper aims to promote the use of simple interrupted time series (ITS) analyses of routine data as a responsive feedback tool to improve public health programs. Although advanced ITS techniques exist, their use is often not feasible due to limitations in funding or research capacity. We propose an Excel-based analysis that requires minimal resources or statistical expertise, and illustrate it by measuring the effect of a radio campaign to promote a family planning call center in Nigeria on the demand for family planning information. Methods We used a single group interrupted time series design (ITS) as a responsive feedback mechanism to determine whether the radio campaign influenced use of the Honey&Banana call center. ITS is ideal when there is no control group. ITS uses the pre-intervention trend to predict what would have happened if the intervention were absent. Results After conducting ITS analyses, the results show that the number of calls requesting family planning information increased throughout the campaign period, with a gain of about 500 additional calls per month, and then decreased after the campaign ended. However, the number of calls gained from the campaign was substantially lower than anticipated. Conclusions While end-of-project impact evaluations are necessary, there should be regular feedback system to provide program implementers with information about the status of the project, such as failures, successes, and areas of improvements. This would allow implementers to make necessary adjustments as needed throughout the intervention period. The finding that the radio campaign was not living up to expectations helped Honey&Banana program implementers to end the campaign prematurely and re-allocate resources to a more promising activity. Our research shows that basic Excel-based ITS analysis of routine data can be a useful tool for receiving regular feedback to guide programming improvements for organizations that have limited resources and/or research capacity.

Abstract Background Advocacy for equity in health service utilization and access, including Family Planning (FP) continues to be a cornerstone in increasing universal health coverage. Inequities in Family planning are highlighted by the differences in reproductive health outcomes or in the distribution of resources among different population groups. In this study we examine inequities in use of modern contraceptives with respect to Socio-economic and Education dimensions in seven sub-regions in Uganda. Methods The data were obtained from a baseline cross-sectional study in seven statistical regions where a program entitled “Reducing High Fertility Rates and Improving Sexual Reproductive Health Outcomes in Uganda, (RISE)” is implemented in Uganda. There was a total of 3,607 respondents, half of whom were women of reproductive age (15-49 years) and the other half men (18-54 years). Equity in family planning utilization was assessed by geography, wealth/economic and social-demographics. The use of modern family planning was measured as; using or not using modern FP. Concentration indices were used to measure the degree of Inequality in the use of modern contraceptives. Prevalence Ratios to compare use of modern FP were computed using modified Poisson regression run in STATA V15. Results Three-quarters (75.6%) of the participants in rural areas were married compared to only 63% in the urban. Overall use of modern contraceptives was 34.2% [CI:30.9, 37.6], without significant variation by rural/urban settings. Women in the higher socio-economic status (SES) were more advantaged in use of modern contraceptives compared to lower SES women. The overall Erreygers Concentration Index, as a measure of inequity, was 0.172, p

Objective: The study aimed to identify the current practice carried out by community pharmacists to dispose of expired medications in their workplace and assess any practical steps utilized to reduce medication waste. Method: A cross-sectional study was conducted among community pharmacists in the United Arab Emirates (UAE). The participants were asked about their routine practice in disposing of different expired medications and the current actions taken to reduce the number of disposed medicines. Results: The study included (n = 418) community pharmacists. More than a third of expired liquid, solid, and semi-solid dosage forms were collected by licensed contractors. In addition, more than a third of the pharmacists disposed of different dosage forms via unauthorized methods (general garbage, sink and toilet). Most expired drugs were skin and hair products, antibiotics and analgesics. The majority of pharmacists (68.4 %, n = 286) agreed that expired pharmaceutical and non-pharmaceutical products, other than those disposed of via contractor, should be done through a specialized centre. This opinion was found to be strongly associated with years of practice as community pharmacists (P

Lack of CD8+ T-cell infiltration into solid tumors is associated with poor responsiveness to immune checkpoint therapy (ICT). Here, the authors show that blocking the phosphorylation of HRS to reduce the induction of immunosuppressive exosomes promotes CD8+ T-cell infiltration into tumors and enhances the efficacy of ICT in mouse melanoma models.

Abstract Background Population ageing will accelerate rapidly in Mongolia in the coming decades. We explore whether this is likely to have deleterious effects on economic growth and health spending trends and whether any adverse consequences might be moderated by ensuring better health among the older population. Methods Fixed-effects models are used to estimate the relationship between the size of the older working-age population (55–69 years) and economic growth from 2020 to 2100 and to simulate how growth is modified by better health among the older working-age population, as measured by a 5% improvement in years lived with disability. We next use 2017 data on per capita health spending by age from the National Health Insurance Fund to project how population ageing will influence public health spending from 2020 to 2060 and how this relationship may change if the older population (≥ 60 years) ages in better or worse health than currently. Results The projected increase in the share of the population aged 55–69 years is associated with a 4.1% slowdown in per-person gross domestic product (GDP) growth between 2020 and 2050 and a 5.2% slowdown from 2020 to 2100. However, a 5% reduction in disability rates among the older population offsets these effects and adds around 0.2% to annual per-person GDP growth in 2020, rising to nearly 0.4% per year by 2080. Baseline projections indicate that population ageing will increase public health spending as a share of GDP by 1.35 percentage points from 2020 to 2060; this will occur slowly, adding approximately 0.03 percentage points to the share of GDP annually. Poorer health among the older population (aged ≥ 60 years) would see population ageing add an additional 0.17 percentage points above baseline estimates, but healthy ageing would lower baseline projections by 0.18 percentage points, corresponding to potential savings of just over US$ 46 million per year by 2060. Conclusions Good health at older ages could moderate the potentially negative effects of population ageing on economic growth and health spending trends in Mongolia. Continued investment in the health of older people will improve quality of life, while also enhancing the sustainability of public budgets.

Abstract Background Cross-sectional studies have reported that ventricular dilation and dysfunction are associated with adverse clinical outcome in Fontan patients; however, longitudinal changes and their relationship with outcome are not known. Methods This was a single-center retrospective analysis of Fontan patients with at least 2 cardiovascular magnetic resonance (CMR) scans without intervening interventions. Serial measures of end-diastolic volume index (EDVI), end-systolic volume index (ESVI), ejection fraction (EF), indexed mass (mass i ), mass-to-volume ratio, and end-systolic wall stress (ESWS) were used to estimate within-patient change over time. Changes were compared for those with and without a composite outcome (death, heart transplant, or transplant listing) as well as between patients with left (LV) and right ventricular (RV) dominance. Results Data from 156 patients were analyzed with a mean age at 1st CMR of 17.8 ± 9.6 years. 490 CMRs were included with median of 3 CMRs/patient (range 2–9). On regression analysis with mixed effects models, volumes and ESWS increased, while mass, mass-to-volume ratio, and EF decreased over time. With a median follow-up of 10.2 years, 14% met the composite outcome. Those with the composite outcome had a greater increase in EDVI compared to those without (4.7 vs. 0.8 ml/BSA1.3/year). Compared with LV dominance, RV dominance was associated with a greater increase in ESVI (1.4 vs. 0.5 ml/BSA1.3/year), a greater decrease in EF (− 0.61%/year vs. − 0.24%/year), and a higher rate of the composite outcome (21% vs. 8%). Conclusions Ventricles in the Fontan circulation exhibit a steady decline in performance with an increase in EDVI, ESVI, and ESWS, and decrease in EF, mass index, and mass-to-volume ratio. Those with death or need for heart transplantation have a faster increase in EDVI. Patients with rapid increase in EDVI (> 5 ml/BSA1.3/year) may be at a higher risk of adverse outcomes and may benefit from closer surveillance. RV dominance is associated with worse clinical outcomes and remodeling compared to LV dominance.

Plain English summary Approximately 9.6% of abortion-related deaths occur in Sub-Saharan Africa. These deaths can be prevented if unintended pregnancies are avoided, women can access safe abortions within the expectations of the country’s laws, and post abortion care (PAC) services are provided equitably. Previous research shows that women with abortion complications in the first trimester of pregnancy can be treated with misoprostol by either midwives or physicians. This sharing of tasks between the midwives and physicians is safe, effective, and acceptable. However, there is a gap in evidence on task sharing in the second trimester. To check practicability of task sharing in second trimester, we aimed to evaluate patient acceptability of treatment of incomplete second trimester abortion using misoprostol provided by midwives compared with physicians and also gained a deeper understanding of the patients’ lived treatment experiences. Our study therefore combined quantitative and qualitative approaches. Women’s acceptability of misoprostol treatment for incomplete second trimester abortion was found to be equally acceptable when provided by midwives compared with physicians. Treatment success, feeling calm and safe after treatment increased acceptability, while experience of side effects and worrying bleeding patterns reduced satisfaction. Counselling of women may address some of these problems since it provides reassurance and reduces anxiety. In settings that lack adequate staffing levels of physicians or where midwives are available to provide misoprostol, task sharing second trimester medical PAC with midwives increases patient’s access to PAC services.

Abstract Background To evaluate the relationship between measures of neuromuscular impairment and limb accelerations (LA) collected during sleep among individuals with chronic spinal cord injury (SCI) to provide evidence of construct and concurrent validity for LA as a clinically meaningful measure. Methods The strength (lower extremity motor score), sensation (summed lower limb light touch scores), and spasticity (categorized lower limb Modified Ashworth Scale) were measured from 40 adults with chronic (≥ 1 year) SCI. Demographics, pain, sleep quality, and other covariate or confounding factors were measured using self-report questionnaires. Each participant then wore ActiGraph GT9X Link accelerometers on their ankles and wrist continuously for 1–5 days to measure LA from movements during sleep. Regression models with built-in feature selection were used to determine the most relevant LA features and the association to each measure of impairment. Results LA features were related to measures of impairment with models explaining 69% and 73% of the variance (R²) in strength and sensation, respectively, and correctly classifying 81.6% (F1-score = 0.814) of the participants into spasticity categories. The most commonly selected LA features included measures of power and frequency (frequency domain), movement direction (correlation between axes), consistency between movements (relation to recent movements), and wavelet energy (signal characteristics). Rolling speed (change in angle of inclination) and movement smoothness (median crossings) were uniquely associated with strength. When LA features were included, an increase of 72% and 222% of the variance was explained for strength and sensation scores, respectively, and there was a 34% increase in spasticity classification accuracy compared to models containing only covariate features such as demographics, sleep quality, and pain. Conclusion LA features have shown evidence of having construct and concurrent validity, thus demonstrating that LA are a clinically-relevant measure related to lower limb strength, sensation, and spasticity after SCI. LA may be useful as a more detailed measure of impairment for applications such as clinical prediction models for ambulation.

The product formed by base-induced dimerisation of (2S,5S)-2-tert-butyl-5-methyl-1,3-dioxolan-4-one is shown by X-ray diffraction to be the title compound and not the isomeric fused-ring 1,3-dioxolane/1,3-dioxane-4-one structure proposed by previous researchers. The analogous compound derived from (2S,5S)-5-benzyl-2-tert-butyl-1,3-dioxolan-4-one has also been obtained and characterised.

Abstract Three‐dimensional (3D) charge‐written periodic peak and valley nanoarray surfaces are fabricated on a (112¯0) ZnO single crystal grown via chemical vapor transport. Because the grown ZnO crystals exhibit uniform n‐type conduction, 3D periodic nanoarray patterns are formed via oxygen annealing. These periodically decorated structures show that the peak arrays are conducting at the nanoampere level, whereas the valley arrays are less conductive. Energy dispersive spectroscopy indicates that the valley arrays are deficient in zinc by ≈4–6 at%, and that the peak arrays are deficient in oxygen, respectively. Kelvin probe force microscopy reveals the presence of periodic wiggles featuring variations of ≈70–140‐meV between the peak and valley arrays. A significant decrease in the Fermi level of the valley region is observed (≈190 meV), which corresponds to a high zinc vacancy doping density of 2 × 1018 cm−3. This result indicates the periodic generation of an extremely large electric field (≈11 000 V cm−1) in the vicinity of the peak–valley arrays. Computational analysis corroborates the experimentally observed generation of VZn and the preferential formation of surface protrusions on ZnO (112¯0) rather than on (0001), based on surface effects, along with the generation of peak and valley features.

The mammalian myocardium grows rapidly during early development due to cardiomyocyte proliferation, which later transitions to cell hypertrophy to sustain the heart’s postnatal growth. Although this cell transition in the postnatal heart is consistently preserved in mammalian biology, little is known about the regulatory mechanisms that link proliferation suppression with hypertrophy induction. We reasoned that the production of a micro-RNA(s) could serve as a key bridge to permit changes in gene expression that control the changed cell fate of postnatal cardiomyocytes. We used sequential expression analysis to identify miR205 as a micro-RNA that was uniquely expressed at the cessation of cardiomyocyte growth. Cardiomyocyte-specific miR205 deletion animals showed a 35% increase in heart mass by 3 months of age, with commensurate changes in cell cycle and Hippo pathway activity, confirming miR205’s potential role in controlling cardiomyocyte proliferation. In contrast, overexpression of miR205 in newborn hearts had little effect on heart size or function, indicating a complex, probably redundant regulatory system. These findings highlight miR205’s role in controlling the shift from cardiomyocyte proliferation to hypertrophic development in the postnatal period.

Background: Africa faces diverse and complex population/human health challenges due to climate change. Understanding the health impacts of climate change in Africa in all its complexity is essential for implementing effective strategies and policies to mitigate risks and protect vulnerable populations. This study aimed to outline the major climate change-related health impacts in Africa in the context of economic resilience and to seek solutions and provide strategies to prevent or reduce adverse effects of climate change on human health and well-being in Africa. Methods: For this narrative review, a literature search was conducted in the Web of Science, Scopus, CAB Abstracts, MEDLINE and EMBASE electronic databases. We also searched the reference lists of retrieved articles for additional records as well as reports. We followed a conceptual framework to ensure all aspects of climate change and health impacts in Africa were identified. Results: The average temperatures in all six eco-regions of Africa have risen since the early twentieth century, and heat exposure, extreme events, and sea level rise are projected to disproportionately affect Africa, resulting in a larger burden of health impacts than other continents. Given that climate change already poses substantial challenges to African health and well-being, this will necessitate significant effort, financial investment, and dedication to climate change mitigation and adaptation. This review offers African leaders and decision-makers data-driven and action-oriented strategies that will ensure a more resilient healthcare system and safe, healthy populations—in ways that contribute to economic resiliency. Conclusions: The urgency of climate-health action integrated with sustainable development in Africa cannot be overstated, given the multiple economic gains from reducing current impacts and projected risks of climate change on the continent’s population health and well-being. Climate action must be integrated into Africa’s development plan to meet the Sustainable Development Goals, protect vulnerable populations from the detrimental effects of climate change, and promote economic development.

Background: Over two-thirds of nursing home (NH) residents are eligible for palliative care (PC), yet few receive it, particularly outside of hospice. Little is known about the technical feasibility and acceptability of using telehealth for PC consultations in NHs. Objective: To determine the technical feasibility and acceptability of PC telehealth for NH residents seen by a PC team in the hospital in the previous 30 days. Design: Mixed methods study including data collection from field observations, focus groups about the telehealth experience with content analysis, and a web-based survey about technical feasibility and acceptability. Sample and Approach: Eighteen participants (six PC-eligible NH residents, one PC physician, five family members, six NH nurses) were recruited in 2016 to participate in one of six PC video visits followed by a video-based focus group and web-based survey. Results: All participants were comfortable with the PC video visit format, believed it could improve communication and care coordination, and reported they could see themselves using telehealth in the near future. For technical feasibility, audio quality was rated mostly good/very good (71%) and visual quality was rated fair (50%). Conclusions: PC video visits are technically feasible and acceptable to NH residents, families, and staff, representing an innovative and relatively low-cost opportunity to improve access to needed NH-based PC services. Assessing stakeholder perspectives on the use of this technology can help inform the selection of the proper telehealth platform to meet the clinical and infrastructure needs, as well as protocol modifications required before testing in a larger trial.