Transgenic ferret models define pulmonary ionocyte diversity and function.

Speciation leads to adaptive changes in organ cellular physiology and creates challenges for studying rare cell-type functions that diverge between humans and mice. Rare cystic fibrosis transmembrane conductance regulator (CFTR)-rich pulmonary ionocytes exist throughout the cartilaginous airways of humans1,2, but limited presence and divergent biology in the proximal trachea of mice has prevented the use of traditional transgenic models to elucidate ionocyte functions in the airway. Here we describe the creation and use of conditional genetic ferret models to dissect pulmonary ionocyte biology and function by enabling ionocyte lineage tracing (FOXI1-CreERT2::ROSA-TG), ionocyte ablation (FOXI1-KO) and ionocyte-specific deletion of CFTR (FOXI1-CreERT2::CFTRL/L). By comparing these models with cystic fibrosis ferrets3,4, we demonstrate that ionocytes control airway surface liquid absorption, secretion, pH and mucus viscosity-leading to reduced airway surface liquid volume and impaired mucociliary clearance in cystic fibrosis, FOXI1-KO and FOXI1-CreERT2::CFTRL/L ferrets. These processes are regulated by CFTR-dependent ionocyte transport of Cl- and HCO3-. Single-cell transcriptomics and in vivo lineage tracing revealed three subtypes of pulmonary ionocytes and a FOXI1-lineage common rare cell progenitor for ionocytes, tuft cells and neuroendocrine cells during airway development. Thus, rare pulmonary ionocytes perform critical CFTR-dependent functions in the proximal airway that are hallmark features of cystic fibrosis airway disease. These studies provide a road map for using conditional genetics in the first non-rodent mammal to address gene function, cell biology and disease processes that have greater evolutionary conservation between humans and ferrets.

The challenges and opportunities of battery-powered flight.

Aircraft, and the aviation ecosystem in which they operate, are shaped by complex trades among technical requirements, economics and environmental concerns, all built on a foundation of safety. This Perspective explores the requirements of battery-powered aircraft and the chemistries that hold promise to enable them. The difference between flight and terrestrial needs and chemistries are highlighted. Safe, usable specific energy rather than cost is the major constraint for aviation. We conclude that battery packs suitable for flight with specific energy approaching 600 kilowatt hours per kilogram may be achievable in the next decade given sufficient investment targeted at aeronautical applications.

Social Vulnerability and Mental Health Among People with HIV and Substance Use: The Role of Race.

Poor mental health significantly impacts people with HIV (PWH) and those who drink alcohol. Limited data exist on the combined effects of social determinants of health (social vulnerability) on mental health in PWH with unhealthy substance use. We investigated the relationship between social vulnerability and poor mental health in PWH and whether this relationship differed by race/ethnicity. We conducted a cross-sectional analysis using data from the Boston ARCH Cohort among PWH with current or past unhealthy substance use. We created a 23-item social vulnerability index (SVI) using a deficit accumulation approach comprised of social determinants of health indicators. We estimated whether higher SVI score is associated with anxiety and depressive symptoms using logistic regression analysis. Among 251 participants with a mean age of 52 (SD = 10) years, 67.3% were male, 52% Black, 21% Hispanic, 19% White, and 73% unemployed. The SVI had a mean of 9.30 (SD = 3.4) with a 1.5-18 range. Nearly two in five persons reported past month heavy alcohol use and 35% illicit drug use. The prevalence of anxiety and depressive symptoms was 34.4% and 54.2% respectively. Higher SVI score was associated with anxiety symptoms (adjusted odds ratio [aOR] = 2.01, 95% confidence interval [CI] 1.46, 2.76, p ≤ 0.001), and depressive symptoms (aOR = 2.42, 95% CI 1.74, 3.36, p ≤ 0.001). Race/ethnicity did not moderate the relationship between SVI and each mental health outcome. SVI was significantly associated with poor mental health across racial/ethnicity groups in this cohort. Interventions that address social vulnerability may improve well-being and quality of life for PWH.

Self-medication of pain and discomfort with alcohol and other substances by people with HIV infection and substance use disorder: preliminary findings from a secondary analysis.

There is a limited literature regarding factors associated with self-medication of pain and discomfort using alcohol, non-prescription substances or overuse of prescription medications among people living with Human Immunodeficiency Virus (HIV). This cross-sectional analysis used data from the Boston ARCH Cohort among participants with HIV infection and a history of alcohol or other substance use. Among 248 participants, 37% were female, 50% Black, 25% Latinx; 36% reported fair to poor health and 89% had CD4 cell counts >200/mm3. Half reported self-medication and of those, 8.8% reported doing so only with alcohol, 48.8% only with other substances and 42.4% with both alcohol and other substances. Those reporting self-medication were significantly (p < .05) younger (mean 47 vs 50 years), less employed (11% vs 21%), and less likely to have HIV viral suppression (60% vs. 80%). Depression, anxiety, and HIV symptoms were associated with significantly greater odds of self-medicating, as were substance dependence, recent injection substance use, heavy alcohol use, cocaine use, opioid use, sedative use, and cannabis use. Self-medication, highly prevalent and associated with worse mental health symptoms, greater substance use, and lesser HIV disease control, should be explored by HIV clinicians caring for people who use substances.

Considerations for the Identification and Conveyance of Clinical Pathology Findings in Preclinical Toxicity Studies: Results From the 9th ESTP International Expert Workshop.

The European Society of Toxicologic Pathology (ESTP) organized a panel of 24 international experts from many fields of toxicologic clinical pathology (e.g., industry, academia, and regulatory) that came together in 2021 to align the use of terminology to convey the importance of clinical pathology findings in preclinical toxicity studies. An additional goal consisted of how to identify important findings in standard and nonstandard clinical pathology associated endpoints. This manuscript summarizes the information and opinions discussed and shared at the ninth ESTP International Expert Workshop, April 5 to 6, 2022. In addition to terminology usage, the workshop considered topics related to the identification and conveyance of the importance of test item-related findings. These topics included sources of variability, comparators, statistics, reporting, correlations to other study data, nonstandard biomarkers, indirect/secondary findings, and an overall weight-of-evidence approach.

(Thio)urea Containing Chiral Ammonium Salt Catalysts.

(Thio)-urea-containing bifunctional quaternary ammonium salts emerged as powerful non-covalently interacting organocatalysts over the course of the last decade. The most commonly employed catalysts in this field are either based on Cinchona alkaloids, α-amino acids, or trans-cyclohexane-1,2-diamine. Our group has been heavily engaged in the design and use of such catalysts, i. e. trans-cyclohexane-1,2-diamine-based ones for around 10 years now, and it is therefore the intention of this short personal account to provide an overview of the, at least in our opinion, most significant and pioneering achievements in this field by looking on catalyst design and asymmetric method development, with a special focus on our own contributions.

Effectiveness of an Immersive Telemedicine Platform for Delivering Diabetes Medical Group Visits for African American, Black and Hispanic, or Latina Women With Uncontrolled Diabetes: The Women in Control 2.0 Noninferiority Randomized Clinical Trial.

BACKGROUND: Medically underserved people with type 2 diabetes mellitus face limited access to group-based diabetes care, placing them at risk for poor disease control and complications. Immersive technology and telemedicine solutions could bridge this gap. OBJECTIVE: The purpose of this study was to compare the effectiveness of diabetes medical group visits (DMGVs) delivered in an immersive telemedicine platform versus an in-person (IP) setting and establish the noninferiority of the technology-enabled approach for changes in hemoglobin A1c (HbA1c) and physical activity (measured in metabolic equivalent of task [MET]) at 6 months. METHODS: This study is a noninferiority randomized controlled trial conducted from February 2017 to December 2019 at an urban safety net health system and community health center. We enrolled adult women (aged ≥18 years) who self-reported African American or Black race or Hispanic or Latina ethnicity and had type 2 diabetes mellitus and HbA1c ≥8%. Participants attended 8 weekly DMGVs, which included diabetes self-management education, peer support, and clinician counseling using a culturally adapted curriculum in English or Spanish. In-person participants convened in clinical settings, while virtual world (VW) participants met remotely via an avatar-driven, 3D VW linked to video teleconferencing. Follow-up occurred 6 months post enrollment. Primary outcomes were mean changes in HbA1c and physical activity at 6 months, with noninferiority margins of 0.7% and 12 MET-hours, respectively. Secondary outcomes included changes in diabetes distress and depressive symptoms. RESULTS: Of 309 female participants (mean age 55, SD 10.6 years; n=195, 63% African American or Black; n=105, 34% Hispanic or Latina; n=151 IP; and n=158 in VW), 207 (67%) met per-protocol criteria. In the intention-to-treat analysis, we confirmed noninferiority for primary outcomes. We found similar improvements in mean HbA1c by group at 6 months (IP: -0.8%, SD 1.9%; VW: -0.5%, SD 1.8%; mean difference 0.3, 97.5% CI -∞ to 0.3; P<.001). However, there were no detectable improvements in physical activity (IP: -6.5, SD 43.6; VW: -9.6, SD 44.8 MET-hours; mean difference -3.1, 97.5% CI -6.9 to ∞; P=.02). The proportion of participants with significant diabetes distress and depressive symptoms at 6 months decreased in both groups. CONCLUSIONS: In this noninferiority randomized controlled trial, immersive telemedicine was a noninferior platform for delivering diabetes care, eliciting comparable glycemic control improvement, and enhancing patient engagement, compared to IP DMGVs. TRIAL REGISTRATION: ClinicalTrials.gov NCT02726425; https://clinicaltrials.gov/ct2/show/NCT02726425.

Anxiety and depression in colorectal cancer survivors: Are there differences by sexual orientation?

OBJECTIVE: To examine sexual minority compared to heterosexual survivors' health-related anxiety, anxiety, and depression. METHODS: Four hundred and eighty eligible survivors participated in a telephone survey, which measured their anxiety and depression. These survivors were diagnosed with stage I, II, or III colorectal cancer an average of three years prior to the survey and were recruited from four cancer registries. As explanatory factors, we considered individual, social and contextual characteristics, prior psychological factors, psychological responses to cancer, and characteristics of cancer and its treatments. Using forward selection with generalized linear models or logistic regression models, we identified significant correlates for each outcome. RESULTS: Prior to adjusting for covariates, depression was similar for all survivors, while sexual minority survivors had worse health-related anxiety and anxiety compared to heterosexual survivors. After adjustment, these differences were no longer statistically significant. Individual, social and contextual characteristics, characteristics of cancer, and psychological responses to cancer explained 44% of the variance in anxiety and 60% of the variance in depression. CONCLUSION: There are modifiable factors associated with health-related and generalized anxiety as well as depression that can be changed to improve cancer survivorship among diverse survivors.

Alcohol and falls among people with HIV infection: A view from Russia and the United States.

BACKGROUND: Both human immunodeficiency virus (HIV) infection and alcohol use predispose to autonomic/sensory neuropathy, imbalance symptoms, and cognitive impairment-conditions associated with a greater risk of falls-yet it is unclear how to identify people with HIV (PWH) whose drinking is associated with falls. Research on alcohol and falls using the same instruments in different countries could help to specify the level of alcohol use associated with fall risk. We examined whether a consumption-based measure (the Alcohol Use Disorders Identification Test-Consumption [AUDIT-C]) and/or a symptom-based measure (DSM-5 criteria for alcohol use disorder [AUD]) are associated with sustaining a fall among PWH in St Petersburg, Russia and Boston, Massachusetts in the United States. METHODS: Separate multivariate logistic regressions were used for each cohort to examine cross-sectional associations for each alcohol measure predicting fall. Potential confounders included physical functioning, depressive symptoms, and other substance use (measured with the Addiction Severity Index). RESULTS: A fall was reported by 35% (87/251) of the sample in Boston and 12% (46/400) in St Petersburg. Each additional AUD criterion-but not higher AUDIT-C score-was significantly associated with a fall in both Boston (odds ratio [OR] = 1.10; 95% confidence interval [CI] 1.02, 1.18) and St Petersburg (adjusted OR AOR = 1.10; 95% CI 1.02, 1.18). Heavy alcohol use (>6 drinks/occasion, any vs. none) was associated with more than twice the odds of a fall (AOR = 2.24; 95% CI 1.21, 4.13) in Boston. CONCLUSIONS: These findings suggest that while fall risk may vary by setting and population, heavy alcohol use and AUD symptom severity are potential targets for interventions to prevent falls. Studies in diverse global settings advance our understanding of the relationship between alcohol and falls in PWH.

Alcohol Consumption and Tryptophan Metabolism Among People with HIV Prior to Antiretroviral Therapy Initiation: The Uganda ARCH Cohort Study.

AIMS: Alcohol is hypothesized to have effects on the kynurenine pathway of tryptophan catabolism, a potential mechanism for alcohol-induced depression and aggression. A biomarker of this pathway, the plasma kynurenine to tryptophan ratio (K/T ratio), has been associated with HIV progression, mortality and depression. Our aim was to assess whether hazardous alcohol consumption is associated higher K/T ratio among people with HIV. METHODS: Participants were a subset of the Uganda Alcohol Research Collaboration on HIV/AIDS Cohort. Alcohol consumption was categorized (abstinent, moderate and hazardous alcohol use) using the Alcohol Use Disorders Identification Test-Consumption and phosphatidylethanol (PEth). K/T ratio was the primary outcome. We used linear regression adjusted for age, sex, FIB-4, hepatitis B surface antigen, log (HIV viral load) to estimate the association between alcohol consumption and K/T ratio. RESULTS: Compared to abstinent participants, hazardous drinkers and moderate drinkers had higher K/T ratio but these differences did not reach statistical significance. CONCLUSIONS: Our results suggest that hazardous alcohol consumption, in the context of untreated HIV infection, may not significantly alter kynurenine to tryptophan ratio as a measure of activity of the kynurenine pathway of tryptophan metabolism.

The role of the livestock auction mart in promoting help-seeking behavior change among farmers in the UK.

Certain physical and mental health issues are particularly prevalent in farming occupations, yet frequently, farmers, particularly males, are resistant to seeking help from primary care practitioners. A qualitative approach examined the perspective of stakeholders at livestock auction marts to identify the determinants for, or barriers to, seeking help, perceptions regarding basing primary care services on-site at livestock auction marts, and the role of a site-based approach, i.e. placing primary healthcare services within a traditional farmers' meeting place, in facilitating changes in help-seeking beliefs and behaviors. Findings support previous studies regarding barriers to seeking help, but demonstrate that by deconstructing these barriers through specifically designed workplace/site-oriented support services, more positive behaviors are facilitated. The study highlights how collaboration between livestock auction marts and primary healthcare services allows access to a hard-to-reach demographic in terms of healthcare, and illustrates how such socially integrative opportunities can contribute to the improvement of the mental and physical health and wellbeing of the agricultural community.

Food insecurity and substance use in people with HIV infection and substance use disorder.

BACKGROUND: Food insecurity and substance use are common among people living with HIV (PLWH). Substance use may help people cope with hunger and thus be associated with food insecurity, but the association is uncertain. This study assessed whether, in PLWH and substance dependence, if there was an association between food insecurity and substance use.Methods: We studied adults with HIV and current substance dependence or ever injection drug use interviewed at 12 and 24 months after enrollment in a prospective cohort study. The presence of food insecurity (insufficient food quantity or quality, or anxiety about its availability) was assessed using the Household Food Insecurity Assessment Scale questionnaire (HFIAS). Unhealthy alcohol use was assessed with the Alcohol Use Disorder Identification Test - Consumption (AUDIT-C) and past 30-day other drug use with the Addiction Severity Index. Associations using repeat cross-sectional data from each of two time-points, 12 months apart, from the same participants were tested using generalized estimating equations logistic regressions.Results: The 233 participants had a mean age of 50 years and 65% were male. At the first interview, 44% reported food insecurity, 40% unhealthy alcohol use, 25% past 30-day cocaine use, and 17% past 30-day illicit opioid use. In analyses adjusted for demographics, social factors, physical and mental health function, and substance use related variables, there was no significant association between food insecurity and unhealthy alcohol use (adjusted odds ratio (aOR) = 1.06 (95% CI: 0.59, 1.87)). Those with food insecurity had higher odds of illicit opioid use (aOR = 2.5 (95% CI: 1.12, 5.58)) and cocaine use (aOR = 1.95 (CI 95%: 1.00, 3.81)).Conclusion: Food insecurity was not associated with unhealthy alcohol use but was associated with cocaine and illicit opioid use. Given the prevalence and impact substance use has on PLWH, food insecurity should be identified and addressed.

Interprofessional education in the clinical learning environment: a mixed-methods evaluation of a longitudinal experience in the primary care setting.

Team collaboration in our healthcare workforce is necessary to effectively address multifaceted medical and social needs, especially for those impacted by systemic inequities. Effective interprofessional practice and education models including curricula are needed to prepare a practice ready healthcare workforce for team collaboration. Most healthcare trainee interprofessional experiences take place episodically in classroom settings. However, creating a culture that supports team-based learning and interprofessional clinical practice requires teaching skills (e.g., communication, collaboration, shared decision-making, coordination of care) longitudinally in the clinical setting. A weekly interprofessional clinic for patients/clients with chronic health conditions was organized in three primary care practices. Trainees from nutrition, social work, medicine, and physician assistant programs worked with supervising clinicians from each field. Surveys, interviews, and focus groups assessed the effects of interprofessional education and training in the primary care setting. Results show the longitudinal experiential IPE program significantly improved knowledge, attitudes, skills, and values addressing key interprofessional competencies. Qualitative results complement survey data and highlight key themes addressing patient-centered care and team dynamics. These findings demonstrate the importance of longitudinal, immersive team-based interprofessional training in the clinical learning environment.

Health-related quality of life among colorectal cancer survivors of diverse sexual orientations.

BACKGROUND: The purpose of this study was to examine the health-related quality of life of sexual minority survivors in comparison with heterosexual survivors. METHODS: Four hundred eighty eligible survivors participated in a telephone survey that measured survivors' outcomes, which consisted of physical and mental quality of life and self-rated fair or poor health. These survivors were diagnosed with stage I, II, or III colorectal cancer an average of 3 years before the survey and were recruited from 4 cancer registries. Using forward selection with generalized linear models or logistic regression models, the authors considered 4 domains-personal factors, environmental factors, health condition characteristics, and body function and structure-as correlates for each survivorship outcome. RESULTS: The authors found that unadjusted physical quality of life and self-rated fair/poor health were similar for all survivors. Sexual minority survivors had poorer unadjusted mental quality of life in comparison with heterosexual survivors. After adjustments for covariates, this difference was no longer statistically significant. Three domains (personal factors, health condition characteristics, and body function and structure) explained colorectal cancer survivors' fair/poor health and 46% of the variance in physical quality of life, whereas 56% of the variance in mental quality of life was explained by personal factors, body function and structure, and environmental factors. CONCLUSIONS: This study has identified modifiable factors that can be used to improve cancer survivors' quality of life and are, therefore, relevant to ongoing efforts to improve the survivorship experience.

Safety, Tissue Distribution, and Metabolism of LNA-Containing Antisense Oligonucleotides in Rats.

Antisense oligonucleotides (ASOs) are chemically modified nucleic acids with therapeutic potential, some of which have been approved for marketing. We performed a study in rats to investigate mechanisms of toxicity after administration of 3 tool locked nucleic acid (LNA)-containing ASOs with differing established safety profiles. Four male rats per group were dosed once, 3, or 6 times subcutaneously, with 7 days between dosing, and sacrificed 3 days after the last dose. These ASOs were either unconjugated (naked) or conjugated with N-acetylgalactosamine for hepatocyte-targeted delivery. The main readouts were in-life monitoring, clinical and anatomic pathology, exposure assessment and metabolite identification in liver and kidney by liquid chromatography coupled to tandem mass spectrometry, ASO detection in liver and kidney by immunohistochemistry, in situ hybridization, immune electron microscopy, and matrix-assisted laser desorption/ionization mass spectrometry imaging. The highly toxic compounds showed the greatest amount of metabolites and a low degree of tissue accumulation. This study reveals different patterns of cell death associated with toxicity in liver (apoptosis and necrosis) and kidney (necrosis only) and provides new ultrastructural insights on the tissue accumulation of ASOs. We observed that the immunostimulatory properties of ASOs can be either primary from sequence-dependent properties or secondary to cell necrosis.

Subnanometre-resolution electron cryomicroscopy structure of a heterodimeric ABC exporter.

ATP-binding cassette (ABC) transporters translocate substrates across cell membranes, using energy harnessed from ATP binding and hydrolysis at their nucleotide-binding domains. ABC exporters are present both in prokaryotes and eukaryotes, with examples implicated in multidrug resistance of pathogens and cancer cells, as well as in many human diseases. TmrAB is a heterodimeric ABC exporter from the thermophilic Gram-negative eubacterium Thermus thermophilus; it is homologous to various multidrug transporters and contains one degenerate site with a non-catalytic residue next to the Walker B motif. Here we report a subnanometre-resolution structure of detergent-solubilized TmrAB in a nucleotide-free, inward-facing conformation by single-particle electron cryomicroscopy. The reconstructions clearly resolve characteristic features of ABC transporters, including helices in the transmembrane domain and nucleotide-binding domains. A cavity in the transmembrane domain is accessible laterally from the cytoplasmic side of the membrane as well as from the cytoplasm, indicating that the transporter lies in an inward-facing open conformation. The two nucleotide-binding domains remain in contact via their carboxy-terminal helices. Furthermore, comparison between our structure and the crystal structures of other ABC transporters suggests a possible trajectory of conformational changes that involves a sliding and rotating motion between the two nucleotide-binding domains during the transition from the inward-facing to outward-facing conformations.

Assessing the relationship between symptoms and health care utilization in colorectal cancer survivors of different sexual orientations.

OBJECTIVE: The purpose of this study was to determine the association of physical and psychological symptoms with health care utilization in sexual minority and heterosexual colorectal cancer survivors. METHODS: Four hundred eighteen colorectal cancer survivors who were in remission an average of 3 years after their diagnosis were surveyed about their non-emergency health care visits during the preceding 3 months. Survivors reported whether they had experienced any of 21 symptoms common among colorectal cancer survivors in the past week. The relation between having had two or more health care visits in the preceding 3 months and symptoms experienced was assessed using logistic regression, controlling for cancer registry, sexual orientation, sex, age, race/ethnicity, income, and comorbidities. RESULTS: Of the survivors, 12% reported no symptoms, while 12% reported six or more symptoms. Sexual minority survivors reported significantly more weight concerns and more health-related and general anxiety as well as worse body image than heterosexual survivors. Frequent worrying about weight and experiencing sore skin around the anal area or stoma were the two symptoms that significantly contributed towards explaining survivors' increased health care utilization. CONCLUSION: Weight concerns, which are more common among the heaviest survivors, may prompt survivors to seek help from health care providers, which may lead to more frequent visits. On the other hand, some symptoms, despite their prevalence, had no relationship with the frequency of health care visits, raising questions about whether survivors share these concerns with providers.

Prenatal and early childhood exposure to tetrachloroethylene (PCE) and non-medical use of prescription drugs: A retrospective cohort study in Cape Cod, MA.

BACKGROUND: Between 1968 and 1983, public drinking water supplies of Cape Cod, Massachusetts were contaminated with the chlorinated solvent tetrachloroethylene (PCE). We previously found an affinity for risk-taking behaviors, including the use of illicit drugs, following prenatal and early childhood exposure to PCE. Using newly collected data, we investigated the risk of non-medical use of prescription drugs (NMUPD) following prenatal and early childhood PCE exposure. METHODS: Participants were identified from a retrospective cohort study ("Cape Cod Health Study") via cross-matching birth certificates and water system data. The original self-administered questionnaire gathered data on demographics, work and medical history, and alcohol and illicit drug use from 618 individuals (363 exposed and 255 unexposed). The follow-up survey added questions on non-medical use of prescription pain relievers, tranquilizers, stimulants and sedatives. A validated leaching and transport model was used to estimate exposure to PCE exposure in drinking water. RESULTS: There was a wide distribution of cumulative prenatal and early childhood PCE exposure levels (range: 0.04 g-3722.2 g). PCE exposed subjects had a 1.92-fold increase in risk of any non-medical use of prescription drugs [Adjusted RR: 1.92, (95% CI: 1.31, 2.83)]. Furthermore, the association followed a dose-response relationship where the risk of NMUPD was higher for those exposed to PCE levels greater than or equal the median level versus those exposed to levels less than the median [Adjusted RR: 2.05 (95% CI: 1.34, 3.15) vs. 1.83 (95% CI: 1.20, 2.79) (p-value for trend < 0.01)]. Additionally, we found moderate increases in risk by level of non-medical use (any non-medical use, non-medical use of 1 or more categories of prescription drugs, or 2+ categories) as well as by category of drug for pain relivers, stimulants and tranquilizers. CONCLUSION: We found that prenatal and early childhood exposure to PCE was associated with a moderate increase in the risk of NMUPD. Exposed subjects had dose-related increased risks of NMUPD of pain relievers, tranquilizers, and stimulants. This study has a number of limitations and is the first to report this association. Additional longitudinal studies of populations exposed to PCE during early life should be conducted to examine its long-term neurotoxic effects.

Hemophagocytic Lymphohistiocytosis Occurring in Inflammatory Bowel Disease: Systematic Review.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and aggressive syndrome of excessive cytokine requiring prompt recognition and aggressive therapy. AIMS: We aimed to systematically characterize HLH in moderate-to-severe inflammatory bowel disease (IBD). METHODS: We performed a systematic review of the literature (PubMED; EMBASE) and FDA Adverse Event Reporting System in accordance with the PRISMA statement. Use of biologics was used as a surrogate definition for disease severity (consistent with usual and contemporary clinical management), to enable identification of rare HLH cases with the highest fidelity. RESULTS: 58 cases of HLH occurring in IBD patients are known (mean age: 26.0 years, 70% male, 83% with Crohn's disease, mean disease duration 7.0 years). 34.5% of patients were undergoing induction therapy at HLH diagnosis. All cases occurred on patients exposed to anti-TNF agents, but cases with anti-integrin or anti-IL-12/23 exposure were reported. 2/3 of cases did not report prior AZA/6MP exposure. Underlying opportunistic infection or lymphoma was found in > 80% of cases. Survival was 70% if promptly recognized and treated. Five patients restarted biologics after HLH resolved, and one patient developed recurrent HLH. CONCLUSIONS: HLH is rare among IBD patients exposed to biologic therapy. Most cases had an identifiable infection or malignancy at the time of diagnosis as well as history of immunomodulator use. Risk factors may include younger age, male gender, presence of Crohn's disease, and induction phase of treatment. Our study is not intended to assess risk of HLH with specific IBD therapies.