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Background and Objective: STS101 is an investigational drug-device combination comprising 5.2 mg dihydroergotamine (DHE) powder (6.0 mg DHE mesylate) in a single-use nasal delivery device for the acute treatment of migraine. The primary objective of the ASCEND trial was to assess long-term safety and tolerability of STS101 in the acute treatment of migraine attacks across 12-18 months, with secondary objectives describing efficacy., Methods: ASCEND was an open-label study of STS101 in adults aged 18-65 years with a ≥ 1 year history of migraine with or without aura, with onset before the age of 50 years and 4-12 migraine attacks/month and < 15 headache days/month in each of the 3 months prior to screening. Exclusion criteria included diagnosis of non-migraine headache, history of cerebrovascular disease, and ≥ 2 cardiovascular risk factors. After establishing eligibility, participants could self-administer STS101 5.2 mg as needed for up to 2 doses within 24 h to treat a single migraine attack and up to 12 doses/month. Safety and tolerability evaluations included physical and nasal examinations, vital signs, laboratory tests, and treatment-emergent adverse event (TEAE) assessments. Participants used an electronic diary to record exploratory efficacy parameters, including intensity of headache pain and associated migraine symptoms (photophobia, phonophobia, and nausea). Participant impression questions were asked at months 3, 6, and 12., Results: Of the 6610 migraine attacks treated with a total of 8234 STS101 doses in 344 participants, 945/6610 (14.3%) were associated with a TEAE. Events were predominantly mild or moderate in nature and rarely led to premature study discontinuation (15/344 [4.4%] participants). Treatment was associated with rapid onset of freedom from pain (36.6%, 67.1%, and 85.5% of treated attacks 2, 4, and 24 h post-dose, respectively), freedom from most bothersome symptoms (54.3%, 79.6%, and 91.3%), and headache relief (66.5%, 89.1%, and 94.3%). Most participants rated treatment results as good or very good and ease of use as easy or very easy at all time points (months 3, 6, and 12) and indicated they were likely or very likely to use STS101 again., Conclusions: The repeated long-term, as-needed use of STS101 was well tolerated, demonstrating a favorable safety profile in the acute treatment of migraine attacks in appropriately indicated adults. Exploratory efficacy evaluations indicated beneficial effects, which warrant further evaluation., Trial Registration: ClinicalTrials.gov identification NCT04406649., (© 2024. The Author(s).)

Photodynamic therapy delivers more targeted cell killing than classical chemotherapy. It uses light-absorbing compounds, photosensitizers (PSs), to generate lethal reactive oxygen species (ROS) at sites of localized irradiation. Transition metal complexes are attractive PSs due to their photostability, visible-light absorption, and high ROS yields. Here, we introduce a low-molecular weight, photostable iridium complex, [Ir(thpy) 2 (benz)]Cl, 1 , that localizes to the Golgi apparatus, mitochondria, and endoplasmic reticulum, absorbs visible light, phosphoresces strongly, generates 1 O 2 with 43% yield, and undergoes cellular elimination after 24 h. 1 shows low dark toxicity and under remarkably low doses (3 min, 20-30 mJ s -1 cm -2 ) of 405 or 455 nm light, it causes killing of bladder (EJ), malignant melanoma (A375), and oropharyngeal (OPSCC72) cancer cells, with high phototoxic indices > 100-378. 1 is also an efficient PS in 3D melanoma spheroids, with repeated short-time irradiation causing cumulative killing.

Comparative studies suggest remarkable similarities among food webs across habitats, including systematic changes in their structure with diversity and complexity (scale-dependence). However, historic aboveground terrestrial food webs (ATFWs) have coarsely grouped plants and insects such that these webs are generally small, and herbivory is disproportionately under-represented compared to vertebrate predator-prey interactions. Furthermore, terrestrial herbivory is thought to be structured by unique processes compared to size-structured feeding in other systems. Here, we present the richest ATFW to date, including approximately 580 000 feeding links among approximately 3800 taxonomic species, sourced from approximately 27 000 expert-vetted interaction records annotated as feeding upon one of six different resource types: leaves, flowers, seeds, wood, prey and carrion. By comparison to historical ATFWs and null ecological hypotheses, we show that our temperate forest web displays a potentially unique structure characterized by two properties: (i) a large fraction of carnivory interactions dominated by a small number of hyper-generalist, opportunistic bird and bat predators; and (ii) a smaller fraction of herbivory interactions dominated by a hyper-rich community of insects with variably sized but highly specific diets. We attribute our findings to the large-scale, even resolution of vertebrate, insect and plant guilds in our food web.This article is part of the theme issue 'Connected interactions: enriching food web research by spatial and social interactions'.

Because it can lead to retaliatory killing, livestock depredation by large carnivores is among the foremost threats to carnivore conservation, and it severely impacts human well-being worldwide. Ongoing climate change can amplify these human-wildlife conflicts, but such issues are largely unexplored, though are becoming increasingly recognized. Here, we assessed how the availability of primary resources and wild prey interact to shape large carnivore selection for livestock rather than wild prey (i.e., via prey switching or apparent competition). Specifically, we combined remotely sensed estimates of primary resources (i.e., water availability and primary productivity), wild prey movement, and 7 years (2015-2021) of reports for livestock depredation by African lions ( Panthera leo ) in the Makgadikgadi Pans ecosystem, Botswana. Although livestock depredation did not vary between wet versus dry seasons, analyses at finer temporal scales revealed higher incidences of livestock depredation when primary production, water availability, and wild prey availability were lower, though the effects of wild prey availability were mediated by water availability. Increased precipitation also amplified livestock depredation events despite having no influence on wild prey availability. Our results suggest that livestock depredation is influenced by the diverse responses of livestock, wild prey, and lions to primary resource availability, a driver that is largely overlooked or oversimplified in studies of human-carnivore conflict. Our findings provide insight into tailoring potential conflict mitigation strategies to fine-scale changes in resource conditions to efficiently reduce conflict and support human livelihoods., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Ecology and Evolution published by John Wiley & Sons Ltd.)

The ability to spatially map multiple layers of the omics information over different time points allows for exploring the mechanisms driving brain development, differentiation, arealization, and alterations in disease. Herein we developed and applied spatial tri-omic sequencing technologies, DBiT ARP-seq (spatial ATAC-RNA-Protein-seq) and DBiT CTRP-seq (spatial CUT&Tag-RNA-Protein-seq) together with multiplexed immunofluorescence imaging (CODEX) to map spatial dynamic remodeling in brain development and neuroinflammation. A spatiotemporal tri-omic atlas of the mouse brain was obtained at different stages from postnatal day P0 to P21, and compared to the regions of interest in the human developing brains. Specifically, in the cortical area, we discovered temporal persistence and spatial spreading of chromatin accessibility for the layer-defining transcription factors. In corpus callosum, we observed dynamic chromatin priming of myelin genes across the subregions. Together, it suggests a role for layer specific projection neurons to coordinate axonogenesis and myelination. We further mapped the brain of a lysolecithin (LPC) neuroinflammation mouse model and observed common molecular programs in development and neuroinflammation. Microglia, exhibiting both conserved and distinct programs for inflammation and resolution, are transiently activated not only at the core of the LPC lesion, but also at distal locations presumably through neuronal circuitry. Thus, this work unveiled common and differential mechanisms in brain development and neuroinflammation, resulting in a valuable data resource to investigate brain development, function and disease.

Background: Recent studies show e-cigarette (EC) users have increased rates of chronic bronchitic symptoms that may be associated with depressed mucociliary clearance (MCC). Little is known about the acute or chronic effects of EC inhalation on in vivo MCC. Methods: In vivo MCC was measured in young adult vapers ( n  = 5 males, mean age = 21) after controlled inhalation of a radiolabeled (Tc99m sulfur colloid) aerosol. Whole-lung clearance of radiolabeled deposited particles was measured over a 90-minute period for baseline MCC and associated with controlled periodic vaping over the first 60 minutes of MCC measurements. The vaping challenge was administered from a fourth generation box mod EC containing unflavored e-liquid (65% propylene glycol/35% vegetable glycerin, 3 mg/mL freebase nicotine). The challenge was administered at the start of each 10-minute interval of MCC measurements and consisted of 1 puff every 30 seconds for 5 minutes (i.e., 10 puffs for each 10-minute period for a total of 60 puffs during the initial 60 minutes of MCC measurements). Results: Compared with baseline, peripheral lung average clearance (%) over the 90 minutes of MCC measures was enhanced, associated with EC challenge, 12 (±6) versus 24 (±6), respectively ( p  < 0.05 by Wilcoxon signed-rank test). Conclusions: Acute enhancement of in vivo MCC during EC challenge is contrary to recent studies showing nicotine-associated slowing of ciliary beat and mucus transport at higher nicotine levels than those used here. However, our findings are consistent with an acute increase in fluid volume and mucin secretion to the bronchial airway surface that is likely short lived. Research reported in this publication was supported by the National Institutes of Health R01HL139369 and registered with ClinicalTrials.gov (NCT03700892).

Introduction: Loneliness has been identified as an important public health issue, peaking during adolescence. Previous research has suggested that social interaction is a key factor in loneliness, and positive social interaction can act as a protective factor against loneliness. However, it is unclear whether there are differing impacts of in-person and online social interaction on adolescents' loneliness and mental health. Ecological Momentary Assessment (EMA) designs are ideally suited for better understanding these associations., Method and Analysis: In the 'Loneliness in the Digital World' study, we will use a co-developed EMA design to capture daily social interactions, loneliness and mental health such as positive and negative emotions, depression and anxiety in approximately 200 adolescents aged 12-15 years. We will combine this with comprehensive information gathered from online surveys. Analysing the data using techniques such as dynamic structural equation modelling, we will examine, among other research questions, the associations between online and in-person social interaction and feelings of loneliness. The results can help inform interventions to support adolescents with high levels of loneliness and poor mental health., Ethics and Dissemination: We received the ethics approval for the data collection from The Academic and Clinical Central Office for Research and Development, followed by the College of Medicine and Veterinary Medicine Ethics panel at University of Edinburgh, and finally reviewed by East of Scotland Research Ethics Service. The results will be disseminated through journal publications, conferences and seminar presentations and to relevant stakeholders such as teachers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Perfluorododecyl iodide (I-PFC12) is of interest for area-selective deposition (ASD) applications as it exhibits intriguing properties such as ultralow surface energy, the ability to modify silicon's band gap, low surface friction, and suitability for micro-contact patterning. Traditional photolithography is struggling to reach the required critical dimensions. This study investigates the potential of using I-PFC12 as a way to produce contrast between the growth area and non-growth areas of a surface subsequent to extreme ultraviolet (EUV) exposure. Once exposed to EUV, the I-PFC12 molecule should degrade with the help of the photocatalytic substrate, allowing for the subsequent selective deposition of the hard mask. The stability of a vapor-deposited I-PFC12 self-assembled monolayer (SAM) was examined when exposed to ambient light for extended periods of time by using X-ray photoelectron spectroscopy (XPS). Two substrates, SiO 2 and TiO 2 , are investigated to ascertain the suitability of using TiO 2 as a photocatalytic active substrate. Following one month of exposure to light, the atomic concentrations showed a more substantial fluorine loss of 10.2% on the TiO 2 in comparison to a 6.2% loss on the SiO 2 substrate. This more pronounced defluorination seen on the TiO 2 is attributed to its photocatalytic nature. Interestingly, different routes to degradation were observed for each substrate. Reference samples preserved in dark conditions with no light exposure for up to three months show little degradation on the SiO 2 substrate, while no change is observed on the TiO 2 substrate. The results reveal that the I-PFC12 SAM is an ideal candidate for resistless EUV lithography.

Aim: To explore factors affecting participation in the pilot of the synchronous online national diabetes prevention programme (NDPP) in Ireland from the perspectives of those who attended and the educators who recruited for and delivered the programme., Methods: A qualitative study involving semi-structured interviews and focus groups with NDPP attenders (attended the assessment and at least one session) and educators (dietitians) on the programme. The Framework Method using the Theoretical Domains Framework (TDF) guided the analysis., Results: Thirteen attenders took part in two online focus groups and five online or phone interviews. Eight educators took part. Four themes which cut across the TDF domains were identified as factors influencing participation; (i) lack of awareness of prediabetes and fear of diabetes, relating to attenders' fear of diabetes and lack of knowledge of prediabetes and diabetes prevention; (ii) perceived need for programme support to change health behaviour, concerning attenders' and educators' recognition of the need for the NDPP; (iii) trust in healthcare professionals (HCPs), relating to trust in HCPs to convey the seriousness of prediabetes and the value of diabetes prevention programmes (DPPs) and (iv) practical and personal ease of joining online, relating to the flexibility and accessibility of the synchronous online group format, the IT skills of attenders and educators and apprehension about group education., Conclusions: Raising awareness of prediabetes and the need for prevention programmes should be a priority for health services and HCPs. The synchronous online group format was seen as less daunting to join than a face-to-face programme and may be a useful option to encourage participation., (© 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Aims: Research capacity strengthening (RCS) is crucial in enhancing healthcare outcomes, particularly in low- and middle-income countries (LMICs), which face challenges due to limited resources, unequal access to care and the need for evidence-based decision-making. We seek to move beyond a surface-level understanding of RCS, unearthing the core attributes, the factors that precede its implementation and the transformative outcomes it generates within the LMIC healthcare landscape., Design: This study employs the Walker and Avant approach to concept analysis to comprehensively explore the dimensions and attributes of RCS as it pertains to allied and public health professionals in LMICs, propose empirical referents and suggest an operational definition., Data Sources: Ovid MEDLINE, Embase, CINAHL and Cochrane CENTRAL were searched from inception to 27 July 2023, to identify studies on RCS in LMICs. The Walker and Avant approach to concept analysis was selected because it provides a framework for systematically examining and clarifying the meaning and implications of RCS. This method involves a structured process of defining RCS, identifying its attributes, antecedents, consequences and cases, and ultimately providing a clear understanding of its meaning and implications. Identifying empirical referents offers measurable indicators that researchers and policymakers can use to assess the effectiveness of RCS initiatives in LMICs., Conclusion: RCS for health professionals in LMICs involves a sustainable process that equips them with essential research skills, fostering the ability to conduct high-quality research and improve healthcare delivery in resource-constrained settings., Implications: RCS aims to empower health professionals to apply evidence-based practices, reduce disparities and enhance the well-being of populations in LMICs., Impact: Ultimately, a concept analysis of RCS empowers us to harness the full potential of research to enhance healthcare delivery, improve patient outcomes and advance the well-being of populations worldwide., (© 2024 The Authors. Journal of Advanced Nursing published by John Wiley & Sons Ltd.)

Pesticides have well-documented negative consequences to control crop pests, and natural predators are alternatives and can provide an ecosystem service as biological control agents. However, there remains considerable uncertainty regarding whether such biological control can be a widely applicable solution, especially given ongoing climatic variation and climate change. Here, we performed a meta-analysis focused on field studies with natural predators to explore broadly whether and how predators might control pests and in turn increase yield. We also contrasted across studies pest suppression by a single and multiple predators and how climate influence biological control. Predators reduced pest populations by 73% on average, and increased crop yield by 25% on average. Surprisingly, the impact of predators did not depend on whether there were many or a single predator species. Precipitation seasonality was a key climatic influence on biological control: as seasonality increased, the impact of predators on pest populations increased. Taken together, the positive contribution of predators in controlling pests and increasing yield, and the consistency of such responses in the face of precipitation variability, suggest that biocontrol has the potential to be an important part of pest management and increasing food supplies as the planet precipitation patterns become increasingly variable.

Background: Zirconia is a widely used material in the dental industry due to its excellent mechanical and aesthetic properties. Recently, a new 3D printing process called suspension-enclosing projection stereolithography (SEPS) was introduced to fabricate zirconia dental restorations. However, the effect of the sintering time and temperature on the properties of zirconia produced via SEPS has not been fully investigated., Methods: Zirconia slurries were prepared with varying percentages of zirconia powders and 3D printing resins, and 5Y-TZP (5 mol% yttria-stabilized zirconia) ( n = 40) and 3Y-TZP (3 mol% yttria-stabilized zirconia) ( n = 40) bar specimens were fabricated via SEPS manufacturing. The specimens were sintered at different temperatures and dwell times, and their flexural strength, density, and phase composition were measured. The viscosity of the slurries was also measured. Statistical analysis was performed using Welch's ANOVA and Kruskal-Wallis tests to evaluate the impact of the sintering conditions., Results: Significant differences in flexural strength ( p < 0.01) were observed between the 5Y-TZP samples, with those sintered at 1530 °C for 120 min showing an average strength of 268.34 ± 44.66 MPa, compared to 174.16 ± 42.29 MPa for those sintered at 1450 °C for 120 min. In terms of density, significant differences ( p < 0.01) were noted for the 3Y-TZP specimens, with an average density of 6.66 ± 0.49 g/cm 3 for samples sintered at 1530 °C for 120 min, versus 5.75 ± 0.55 g/cm 3 for those sintered at 1530 °C for 10 min. X-ray diffraction confirmed the presence of a predominantly tetragonal phase in both materials., Conclusions: Zirconia printed via SEPS manufacturing can be sintered at a higher temperature with shorter dwell times, thereby producing high density samples. Different sintering conditions can be used to fully sinter 3D-printed zirconia for potential dental applications.

Wide-ranging carnivores experience tradeoffs between dynamic resource availabilities and heterogeneous risks from humans, with consequences for their ecological function and conservation outcomes. Yet, research investigating these tradeoffs across large carnivore distributions is rare. We assessed how resource availability and anthropogenic risks influence the strength of lion (Panthera leo) responses to disturbance using data from 31 sites across lions' contemporary range. Lions avoided human disturbance at over two-thirds of sites, though their responses varied depending on site-level characteristics. Lions were more likely to exploit human-dominated landscapes where resources were limited, indicating that resource limitation can outweigh anthropogenic risks and might exacerbate human-carnivore conflict. Lions also avoided human impacts by increasing their nocturnal activity more often at sites with higher production of cattle. The combined effects of expanding human impacts and environmental change threaten to simultaneously downgrade the ecological function of carnivores and intensify human-carnivore conflicts, escalating extinction risks for many species., (© 2023. Springer Nature Limited.)

Objective: To explore how patients, community-based perinatal support professionals, and health system clinicians and staff perceived facilitators and barriers to implementation of a randomized clinical trial (RCT) designed to optimize Black maternal heart health., Methods: This article describes the formative work that we believed needed to occur before the start of the Change of H.E.A.R.T (Here for Equity, Advocacy, Reflection and Transformation) RCT. We used a qualitative, descriptive design and community-based, participatory approach, the latter of which allowed our team to intentionally focus on avoiding harm and equalizing power dynamics throughout the research process. Data were collected between November 2021 and January 2022 through six semistructured focus groups that included attending physicians and midwives (n=7), residents (n=4), nurses (n=6), support staff (n=7), community-based perinatal support professionals (n=6), and patients (n=8)., Results: Four primary themes emerged. The first three themes were present across all groups and included: 1) Trauma in the Community and Health System, 2) Lack of Trust, and 3) Desire to Be Heard and Valued. The fourth theme, Hope and Enthusiasm, was expressed predominantly by patients, community-based perinatal support professionals, residents, and support staff, and less so by the attending physician group., Conclusion: Participants articulated a number of key sentiments regarding facilitators and barriers to implementing Change of H.E.A.R.T. We noted variability in perceptions from different groups. This has important implications for health equity efforts in similarly underresourced health systems where Black birthing people experience the greatest morbidity and mortality., Clinical Trial Registration: ClinicalTrials.gov, NCT05499507., Competing Interests: Financial Disclosure The authors did not report any potential conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Face masks reduce disease transmission by protecting the wearer from inhaled pathogens and reducing the emission of infectious aerosols. Although methods quantifying efficiency for wearer protection are established, current methods for assessing face mask containment efficiency rely on measurement of a low concentration of aerosols emitted from an infected or noninfected individual., Methods: A small port enabled the introduction of 0.05 µm sodium chloride particles at a constant rate behind the mask worn by a study participant. A condensation particle counter monitored ambient particle numbers 60 cm in front of the participant over 3-minute periods of rest, speaking, and coughing. The containment efficiency (%) for each mask and procedure was calculated as follows: 100 × (1 - average ambient concentration with face covering worn/average ambient concentration with a sham face covering in place). The protection efficiency (%) was also measured using previously published methods. The probability of transmission (%) from infected to uninfected (a function of both the containment efficiency and the protection efficiency) was calculated as follows: {1 - (containment efficiency/100)}×{1 - (protection efficiency/100)}×100., Results: The average containment efficiencies for each mask over all procedures and repeated measures were 94.6%, 60.9%, 38.8%, and 43.2%, respectively, for the N95 mask, the KN95 mask, the procedure face mask, and the gaiter. The corresponding protection efficiencies for each mask were 99.0%, 63.7%, 45.3%, and 24.2%, respectively. For example, the transmission probability for 1 infected and 1 uninfected individual in close proximity was ∼14.2% for KN95 masks, compared to 36%-39% when only 1 individual wore a KN95 mask., Conclusion: Overall, we detected a good correlation between the protection and containment that a face covering afforded to a wearer.

Lay Abstract: The Autism Act 10 Years On found few autistic adults thought health and social care professionals had a good understanding of autism. Autism training has been made law in the United Kingdom for health and social care staff to tackle health inequality. The county wide Autism Champion Network evaluated here is an equal partnership of interested staff across sectors (Autism Champions) and autistic experts by virtue of lived experience (Autism Advisory Panel). With knowledge flowing both ways, the Autism Champions take learning back to teams to support continuous development of services to meet autistic need. Seven health and social sector professionals from the Network participated in semi-structured interviews on sharing knowledge of autism gained with their teams. All participants provide care and support for autistic people, some working in specialist positions. Results showed that developing new relationships with people outside their own team to signpost to, answer questions and share resources, and informal learning from autistic people, was more valued and used in practice than information gained from presentations. These results have implications in developing learning for those who need above a basic knowledge of autism and may be useful for others considering setting up an Autism Champion Network.

Amid a growing disciplinary commitment to inclusion in ecology and evolutionary biology (EEB), it is critical to consider how the use of scientific language can harm members of our research community. Here, we outline a path for identifying and revising harmful terminology to foster inclusion in EEB., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Multi-output Gaussian process (MGP) has been attracting increasing attention as a transfer learning method to model multiple outputs. Despite its high flexibility and generality, MGP still faces two critical challenges when applied to transfer learning. The first one is negative transfer, which occurs when there exists no shared information among the outputs. The second challenge is the input domain inconsistency, which is commonly studied in transfer learning yet not explored in MGP. In this paper, we propose a regularized MGP modeling framework with domain adaptation to overcome these challenges. More specifically, a sparse covariance matrix of MGP is constructed using convolution process, where penalization terms are added to adaptively select the most informative outputs for knowledge transfer. To deal with the domain inconsistency, a domain adaptation method is proposed by marginalizing inconsistent features and expanding missing features to align the input domains among different outputs. Statistical properties of the proposed method are provided to guarantee the performance practically and asymptotically. The proposed framework outperforms state-of-the-art benchmarks in comprehensive simulation studies and one real case study of a ceramic manufacturing process. The results demonstrate the effectiveness of our method in dealing with both the negative transfer and the domain inconsistency.

Background: Cutaneous vulval Crohn disease (VCD) is an under-recognised extra-intestinal manifestation of Crohn disease (CD) which is challenging to identify and treat. It causes significant oedema, painful deep fissures, and has potential to cause permanent disfiguring changes to vulval anatomy. There is no agreement on the best management for VCD., Objectives: This systematic review evaluates the use of metronidazole for the treatment of VCD in women and children., Methods: We conducted a systematic review (PROSPERO CRD42021285033) of the use of metronidazole in clinically or histologically diagnosed non-contiguous VCD in patients of all ages and ethnicities. We recorded clinical improvement, reduction in flares, relapse and adverse events using a standardised form., Results: 49 records (40 case reports and 9 case series) met inclusion criteria, comprising a total of 57 patients with an age range of 5-61 years. The most reported presenting features in VCD were: oedema, erythema, ulcers/fissures and induration/thickening. Gastrointestinal CD was present in 33/57 (58%). Vulval biopsies were undertaken in 47/57 (83%). Daily doses ranged from 250 to 1500 mg with treatment duration 8 days to 18 months. Improvement of any magnitude was observed in 40/57 (70%) cases. Relapse was described in 11/57 (19%) cases. No response/worsening was reported in 17/57 (30%) cases. Adverse events occurred in two patients., Conclusion: Metronidazole appears to be useful in managing VCD, either as a primary treatment or adjunctive therapy. However, the evidence is insufficient for firm conclusions to be drawn. Further studies including randomised controlled trials are recommended., Competing Interests: None to declare., (© 2023 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

High-quality peer-reviewer training open to researchers across the globe has the potential to improve the published literature, however, this type of training is not widely available. In this paper, we describe an online peer-reviewer training programme, highlight its effectiveness in building peer review and writing skills, and discuss challenges and lessons learnt. This training programme, open to researchers across the globe, acquaints participants with challenges to and inequities in publishing and educates them about writing effective peer reviews. A focal point is how to provide specific and respectful feedback to help authors get accepted for peer review at an academic journal. Forty-nine participants from or residing in six continents completed the training. All programme evaluation respondents agreed that the orientation helped them gain a better understanding of their role as a peer reviewer at Pre-Publication Support Service. Most agreed that the training was helpful in improving their peer-review skills, and that the training was helpful in improving their writing skills. Participants wanted more networking and collaboration opportunities with other peer reviewers, inclusion of a qualitatively researched example paper and improved communication about the required time commitment. Our online programme with multiple time options was geographically inclusive but internet connectivity was challenging for some participants. Peer-reviewer training programmes can help researchers build their peer review and writing skills and enhance participants' understanding of disparities in publishing. Integrating a geographically diverse group of researchers has the potential to enrich the discussions and learning in such a programme., Competing Interests: Competing interests: EA is the founder and editor-in-chief of the non-profit organisation PREPSS (Pre-Publication Support Service) and the programme described in the paper is a PREPSS programme. VMD and JMB are PREPSS peer reviewers, though they were not participants in the training programme described in the paper. KLM is employed by PREPSS. YRS and TE are funded by the Center for International Reproductive Health Training (CIRHT) at the University of Michigan and this organisation is one of PREPSS’s primary research partners and the funder of this manuscript. Though these are competing interests, it would be impossible to write this paper if we were not affiliated with the organisation., (© 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.)

Aberrant cell-cycle progression is characteristic of melanoma, and CDK4/6 inhibitors, such as palbociclib, are currently being tested for efficacy in this disease. Despite the promising nature of CDK4/6 inhibitors, their use as single agents in melanoma has shown limited clinical benefit. Herein, we discovered that treatment of tumor cells with palbociclib induces the phosphorylation of the mRNA translation initiation factor eIF4E. When phosphorylated, eIF4E specifically engenders the translation of mRNAs that code for proteins involved in cell survival. We hypothesized that cancer cells treated with palbociclib use upregulated phosphorylated eIF4E (phospho-eIF4E) to escape the antitumor benefits of this drug. Indeed, we found that pharmacologic or genetic disruption of MNK1/2 activity, the only known kinases for eIF4E, enhanced the ability of palbociclib to decrease clonogenic outgrowth. Moreover, a quantitative proteomics analysis of melanoma cells treated with combined MNK1/2 and CDK4/6 inhibitors showed downregulation of proteins with critical roles in cell-cycle progression and mitosis, including AURKB, TPX2, and survivin. We also observed that palbociclib-resistant breast cancer cells have higher basal levels of phospho-eIF4E, and that treatment with MNK1/2 inhibitors sensitized these palbociclib-resistant cells to CDK4/6 inhibition. In vivo we demonstrate that the combination of MNK1/2 and CDK4/6 inhibition significantly increases the overall survival of mice compared with either monotherapy. Overall, our data support MNK1/2 inhibitors as promising drugs to potentiate the antineoplastic effects of palbociclib and overcome therapy-resistant disease., (©2022 American Association for Cancer Research.)

Objectives and Design: Information about providing professional and appropriate perinatal care to transgender men in the perinatal setting is scarce, and healthcare providers often have insufficient knowledge or skills to provide this care. In response, a quality improvement educational program for nursing staff was developed and implemented, with the goal of evaluating the impact of this intervention on nurses' knowledge, skills, and attitudes when caring for pregnant transgender men., Setting and Participants: The training was offered to nursing staff of a 24-bed inpatient perinatal unit at a large, private academic medical center in a major East Coast city during the unit's quarterly staff meeting in March 2020., Intervention: The training covered the provision of affirming and inclusive perinatal care for transgender men. The content of the training was based on recommendations in the literature and reviewed by content experts., Measurements: Pre-test (N = 55) and post-test (N = 23) online self-administered surveys assessed nursing staff's knowledge of, comfort, and interest in providing gender affirming care for transgender men. Mann-Whitney U and Fischer's exact tests were used to determine significant changes in knowledge and attitudes over time., Findings: Findings suggest the training improved nursing staff's self-reported knowledge and skills in providing gender affirming care to pregnant transgender men over time, with participants demonstrating improved knowledge about communication around pronouns, gender identity, reproductive systems, and obstetric history. Awareness of resources for both professional development and to refer transgender patients also improved. However, persistent deficits in other knowledge, skills, and attitudes remained, suggesting that nurses would likely benefit from further support and training in transgender-specific health issues., Key Conclusions and Implications for Practice: Findings support the utility of unit-based training in improving affirming and inclusive care in the perinatal setting. This highlights opportunities for supporting nurses' professional practice of caring for transgender patients experiencing pregnancy and may be adapted for use in other specialty units., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: In urban areas, numerous barriers exist for children and families to access needed behavioral health care. Compounding the general deficit of behavioral health workers in the United States is lack of access to culturally responsive care. Additional challenges include inherent racism and oppression in our health and human service systems and siloed approaches to behavioral health care training and practice. Integrated care is an emerging field nationally, yet training and education in integrated care is limited. This article provides an overview of the Child/Adolescent Interprofessional Practice and Education (CAIPE) program, a novel training approach in its first year of implementation for behavioral health students that prioritizes trauma-informed and social-justice oriented practice, integrated care, and interprofessional teamwork., Method: This study employs a mixed-methods approach to program evaluation. Data sources include program application materials (demographics and data related to clinical interests, student goals, and preparedness for interprofessional work). Data is also drawn from measures of student outcomes (self-efficacy navigating complex care patients, empathy, and complex care knowledge)., Results: Baseline data are reported for demographics, students' goals and interprofessional interests, and student outcomes. Information is also presented relevant to trainings conducted in the grant's first year and planned for subsequent years. Preliminary data and implementation suggest that the program has drawn diverse trainees who are committed to interprofessional, integrated care for underserved youth., Discussion: Recruitment and program development challenges are discussed, along with grant goals' fit with students' interests and plans for future evaluation. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Facial feminization surgery (FFS) is an integral aspect of gender-affirming surgery (GAS) for individuals seeking to align secondary sex characteristics and gender identity. Despite the importance of FFS in treating gender dysphoria, current trends and prevalence remain unknown. We sought to examine trends in GAS and FFS and investigate the payer status of facial feminization procedures in the United States., Methods: Data was extracted from the National Inpatient Sample from 2008 to 2017 by using International Classification of Diseases Ninth or Tenth diagnosis codes for gender identity disorder and procedure codes for FFS., Results: From 2008 to 2017, 3015 patients underwent GAS. The yearly number of cases increased as did the average cost of GAS, which rose from $13,657 in 2008 to $50,789 in 2017. From 2015 to 2017, when FFS data was available, 110 of 1215 (9.1%) GAS patients had FFS. Most were non-Hispanic White (66.7%) or Black (23.8%). Fifty percent of FFS cases occurred in the West, followed by the Northeast (31.8%), South (13.6%), and Midwest (4.8%) ( P = 0.015). By payer the cases were, 36.4% self-pay, 31.8% Medicaid, and 27.3% private insurance ( P < 0.0001). Approximately, 18% of patients undergoing male-to-female transition received FFS., Conclusions: From 2008 to 2017, GAS cases increased nationwide while the average cost of surgery rose steeply. FFS cases were primarily in the Western and Northeast United States. Despite high cost, roughly 18% of transgender women in our sample received FFS, highlighting the importance of FFS in gender transition., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Total and regional deposition of inhaled electronic cigarette (E-cig) particles in the respiratory tract (RT) depends on both physical properties of the inhaled particles and biological factors of users, for example, breathing pattern or puff profile, airway anatomy, and regional ventilation. Accurate particle sizing of E-cig aerosols is essential for predicting particle deposition in the RT. Studies using a variety of sizing methods have shown mass median aerodynamic diameters ranging from 0.2 to 1.2 um and secondary count diameters in the ultrafine range (<0.1 μm). Incorporating these particle sizes into a multiple-path particle dosimetry (MPPD) model shows 10% to 45% total lung deposition by mass and 30% to 80% for ultrafine particles depending on the breathing patterns. These predictions are consistent with experimental measures of deposition fraction of submicron and ultrafine particles. While box-mod-type E-cig devices allow for full "direct-lung" inhalations of aerosol, the more recent pod-based, and disposable E-cigs (e.g., JUUL, Puff Bar, Stig) deliver the aerosol as a "mouth-to-lung" puff, or bolus, that is inhaled early in the breath followed to various degrees by further inhalation of ambient air. Measurement of realistic ventilation patterns associated with these various devices may further improve deposition predictions. Finally, while in vivo measures of RT deposition present a challenge, a recent methodology to radiolabel E-cig particles may allow for such measurements by gamma scintigraphy. Supported by NIH/NHLBI R01HL139369. © 2022 American Physiological Society. Compr Physiol 12: 1-10, year., (Copyright © 2022 American Physiological Society. All rights reserved.)

Dimethyl sulphoxide (DMSO) used in haematopoietic stem cell (HSC) cryopreservation has been linked to an increased incidence of adverse reactions following transplantation. In the interest of reducing the required DMSO concentrations, we have evaluated the use of unilamellar liposomes to internalize the non-toxic, cell-impermeable disaccharide, trehalose into HSCs and characterized the cryoprotective efficacy of this strategy. A fluorescent marker, 5(6)-carboxyfluorescein (200 μmol/L), was used for trehalose internalization following a 5 h incubation at 37 °C with liposome concentrations ranging from 0.5 mM to 4 mM. Cells were frozen (1 °C/min to -80 °C) following treatment with either 3 mM or 4 mM of liposomes (5 h, 37 °C) containing 0.2 mol/L trehalose either in the presence or absence of 0.2 mol/L extracellular trehalose. Increasing the liposome concentration from 3 mM to 4 mM corresponded to a significant (p = 0.046) increase in the mean fluorescent intensity (MFI) (3 mM 512 ± 7.07; 4 mM: 916 ± 28.3). Post-thaw membrane integrity indicated that the presence of trehalose both inside and outside when internalized using a liposome concentration of 4 mM significantly improved survival relative to the sole presence of extracellular trehalose (p = 0.02). However, viability was diminished relative to a standard DMSO control (trehalose: 32.5% ± 1.7%; DMSO: 85.0% ± 4.6%). This study confirms that the protective efficacy of trehalose is enhanced when it is present on both sides of the membrane; however, it reinforces concerns surrounding the efficiency of using liposomes as a vehicle to transfer trehalose into cells., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Breast implant surgery remains one of the most common surgical procedures performed in the United States. Implant exchange can be complicated by unavailability of medical records or implant identification cards. Using chest imaging of 154 breast implants, an algorithm for estimating breast implant volume was generated. Based on four simple measurements and patient body mass index, a free, online calculator was created with a mean error of volume estimate of less than 1 cm 3 and a SD of 44 cm 3 . In instances where a surgeon does not have implant records available but has chest imaging, this online tool can be used to obtain a relatively accurate estimate of implant volume., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Multiple sclerosis (MS) is characterized by a targeted attack on oligodendroglia (OLG) and myelin by immune cells, which are thought to be the main drivers of MS susceptibility. We found that immune genes exhibit a primed chromatin state in single mouse and human OLG in a non-disease context, compatible with transitions to immune-competent states in MS. We identified BACH1 and STAT1 as transcription factors involved in immune gene regulation in oligodendrocyte precursor cells (OPCs). A subset of immune genes presents bivalency of H3K4me3/H3K27me3 in OPCs, with Polycomb inhibition leading to their increased activation upon interferon gamma (IFN-γ) treatment. Some MS susceptibility single-nucleotide polymorphisms (SNPs) overlap with these regulatory regions in mouse and human OLG. Treatment of mouse OPCs with IFN-γ leads to chromatin architecture remodeling at these loci and altered expression of interacting genes. Thus, the susceptibility for MS may involve OLG, which therefore constitutes novel targets for immunological-based therapies for MS., Competing Interests: Declaration of interests H.Y.C. is a co-founder of Accent Therapeutics and Boundless Bio and an advisor to 10x Genomics, Arsenal Biosciences, and Spring Discovery. D.M. and D.C. are employees at Roche Pharma Research and Early Development. The other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Predation is a fundamental ecological process that shapes communities and drives evolutionary dynamics. As the world rapidly urbanizes, it is critical to understand how human perturbations alter predation and meat consumption across taxa. We conducted a meta-analysis to quantify the effects of urban environments on three components of trophic ecology in predators: dietary species richness, dietary evenness and stable isotopic ratios (IRs) ( δ 13 C and δ 15 N IR). We evaluated whether the intensity of anthropogenic pressure, using the human footprint index (HFI), explained variation in effect sizes of dietary attributes using a meta-regression. We calculated Hedges' g effect sizes from 44 studies including 11 986 samples across 40 predatory species in 39 cities globally. The direction and magnitude of effect sizes varied among predator taxa with reptilian diets exhibiting the most sensitivity to urbanization. Effect sizes revealed that predators in cities had comparable diet richness, evenness and nitrogen ratios, though carbon IRs were more enriched in cities. We found that neither the 1993 nor 2009 HFI editions explained effect size variation. Our study provides, to our knowledge, the first assessment of how urbanization has perturbed predator-prey interactions for multiple taxa at a global scale. We conclude that the functional role of predators is conserved in cities and urbanization does not inherently relax predation, despite diets broadening to include anthropogenic food sources such as sugar, wheat and corn.

Despite the success of immune checkpoint inhibitors that target cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed-cell-death-1 (PD-1) in the treatment of metastatic melanoma, there is still great need to develop robust options for patients who are refractory to first line immunotherapy. As such there has been a resurgence in interest of adoptive cell transfer (ACT) particularly derived from tumor infiltrating lymphocytes. Moreover, the addition of cyclin dependent kinase 4/6 inhibitors (CDK4/6i) have been shown to greatly extend duration of response in combination with BRAF-MEK inhibitors (BRAF-MEKi) in pre-clinical models of melanoma. We therefore investigated whether combinations of BRAF-MEK-CDK4/6i and ACT were efficacious in murine models of melanoma. Triplet targeted therapy of BRAF-MEK-CDK4/6i with OT-1 ACT led to sustained and robust anti-tumor responses in BRAFi sensitive YOVAL1.1. We also show that BRAF-MEKi but not CDK4/6i enhanced MHC Class I expression in melanoma cell lines in vitro. Paradoxically CDK4/6i in low concentrations of IFN-γ reduced expression of MHC Class I and PD-L1 in YOVAL1.1. Overall, this work provides additional pre-clinical evidence to pursue combination of BRAF-MEK-CDK4/6i and to combine this combination with ACT in the clinic.

Objective : A series of studies report elevated rates of autism and autistic characteristics among gender-diverse youth seeking gender services. Although youth with the co-occurrence present with complex care needs, existing studies have focused on co-occurrence rates. Further, clinical commentaries have emphasized provider-centered interpretations of clinical needs rather than key stakeholder-driven clinical approaches. This study aimed to employ community-based participatory research methodologies to develop a key stakeholder-driven clinical group program. Method : Autistic/neurodiverse gender-diverse (A/ND-GD) youth ( N = 31), parents of A/ND-GD youth ( N = 46), A/ND-GD self-advocates ( N = 10), and expert clinical providers ( N = 10) participated in a multi-stage community-based participatory procedure. Needs assessment data were collected repeatedly over time from A/ND-GD youth and their parents as the youth interacted with one another through ongoing clinical groups, the curriculum of which was developed progressively through the iterative needs assessments. Results : Separate adolescent and parent needs assessments revealed key priorities for youth (e.g., the importance of connecting with other A/ND-GD youth and the benefit of experiencing a range of gender-diverse role models to make gender exploration and/or gender affirmation more concrete) and parents (e.g., the need for A/ND-related supports for their children as well as provision of an A/ND-friendly environment that fosters exploration of a range of gender expressions/options). Integration and translation of youth and parent priorities resulted in 11 novel clinical techniques for this population. Conclusions : With generally high acceptability ratings for each component of the group program, this study presents a community-driven clinical model to support broad care needs and preferences of A/ND-GD adolescents.

Background: Globally, a large percentage of men keep a beard at least occasionally. Workplace regulations prohibit beards with N95 respirators, but there is little information on the effect of beards with face masks worn by the public for protection against SARS-CoV-2., Methods and Findings: We examined the fitted filtration efficiency (FFE) of five commonly worn protective face masks as a function of beard length following the US Occupational Safety and Health Administration Quantitative Fit Test: N95 (respirator), KF94 and KN95, surgical/procedure, and cloth masks. A comparison using N95 respirators was carried out in shaven and bearded men. A detailed examination was conducted for beard lengths between 0 and 10 mm (0.5 mm increments). The effect of an exercise band covering the beard on FFE was also tested. Although N95 respirators showed considerable variability among bearded men, they had the highest FFE for beard lengths up to 10 mm. KF94 and KN95 masks lost up to 40% of their FFE. Procedure and cotton masks had poor performance even on bare skin (10-30% FFE) that did not change appreciably with beard length. Marked performance improvements were observed with an exercise band worn over the beard., Conclusions: Though variable, N95 respirators offer the best respiratory protection for bearded men. While KF94 and KN95 FFE is compromised considerably by increasing beard length, they proved better options than procedure and cotton face masks. A simple exercise band improves FFE for face masks commonly used by bearded men during the COVID-19 pandemic., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Rationing in health care is controversial, and even more so in pediatrics. Children are an inherently vulnerable group because they are reliant on their parents and caregivers to make decisions in their best interests and have no political voice. Historically, there has been general acceptance of the need to ration healthcare at a systems level, however there is controversy over whether healthcare professionals should be involved in rationing at the bedside. The COVID-19 pandemic has highlighted that bedside rationing is unavoidable, at least in times of extreme resource scarcity. Internationally, there has been significant ethical analysis and guideline development to guide intensive care rationing decisions in the event that resources are overwhelmed. This paper explores the principles underlying distributive justice in healthcare rationing and discusses how these were operationalized in ethical guidelines for the COVID-19 pandemic. In fact, rationing is unavoidable and occurs constantly in everyday nursing and medical ICU practice, often in mundane and uncontroversial ways. Some argue that these everyday decisions are not true rationing decisions, but resource allocation, or stewardship decisions. We argue there are no clear lines between resource allocation and rationing decisions, rather that they occur on a spectrum. These everyday rationing decisions are particularly susceptible to personal biases that are often implicit. Due to the subtle and constant nature of most everyday rationing decisions, specific guideline development will rarely be practical or appropriate. However, it is possible to develop other processes to improve decision making. There are a variety of strategies we recommend for this including, encouraging reflective practice; developing explicit frameworks that promote collaborative decision making; being transparent about resource allocation and rationing decisions with colleagues, patients, and families; and promoting a workplace culture of speaking up and accessing support in identifying and managing everyday rationing decisions., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tp-20-334). The series “Pediatric Critical Care” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2021 Translational Pediatrics. All rights reserved.)

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, whereas their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic, and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunologic T-cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous antitumor T-cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor T cells, and induced a retinoblastoma-dependent T-cell phenotype supportive of favorable responses to immune checkpoint blockade in patients with melanoma. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost antitumor T-cell immunity. SIGNIFICANCE: Immunologic memory is critical for sustained antitumor immunity. Our discovery that CDK4/6 inhibitors drive T-cell memory fate commitment sheds new light on their clinical activity, which is essential for the design of clinical trial protocols incorporating these agents, particularly in combination with immunotherapy, for the treatment of cancer. This article is highlighted in the In This Issue feature, p. 2355 ., (©2021 American Association for Cancer Research.)

Shortages of efficient filtering facepiece respirators leave the public vulnerable to transmission of infectious diseases in small particle aerosols. This study demonstrates that a high-filtration-efficiency facepiece capable of filtering out >95% of 0.05μm particles while being worn can be simply produced with available materials., (Copyright © 2021 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Oligodendrocytes and their progenitors are glial cells in the central nervous system, which have been mainly implicated with the homeostatic roles of axonal myelin ensheathment but serve as targets of the peripheral immune system attack in the context of diseases like multiple sclerosis. This view of oligodendroglia as passive bystanders with no immunological properties was first challenged in the 1980s when it was reported that the cytokine interferon γ could induce the gene expression of the major histocompatibility complexes (MHC) class I and II. While the physiological role of this induction was controversial for decades to follow, recent studies suggest that oligodendroglia survey their environment, respond to a larger array of cues and can indeed exert immunomodulatory functions, which are particularly relevant in the context of neurodegeneration and demyelinating diseases. The alternative functionality of oligodendroglia not only regulates immune cell responses, but also hinders remyelination, and might thereby be key to understanding MS disease pathology and promoting regeneration after immune-mediated demyelination., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Lichen sclerosus (LS) is a chronic, inflammatory dermatosis. Initial treatment with superpotent topical corticosteroids is the accepted and evidence-based first-line therapy. For those who do not respond after exclusion of other potentiating factors, the best second-line therapy is unclear. Laser therapy is an emerging treatment for genital LS and despite uncertain efficacy its use is gaining popularity in the private sector., Objectives: We aimed to review the effectiveness of laser therapy for genital LS in men, women and children., Methods: We conducted a systematic review of all primary studies reporting the use of laser in genital LS. Ovid MEDLINE, PubMed, Ovid Embase, Cochrane CENTRAL, Web of Science, CINAHL and PsycINFO were searched from inception to February 2021. The quality of the studies was assessed using the revised Cochrane risk-of-bias tool for randomized trials, ROBINS-I tool for non-randomized trials and Joanna Briggs Institute checklist for case studies., Results: A total of 24 studies, involving 616 adults, met inclusion criteria. These were six randomized controlled trials (RCTs), one non-randomized trial, nine single arm trials and eight case series. Where assessed, most studies suggest that laser therapy in patients with LS may improve symptoms, clinical signs, quality of life and sexual function. However, results were highly heterogeneous and methodological quality was very low, therefore meta-analysis was not possible., Conclusions: There is poor evidence to support the use of laser therapy for genital LS at present. Effectiveness of laser needs to be robustly investigated in well-conducted RCTs., Competing Interests: None to declare., (© 2021 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Palmoplantar pustulosis (PPP) is a chronic inflammatory disease in which sterile and relapsing pustules appear on the palms and soles., Objectives: To assess the effects of interventions for chronic PPP to induce and maintain complete remission., Methods: We searched for randomized controlled trials (RCTs), including people with PPP or chronic palmoplantar pustular psoriasis, in the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and eight trials registers up to July 2020. Study selection, data extraction and risk-of-bias assessment were carried out independently by two review authors. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method., Results: We included 37 RCTs (1663 participants, 76% women, mean age 50 years). Mean treatment duration was 11 weeks. Topical vitamin D derivative may be more effective than placebo in achieving clearance [risk ratio (RR) 7·83, 95% confidence interval (CI) 1·85-33·12; low-certainty evidence from two trials]. Concerning biological therapies, there was little or no difference between etanercept and placebo in achieving clearance (low-certainty evidence from one trial), ustekinumab is less effective than placebo in reducing severity (low-certainty evidence from one trial), and guselkumab (RR 2·88, 95% CI 1·24-6·69) and secukinumab (RR 1·55, 95% CI 1·02-2·35) are probably better in reducing disease severity (moderate-certainty evidence from two and one trial(s), respectively) but may cause more serious adverse events than placebo., Conclusions: Evidence is lacking for or against major chronic PPP treatments. Risk of bias and imprecision limit our confidence in the results., (© 2020 British Association of Dermatologists.)

Importance: During the coronavirus disease 2019 (COVID-19) pandemic, the general public has been advised to wear masks or improvised face coverings to limit transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there has been considerable confusion and disagreement regarding the degree to which masks protect the wearer from airborne particles., Objectives: To evaluate the fitted filtration efficiency (FFE) of various consumer-grade and improvised face masks, as well as several popular modifications of medical procedure masks that are intended to improve mask fit or comfort., Design, Setting, and Participants: For this study conducted in a research laboratory between June and August 2020, 7 consumer-grade masks and 5 medical procedure mask modifications were fitted on an adult male volunteer, and FFE measurements were collected during a series of repeated movements of the torso, head, and facial muscles as outlined by the US Occupational Safety and Health Administration Quantitative Fit Testing Protocol. The consumer-grade masks tested included (1) a 2-layer nylon mask with ear loops that was tested with an optional aluminum nose bridge and filter insert in place, (2) a cotton bandana folded diagonally once (ie, "bandit" style) or in a (3) multilayer rectangle according to the instructions presented by the US Surgeon General, (4) a single-layer polyester/nylon mask with ties, (5) a polypropylene mask with fixed ear loops, (6) a single-layer polyester gaiter/neck cover balaclava bandana, and (7) a 3-layer cotton mask with ear loops. Medical procedure mask modifications included (1) tying the mask's ear loops and tucking in the side pleats, (2) fastening ear loops behind the head with 3-dimensional-printed ear guards, (3) fastening ear loops behind the head with a claw-type hair clip, (4) enhancing the mask/face seal with rubber bands over the mask, and (5) enhancing the mask/face seal with a band of nylon hosiery over the fitted mask., Main Outcomes and Measures: The primary study outcome was the measured FFE of common consumer-grade and improvised face masks, as well as several popular modifications of medical procedure masks., Results: The mean (SD) FFE of consumer grade masks tested on 1 adult male with no beard ranged from 79.0% (4.3%) to 26.5% (10.5%), with the 2-layer nylon mask having the highest FFE. Unmodified medical procedure masks with ear loops had a mean (SD) FFE of 38.5% (11.2%). All modifications evaluated in this study increased procedure mask FFE (range [SD], 60.3% [11.1%] to 80.2% [3.1%]), with a nylon hosiery sleeve placed over the procedure mask producing the greatest improvement., Conclusions and Relevance: While modifications to improve medical procedure mask fit can enhance the filtering capability and reduce inhalation of airborne particles, this study demonstrates that the FFEs of consumer-grade masks available to the public are, in many cases, nearly equivalent to or better than their non-N95 respirator medical mask counterparts.

Background: Lichen sclerosus (LS) is a scarring chronic inflammatory disease with a predilection for genital skin in both sexes. The aetiology of LS is controversial, but evidence increasingly suggests that the occluded exposure of susceptible epithelium to urine is involved in the pathogenesis of genital LS in males. This theory has not yet been robustly investigated in females., Objectives: This review and meta-analysis examined whether there is an association between urinary incontinence (UI) and genital lichen LS in females., Methods: We performed a comprehensive search of MEDLINE, Embase and CINAHL to identify observational studies assessing the prevalence of UI in females with LS. DerSimonian and Laird random-effects models were used to estimate the overall pooled prevalence and risk ratio compared to controls. Heterogeneity was assessed., Results: In total, eight studies met the inclusion criteria and five studies were included in a meta-analysis. Three studies were graded as moderate quality and five were poor. The pooled prevalence for UI in LS was 0.35 (95% confidence interval [CI] 0.13-0.58, I 2  = 98.4%). The risk ratio of UI in LS was 0.97 (95% CI 0.53-1.75, I 2  = 87.5%)., Conclusion: There appears to be no difference between patients with LS and those without LS in terms of UI. Studies are limited by clinical and methodological quality and heterogeneity is high. Well-designed prospective studies are needed., Competing Interests: The authors declare that there are no conflict of interests., (© 2021 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Combined inhibition of BRAF, MEK, and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a BRAF V600 mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on antitumor immunity remains unexplored. Here, using a syngeneic Braf V600E Cdkn2a -/- Pten -/- melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to immune checkpoint blockade (ICB). Flow cytometric and single-cell RNA sequencing analyses of tumor-infiltrating immune populations revealed that triple therapy markedly depleted proinflammatory macrophages and cross-priming CD103 + dendritic cells, the absence of which correlated with poor overall survival and clinical responses to ICB in patients with melanoma. Indeed, immune populations isolated from tumors of mice treated with triple therapy failed to stimulate T-cell responses ex vivo While combined BRAF, MEK, and CDK4/6 inhibition demonstrates favorable tumor-intrinsic activity, these data suggest that collateral effects on tumor-infiltrating myeloid populations may impact antitumor immunity. These findings have important implications for the design of combination strategies and clinical trials that incorporate BRAF, MEK, and CDK4/6 inhibition with immunotherapy for the treatment of patients with melanoma., (©2020 American Association for Cancer Research.)

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are being tested in numerous clinical trials and are currently employed successfully in the clinic for the treatment of breast cancers. Understanding their mechanism of action and interaction with other therapies is vital in their clinical development. CDK4/6 regulate the cell cycle via phosphorylation and inhibition of the tumour suppressor RB, and in addition can phosphorylate many cellular proteins and modulate numerous cellular functions including cell metabolism. Metabolic reprogramming is observed in melanoma following standard-of-care BRAF/MEK inhibition and is involved in both therapeutic response and resistance. In preclinical models, CDK4/6 inhibitors overcome BRAF/MEK inhibitor resistance, leading to sustained tumour regression; however, the metabolic response to this combination has not been explored. Here, we investigate how CDK4/6 inhibition reprograms metabolism and if this alters metabolic reprogramming observed upon BRAF/MEK inhibition. Although CDK4/6 inhibition has no substantial effect on the metabolic phenotype following BRAF/MEK targeted therapy in melanoma, CDK4/6 inhibition alone significantly enhances mitochondrial metabolism. The increase in mitochondrial metabolism in melanoma cells following CDK4/6 inhibition is fuelled in part by both glutamine metabolism and fatty acid oxidation pathways and is partially dependent on p53. Collectively, our findings identify new p53-dependent metabolic vulnerabilities that may be targeted to improve response to CDK4/6 inhibitors.

Importance: Procuring respiratory protection for clinicians and other health care workers has become a major challenge of the coronavirus disease 2019 (COVID-19) pandemic and has resulted in nonstandard practices such as the use of expired respirators and various decontamination processes to prolong the useful life of respirators in health care settings. In addition, imported, non-National Institute for Occupational Safety and Health (NIOSH)-approved respirators have been donated or acquired by hospitals as a potential replacement for limited NIOSH-approved N95 respirators., Objective: To assess fitted filtration efficiencies (FFEs) for face mask alternatives used during the COVID-19 pandemic., Design, Setting, and Participants: For this quality-improvement study conducted between April and June 2020, we used the Occupational Safety and Health Administration's Quantitative Fit Testing Protocol for Filtering Facepiece Respirators in a laboratory atmosphere supplemented with sodium chloride particles to assess the FFEs of a variety of respirators worn by a male volunteer and female volunteer., Main Outcomes and Measures: The FFEs of respirators commonly worn by clinicians and other health care workers and available respirator alternatives during the COVID-19 pandemic., Results: Of the 29 different fitted face mask alternatives tested on 1 man and 1 woman, expired N95 respirators with intact elastic straps and respirators subjected to ethylene oxide and hydrogen peroxide sterilization had unchanged FFE (>95%). The performance of N95 respirators in the wrong size had slightly decreased performance (90%-95% FFE). All of the respirators not listed as approved in this evaluation (n = 6) failed to achieve 95% FFE. Neither of the 2 imported respirators authorized for use by the Centers for Disease Control and Prevention that were not NIOSH-approved tested in this study achieved 95% FFE, and the more effective of the 2 functioned at approximately 80% FFE. Surgical and procedural face masks had filtering performance that was lower relative to that of N95 respirators (98.5% overall FFE), with procedural face masks secured with elastic ear loops showing the lowest efficiency (38.1% overall FFE)., Conclusions and Relevance: This quality-improvement study evaluating 29 face mask alternatives for use by clinicians interacting with patients during the COVID-19 pandemic found that expired N95 respirators and sterilized, used N95 respirators can be used when new N95 respirators are not available. Other alternatives may provide less effective filtration.

Wildlife respond to human presence by adjusting their temporal niche, possibly modifying encounter rates among species and trophic dynamics that structure communities. We assessed wildlife diel activity responses to human presence and consequential changes in predator-prey overlap using 11,111 detections of 3 large carnivores and 11 ungulates across 21,430 camera trap-nights in West Africa. Over two-thirds of species exhibited diel responses to mainly diurnal human presence, with ungulate nocturnal activity increasing by 7.1%. Rather than traditional pairwise predator-prey diel comparisons, we considered spatiotemporally explicit predator access to several prey resources to evaluate community-level trophic responses to human presence. Although leopard prey access was not affected by humans, lion and spotted hyena access to three prey species significantly increased when prey increased their nocturnal activity to avoid humans. Human presence considerably influenced the composition of available prey, with implications for prey selection, demonstrating how humans perturb ecological processes via behavioral modifications., Competing Interests: KM, NH No competing interests declared, (© 2020, Mills and Harris.)