"We only trust each other": A qualitative study exploring the overdose risk environment among persons who inject drugs living with HIV in Nairobi, Kenya.

In Kenya, overdose remains a major public health concern with approximately 40% of persons who inject drugs (PWID) reporting personal overdoses. PWID living with HIV (PWID-LH) are particularly vulnerable to experiencing fatal and non-fatal overdoses because of the surrounding physical, social, economic, and political environments, which are not fully understood in Kenya. Through qualitative inquiry, this study characterizes Kenya's overdose risk environment. Participants were purposively recruited from a larger cohort study from September to December 2018 using the following inclusion criteria: HIV-positive, age ≥18 years, injected drugs in the last year, and completed cohort study visits. Semi-structured interviews explored experiences of personal and observed overdoses, including injection settings, sequence of events (e.g., pre-, during, and post-overdose), safety strategies, and treatment. Interviews were transcribed, translated (Swahili to English), reviewed, and analyzed thematically, applying a risk environment framework. Nearly all participants described personal and/or observed overdose experiences (96%) and heroin was the most frequently reported substance (79%). Overdose precursors included increased consumption, polysubstance use, recent incarceration, and rushed injections. There were also indications of female-specific precursors, including violence and accessing prefilled syringes within occupational settings. Overdose safety strategies included avoiding injecting alone, injecting drugs incrementally, assessing drug quality, and avoiding polysubstance use. Basic first-aid techniques and naloxone use were common treatment strategies; however, naloxone awareness was low (25%). Barriers to treatment included social network abandonment, police discrimination, medical stigma, fatalism/religiosity, medical and transportation costs, and limited access to treatment services. In Kenya, the overdose risk environment highlights the need for comprehensive overdose strategies that address the physical, social, economic, and political environments. Morbidity and mortality from overdose among PWID-LH could be reduced through overdose prevention initiatives that support harm reduction education, naloxone awareness, and access, destigmatization of PWID, and reforming punitive policies that criminalize PWID-LH.

The Crystal Structure of the Michaelis-Menten Complex of C1 Esterase Inhibitor and C1s Reveals Novel Insights into Complement Regulation.

The ancient arm of innate immunity known as the complement system is a blood proteolytic cascade involving dozens of membrane-bound and solution-phase components. Although many of these components serve as regulatory molecules to facilitate controlled activation of the cascade, C1 esterase inhibitor (C1-INH) is the sole canonical complement regulator belonging to a superfamily of covalent inhibitors known as serine protease inhibitors (SERPINs). In addition to its namesake role in complement regulation, C1-INH also regulates proteases of the coagulation, fibrinolysis, and contact pathways. Despite this, the structural basis for C1-INH recognition of its target proteases has remained elusive. In this study, we present the crystal structure of the Michaelis-Menten (M-M) complex of the catalytic domain of complement component C1s and the SERPIN domain of C1-INH at a limiting resolution of 3.94 Å. Analysis of the structure revealed that nearly half of the protein/protein interface is formed by residues outside of the C1-INH reactive center loop. The contribution of these residues to the affinity of the M-M complex was validated by site-directed mutagenesis using surface plasmon resonance. Parallel analysis confirmed that C1-INH-interfacing residues on C1s surface loops distal from the active site also drive affinity of the M-M complex. Detailed structural comparisons revealed differences in substrate recognition by C1s compared with C1-INH recognition and highlight the importance of exosite interactions across broader SERPIN/protease systems. Collectively, this study improves our understanding of how C1-INH regulates the classical pathway of complement, and it sheds new light on how SERPINs recognize their cognate protease targets.

Patterns of failure after salvage head and neck surgery.

BACKGROUND: Advancements in immunotherapy for recurrent head and neck cancer have necessitated a better understanding of salvage surgical outcomes. This study aimed to determine patterns of failure following salvage head and neck surgery. METHODS: A retrospective cohort study was conducted of 280 patients who underwent salvage surgery for recurrent mucosal squamous cell carcinoma from 1997 to 2018. Cumulative incidence was calculated using the nonparametric Aalen-Johansen estimator. Time to recurrence (TTR) and overall survival (OS) were estimated using the Kaplan-Meier method and multivariable Cox proportional hazard models were used to evaluate associated factors. RESULTS: The 2 and 5-year cumulative incidence rates of second recurrence were 48.3 % (95 % CI 42.4-54.3) and 54.9 % (95 % CI 48.9-60.8), respectively. At 5 years, second locoregional recurrence was twice as common as distant recurrence (41.5 % [95 % CI 35.6-47.4] vs. 21.7 % [95 % CI 16.8-26.6]). The median TTR was 21.1 months (95 % CI 4.4-34.8), which varied by site (38.2 larynx/hypopharynx, 13.9 oral cavity, 8.3 sinonasal, and 7.8 oropharynx, P=.0001). The median OS was 32.1 months (95 % CI 24.1-47.6) and was worse for patients who were Black (hazard ratio [HR] 2.15, 95 % CI 1.19-3.9), current smokers (HR 2.73, 95 % CI 1.53-4.88), former smokers (HR 2.00, 95 % CI 1.19-3.35), ≥ 60 years of age (HR 1.41, 95 % CI 1.01-1.97), or received multimodal primary therapy (HR 1.98, 95 % CI 1.26-3.13). CONCLUSION: Rates of recurrence and mortality after salvage surgery were poor but worse for patients who were Black, older, smoked, had initial multimodal therapy, or had sinonasal or oropharyngeal cancers.

Exercise for the Prevention and Treatment of Depression.

Depression is among the world's leading causes of disability and accounts for a significant loss of life. Despite large investments in research for antidepressants and psychotherapies, non-response, partial response, and small effects remain significant problems. Exercise and physical activity are two lifestyle behaviors that have been studied for well over half a century for the prevention and treatment of depression. The aim of this chapter is to summarize the current evidence base supporting the efficacy of exercise and physical activity in the prevention and treatment of depression, including evidence supporting exercise as a monotherapy and adjunct to antidepressant medication and psychotherapies. We conclude the chapter by outlining challenges to prescribing exercise for depression and general recommendations for encouraging behavioral adoption for individuals suffering from depression.

The Glymphatic System and Subarachnoid Lymphatic-Like Membrane: Recent Developments in Cerebrospinal Fluid Research.

INTRODUCTION: Cerebrospinal fluid (CSF) circulates throughout the ventricles, cranial and spinal subarachnoid spaces, and central spinal cord canal. CSF protects the central nervous system through mechanical cushioning, regulation of intracranial pressure, regulation of metabolic homeostasis, and provision of nutrients. Recently, investigators have characterized the glial-lymphatic (glymphatic) system, the analog of the lymphatic system in the CNS, and described a fourth meningeal layer; the subarachnoid lymphatic-like membrane relevant to the CSF. METHODS: A narrative review was conducted. RESULTS: In this review, we summarize these advances. We describe the development of the original model, controversies, a revised model, and a new conceptual framework. We characterize the biological functions, influence of sleep-wake cycles, and effect of aging with relevance to the glymphatic system. We highlight the role of the glymphatic system in Alzheimer's disease, idiopathic normal pressure hydrocephalus, ischemic stroke, subarachnoid hemorrhage, and traumatic brain injury. Next, we characterize the structure and role of the subarachnoid lymphatic-like membrane. Finally, we explore the relevance of the glymphatic system and subarachnoid lymphatic-like membrane to neurosurgery. CONCLUSION: This manuscript will inform clinicians and scientists regarding preclinical and translational advances in the understanding of the structure, dynamics, and function of the CSF.

APC/C prevents a noncanonical order of cyclin/CDK activity to maintain CDK4/6 inhibitor-induced arrest.

Regulated cell cycle progression ensures homeostasis and prevents cancer. In proliferating cells, premature S phase entry is avoided by the E3 ubiquitin ligase anaphasepromoting complex/cyclosome (APC/C), although the APC/C substrates whose degradation restrains G1-S progression are not fully known. The APC/C is also active in arrested cells that exited the cell cycle, but it is not clear whether APC/C maintains all types of arrest. Here, by expressing the APC/C inhibitor, EMI1, we show that APC/C activity is essential to prevent S phase entry in cells arrested by pharmacological cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition (Palbociclib). Thus, active protein degradation is required for arrest alongside repressed cell cycle gene expression. The mechanism of rapid and robust arrest bypass from inhibiting APC/C involves CDKs acting in an atypical order to inactivate retinoblastoma-mediated E2F repression. Inactivating APC/C first causes mitotic cyclin B accumulation which then promotes cyclin A expression. We propose that cyclin A is the key substrate for maintaining arrest because APC/C-resistant cyclin A, but not cyclin B, is sufficient to induce S phase entry. Cells bypassing arrest from CDK4/6 inhibition initiate DNA replication with severely reduced origin licensing. The simultaneous accumulation of S phase licensing inhibitors, such as cyclin A and geminin, with G1 licensing activators disrupts the normal order of G1-S progression. As a result, DNA synthesis and cell proliferation are profoundly impaired. Our findings predict that cancers with elevated EMI1 expression will tend to escape CDK4/6 inhibition into a premature, underlicensed S phase and suffer enhanced genome instability.

Destabilized reporters for background-subtracted, chemically-gated, and multiplexed deep-tissue imaging.

Tracking gene expression in deep tissues requires genetic reporters that can be unambiguously detected using tissue penetrant techniques. Magnetic resonance imaging (MRI) is uniquely suited for this purpose; however, there is a dearth of reporters that can be reliably linked to gene expression with minimal interference from background tissue signals. Here, we present a conceptually new method for generating background-subtracted, drug-gated, multiplex images of gene expression using MRI. Specifically, we engineered chemically erasable reporters consisting of a water channel, aquaporin-1, fused to destabilizing domains, which are stabilized by binding to cell-permeable small-molecule ligands. We showed that this approach allows for highly specific detection of gene expression through differential imaging. In addition, by engineering destabilized aquaporin-1 variants with orthogonal ligand requirements, it is possible to distinguish distinct subpopulations of cells in mixed cultures. Finally, we demonstrated this approach in a mouse tumor model through differential imaging of gene expression with minimal background.

pH-Responsive Degradable Electro-Spun Nanofibers Crosslinked via Boronic Ester Chemistry for Smart Wound Dressings.

Recent advances in the treatment of chronic wounds have focused on the development of effective strategies for cutting-edge wound dressings based on nanostructured materials, particularly biocompatible poly(vinyl alcohol) (PVA)-based electro-spun (e-spun) nanofibers. However, PVA nanofibers need to be chemically crosslinked to ensure their dimensional stability in aqueous environment and their capability to encapsulate bioactive molecules. Herein, a robust approach for the fabrication of pH-degradable e-spun PVA nanofibers crosslinked with dynamic boronic ester (BE) linkages through a coupling reaction of PVA hydroxyl groups with the boronic acid groups of a phenyl diboronic acid crosslinker is reported. This comprehensive analysis reveals the importance of the mole ratio of boronic acid to hydroxyl group for the fabrication of well-defined BE-crosslinked fibrous mats with not only dimensional stability but also the ability to retain uniform fibrous form in aqueous solutions. These nanofibers degrade in both acidic and basic conditions that mimic wound environments, leading to controlled/enhanced release of encapsulated antimicrobial drug molecules. More importantly, drug-loaded BE-crosslinked fibers show excellent antimicrobial activities against both Gram-positive and Gram-negative bacteria, suggesting that this approach of exploring dynamic BE chemistry is amenable to the development of smart wound dressings with controlled/enhanced drug release.

The Moderating and Mediating Role of Responsive Parenting Behavior in Explaining the Link between Intimate Partner Violence and Posttraumatic Stress Symptoms in Young Children.

Responsive parenting serves an influential role in explaining the link between children's exposure to intimate partner violence (IPV) and children's mental health impairment, but how this occurs is not well elucidated. In some cases, researchers examine parenting as a mediator to explain how IPV leads to maladaptive outcomes (i.e., IPV negatively impacts one's capacity for responsive parenting, which in turn impacts children), whereas others examine moderation in which either the absence of responsive parenting exacerbates adverse outcomes or increased responsive parenting buffers risk. Mediation addresses theoretical questions about how or why IPV leads to maladaptive outcomes, whereas moderation addresses who might be most impacted. However, responsive parenting has rarely, if ever, been tested as both a mediator and moderator of the link between IPV and posttraumatic stress symptoms (PTSS) within the same sample. The current study examined the mediating and moderating role of responsive parenting on physical IPV exposure and child PTSS in a longitudinal sample of 391 children ages 3 to 5 years (M = 4.74, SD = 0.89). Self-report measures of physical IPV exposure, parenting practices, and PTSS were completed by mothers. We found that responsive parenting significantly moderated and mediated the association between physical IPV exposure and child PTSS over time. Studies that include tests of both moderation and mediation are critical for advancing mechanistic insight into the role of parenting in the etiology of mental health impairment in children exposed to IPV.

Occupational Contact Dermatitis in Construction Workers: A Retrospective Analysis of the North American Contact Dermatitis Group Data, 2001-2020.

Background: Construction workers (CWs) are at risk for occupational contact dermatitis (CD) owing to workplace exposures. Objective: Determine the prevalence of occupational allergic CD and characterize common occupational allergens in CWs referred for patch testing in the United States and Canada. Methods: Retrospective cross-sectional analysis of patients patch tested by the North American Contact Dermatitis Group from 2001 to 2020. Results: Of 47,843 patch-tested patients, 681 (1.4%) were CWs. Compared with non-CWs, CWs were more likely to be male (91.0% vs 30.9%) have occupational skin disease (36.9% vs 11.4%) and have hand involvement (37.2% vs 22.5%) (all P < 0.0001). Of 681 CWs, 60.1% (411) had clinically relevant positive patch test reactions, and nearly 1/3 of CWs (128) had occupationally relevant reactions. Most common occupationally relevant allergens were potassium dichromate 0.25% pet. (30.5%, 39/128), bisphenol A epoxy resin 1% pet. (28.1%, 36/128), carba mix 3% pet. (14.8%, 19/128), cobalt (ii) chloride hexahydrate 1% pet. (14.1%, 18/128), and thiuram mix 1% pet. (14.1%, 18/128). Top sources of occupationally relevant allergens were cement/concrete/mortar (20.4%, 46/225), gloves (15.1%, 34/225), and coatings (paint/lacquer/shellac/varnish/stains) (9.8%, 22/225). Conclusions: Occupational CD in North American CWs is common. In this group, frequently identified etiological sources of occupational allergic CD included metals, epoxy resin, and rubber.

The first record of an established population of Amblyomma maculatum (Acari: Ixodidae) in New Jersey, USA.

Amblyomma maculatum Koch, the Gulf Coast tick, is expanding northward from its original range in the southeastern United States. In 2013, its most northern collection was in Delaware. Amblyomma maculatum has since been found in Connecticut, Illinois, and New York. It is the vector of the human pathogen Rickettsia parkeri, the causative agent of R. parkeri rickettsiosis. We report the first finding of an established population of A. maculatum in Salem County, NJ, with a R. parkeri infection prevalence rate of 23.8%. Our finding of A. maculatum is consistent with other recent findings in the northeastern United States in that specimens were found in open areas devoid of tree canopy. This discovery demonstrates the importance of tick surveillance in order to identify expanding tick populations and the pathogens they may transmit.

Nucleus accumbens neuronal ensembles vary with cocaine reinforcement in male and female rats.

Neuronal ensembles in the medial prefrontal cortex mediate cocaine self-administration via projections to the nucleus accumbens. We have recently shown that neuronal ensembles in the prelimbic cortex form rapidly to mediate cocaine self-administration. However, the role of neuronal ensembles within the nucleus accumbens in initial cocaine-seeking behaviour remains unknown. Here, we sought to expand the current literature by testing the necessity of the cocaine self-administration ensemble in the nucleus accumbens core (NAcCore) 1 day after male and female rats acquire cocaine self-administration by using the Daun02 inactivation procedure. We found that disrupting the NAcCore ensembles after a no-cocaine reward-seeking test increased subsequent cocaine seeking, while disrupting NAcCore ensembles following a cocaine self-administration session decreased subsequent cocaine seeking. We then characterized neuronal cell type in the NAcCore using RNAscope in situ hybridization. In the no-cocaine session, we saw reduced dopamine D1 type neuronal activation, while in the cocaine self-administration session, we found preferential dopamine D1 type neuronal activity in the NAcCore.

[French survey of patients on current and future pulmonary rehabilitation programs]. / Enquête nationale auprès des malades sur la réadaptation respiratoire actuelle et future.

INTRODUCTION: Over recent years, a growing number of studies have demonstrated the effectiveness of alternative models to centre-based pulmonary rehabilitation (PR) such as tele-PR or home-based unsupervised PR, offering perspectives for improved accessibility and adherence. Other studies have demonstrated the relevance and long-term benefits of maintenance PR programs. However, they remain poorly implemented in real-life settings. In order to encourage patient adherence to new PR models and to guide future orientations, we conducted a survey assessing patients' views on PR models and maintenance programs. METHOD: The survey (37 questions) was circulated to COPD patients of the French national respiratory patient F.F.A.A.I.R network and in five specialised PR centres. RESULTS: Among the 298 respondents, 75% had previously taken part in a PR program, mainly in hospital settings (91%), with a high degree of satisfaction. The main barriers to PR were being physically separated from their loved ones (21%) and fears of having to share a double room (47%). Regarding maintenance PR programs, patients expressed diversified opinions, in terms of ideal duration and frequency of follow-up, format of follow-up (home-based, telephone, videoconference) and type of professional involved. CONCLUSIONS: Diversified PR settings offer perspectives to increase access and improve the effectiveness of current programs. Furthermore, comprehensive personalization (professionals involved, content, setting, duration) seems to be the key to success in concrete implementation and achievement of patient satisfaction.

Severe Post-partum Hypothyroidism Triggering Psychogenic Non-epileptiform Seizures, Myopathy, and Myxedema Coma.

This study details the development of severe post-partum hypothyroidism exacerbating psychogenic non-epileptiform seizures (PNES) and culminating in myxedema coma. A 29-year-old female with a history of anxiety, attention-deficit/hyperactivity disorder (ADHD), and post-partum depression presented with confusion, aphasia, and severe bilateral leg cramping five months following vaginal delivery. Initial laboratory tests indicated elevated creatine kinase (CK) levels, suggestive of non-traumatic rhabdomyolysis. Subsequent seizure-like episodes and the absence of epileptiform activity on the electroencephalogram (EEG) raised suspicions of PNES. Further investigation upon readmittance to the hospital revealed a thyroid-stimulating hormone (TSH) level of 216 mIU/L (range: 0.4-4.0 mIU/L), free thyroxine (T4) level of 0.2 ng/dL (range: 0.8-1.8 ng/dL), and a CK level of 2083 U/L (range in females: 30-150 U/L), indicating severe hypothyroidism with myopathy. Reintroducing levothyroxine (Synthroid), which was previously discontinued during pregnancy, rapidly resolved her symptoms, supporting suspicions that her non-epileptic seizures and myopathy were both caused by her underlying severe post-partum hypothyroidism. She was maintained on levothyroxine with only one seizure-like episode following hospital discharge. This case illustrates the importance of a thorough endocrine assessment in patients with neuropsychiatric presentations, particularly in the peripartum period. It highlights the potential for severe thyroid dysfunction to manifest as PNES, emphasizing the complexity of diagnosing and managing such cases. The findings advocate for a multidisciplinary approach to evaluating post-partum females with neurological and psychiatric symptoms and provide evidence for the link between thyroid disorders and PNES, advocating for a nuanced approach in similar clinical scenarios.

Three- and five-year outcomes of an inception cohort of Australian children with juvenile idiopathic arthritis.

BACKGROUND: To describe the 3- and 5-year outcomes of an inception cohort of Australian children with JIA for whom 1-year outcomes have previously been published. METHODS: Data regarding clinical outcomes of the original cohort of 134 patients at 3 and 5 years were sought. Relevant clinical features and medication exposures entered prospectively into an electronic record were collected and analyzed using descriptive statistics. RESULTS: Data were available for 110 and 98 patients at 3 and 5 years, respectively. The proportion of patients with active joints progressively decreased from 34% at 12 months to 21% at 3 years and 16% at 5 years. Cumulative exposure to methotrexate increased between 3 and 5 years (75%-80%), however, point prevalence use decreased (45%-41%). Cumulative exposure and point prevalence use of bDMARDS both increased between 3 and 5 years; 30%-42% and 29%-33%, respectively. Thirty-five percent of patients had inactive joint disease off medications at 5 years, which occurred most frequently in patients with sJIA and oligoarthritis. CONCLUSION: Five-year outcomes of Australian children with JIA are good, with only a small minority having ongoing active joint disease at 5 years. bDMARDS play an increasing role in management over time; however, methotrexate use remains significant. A majority of children remain on medications at 5 years.

Sunscreens Part 2: Regulation and Safety.

The second part of this CME article discusses sunscreen regulation and safety considerations for humans and the environment. First, we provide an overview of the history of the United States Food and Drug Administration's regulation of sunscreen. Recent Food and Drug Administration studies clearly demonstrate that organic ultraviolet filters are systemically absorbed during routine sunscreen use, but to date there is no evidence of associated negative health effects. We also review the current evidence of sunscreen's association with vitamin D levels and frontal fibrosing alopecia, and recent concerns regarding benzene contamination. Finally, we review the possible environmental effects of ultraviolet filters, particularly coral bleaching. While climate change has been shown to be the primary driver of coral bleaching, laboratory-based studies suggest that organic ultraviolet filters represent an additional contributing factor, which led several localities to ban certain organic filters.

Sunscreens Part 1: Mechanisms and Efficacy.

As our knowledge of the harmful effects of ultraviolet radiation continues to evolve, sunscreen remains an integral part of a comprehensive photoprotection strategy against multiple endpoints of ultraviolet-mediated damage. Part 1 of this review covers sunscreen active and additive ingredient properties, mechanisms of action and gaps in coverage. Following an overview of sunscreen's efficacy in protecting against sunburn, photocarcinogenesis, photoaging, pigmentary disorders, and idiopathic photodermatoses, we highlight considerations for product use and selection in children and individuals with skin of color.

Pseudoaromaticity-driven, transition metal detection by squaraine-derived enol phosphonium ylide chemodosimeters.

The addition of PnBu3 to o-substituted dianiline squaraine dyes leads to bench stable ylides. Exposure to a metal analyte in solution, results in PIII abstraction and rapid disruption of the ylide conjugation to promote reversion back to the squaraine dye giving an immediate turn-on colorimetric response. The stoichiometric sensitivity and accessibility of these chemodosimeters constitute effective organic dyes for trace transition metal detection.