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Maintained green space in underserved urban neighborhoods may be an important environmental pathway to improving community health and safety, though effects may vary across population subgroups and by time of day. We examined survey responses from 442 participants (178 men and 264 women), living near vacant lots in a cluster-randomized controlled trial of a cleaning and greening intervention, on perceived safety during the day and at night. At the intervention sites after the intervention, only men reported feeling less unsafe during the day. Women reported more fear, and men reported less fear, after the intervention, although these results and tests for effect modification were not statistically significant. The clean-and-green intervention may have allayed fears for men during the day and supported their ease of movement throughout their neighborhoods. However, at night, it may have had the opposite effect on women. Though our study was under-powered, not designed to test associations stratified by gender, directions and magnitudes of associations differed substantially, indicating a need for further investigations into potential gender differences in the benefits of green space, to inform and better tailor interventions to improve perceived safety for all.

BACKGROUND: We sought to evaluate safety of electrical cardioversion (ECV) for patients with acute atrial fibrillation (AF) or atrial flutter (AFL) in the emergency department (ED). METHODS: This was an analysis of data from four multicentre AF/AFL studies conducted between 2008 and 2019 at 23 large EDs. We included adult patients who received attempts at ECV and who had presented acutely after symptom onset. Staff manually reviewed study and clinical records to abstract data. RESULTS: We evaluated 1,736 ECV cases with mean age 60.1 years and male 67.1%. The overall success of ECV was 90.2% (95% CI 88.7-91.6%) with 4.9% of patients admitted. ED physicians performed the ECV in 95.2% and provided sedation in 96.5%. 13.9% (12.3-15.7%) of cases experienced important adverse events that required treatment and 0.4% were classified life-threatening. Another 5.6% had adverse events that did not require treatment. Logistic regression found that the RAFF3 study cohort (OR 2.0), age ≥85 years (OR 2.1), coronary artery disease (OR 1.5), midazolam (OR 1.9), and fentanyl (OR 1.5) were associated with important adverse events. CONCLUSIONS: This large evaluation of the safety of ECV for acute AF/AFL in the ED found that while serious adverse events were rare, there were a concerning number of events following sedation that required intervention. Physicians should be aware that older age, coronary artery disease, and fentanyl are associated with a higher risk of important adverse events. This study provides more information for shared decision-making discussions with patients when choosing between drug-shock and shock-only cardioversion strategies.

Cutaneous squamous cell carcinomas (SCCs) are frequent heterogeneous tumors arising from sun-exposed regions of the skin and characterized by complex pathogenesis. HOPX is a member of the homeodomain-containing superfamily of proteins holding an atypical homeodomain unable to bind to DNA. First discovered in the heart as a regulator of cardiac development, in the skin, HOPX modulates the terminal differentiation of keratinocytes. There is a particular interest in studying HOPX in squamous skin carcinogenesis because it has the atypical structure and the functional duality as an oncogene and a tumor suppressor gene, reported in different malignancies. In this study, we analyzed the effects of HOPX knockdown and overexpression on SCC tumorigenicity in vitro and in vivo. Our data show that HOPX knockdown in SCC cells inhibits their proliferative and invasive activity through the acceleration of apoptosis. We established that methylation of two alternative HOPX promoters leads to differential expression of HOPX transcripts in normal keratinocytes and SCC cells. Importantly, we report that HOPX acts as an oncogene in the pathogenesis of SCC probably through the activation of the second alternative promoter and the modulation of apoptosis.

Unmaintained vacant land in urban areas is associated with a number of negative outcomes for residents of urban areas, including mental and physical health, safety, and quality of life. Community programs which promote land parcel maintenance in urban neighborhoods have been found to reverse some of the effects that unmaintained land has on nearby residents. We explored how land parcel maintenance is associated with mental health outcomes using data collected in Flint, MI in 2017–2018. Trained observers assessed the maintenance of approximately 7200 land parcels and surveyed 691 residents (57% Female, 53% Black, M age = 51). We aggregated resident and parcel rating data to 463 street segments and compared three structural equation models (SEM) to estimate the mediating effects of fear of crime on the association of parcel qualities on mental distress for residents. We found that fear of crime mediated the association between parcel maintenance values and mental distress indicating that poor maintenance predicted more fear of crime which was associated with mental distress. Our findings add to our understanding about the mechanism by which vacant lot improvements may operate to enhance psychological well-being of residents who live on streets with vacant and unkept lots.

ImportanceEarly and accurate diagnostic testing for SARS-CoV-2 is essential to initiate appropriate treatment and infection control and prevention measures among patients presenting to the hospital.ObjectiveTo evaluate the diagnostic sensitivity of the SARS-CoV-2 nucleic acid amplification test (NAAT) performed within 24 hours of arrival to the emergency department among a nationally representative sample of patients.Design, Setting, and ParticipantsThis diagnostic study was conducted at 47 hospitals across 7 provinces in Canada participating in the Canadian COVID-19 Rapid Response Emergency Department Network among consecutive eligible patients presenting to a participating emergency department who were tested for SARS-CoV-2 from March 1, 2020, to December 31, 2021. Patients not tested within 24 hours of arrival and those presenting with a positive result from a test performed in the community were excluded.Main Outcomes and MeasuresThe primary outcome was a positive result from the SARS-CoV-2 NAAT. Outcome measures were the diagnostic sensitivity and yield of the SARS-CoV-2 NAAT.ResultsOf 132 760 eligible patients (66 433 women [50.0%]; median age, 57 years [IQR, 37-74 years]), 17 174 (12.9%) tested positive for SARS-CoV-2 within 14 days of their first NAAT. The diagnostic sensitivity of the SARS-CoV-2 NAAT was 96.2% (17 070 of 17 740 [95% CI, 95.9%-96.4%]) among all of the tests performed. Estimates ranged from a high of 97.7% (1710 of 1751 [95% CI, 96.8%-98.3%]) on day 2 of symptoms to a low of 90.4% (170 of 188 [95% CI, 85.3%-94.2%]) on day 11 of symptoms among patients presenting with COVID-19 symptoms. Among patients reporting COVID-19 symptoms, the sensitivity of the SARS-CoV-2 NAAT was 97.1% (11 870 of 12 225 [95% CI, 96.7%-97.3%]) compared with 87.6% (812 of 927 [95% CI, 85.2%-89.6%]) among patients without COVID-19 symptoms. The diagnostic yield of the SARS-CoV-2 NAAT was 12.0% (18 985 of 158 004 [95% CI, 11.8%-12.2%]) and varied from a high of 20.0% (445 of 2229 [95% CI, 18.3%-21.6%]) among patients tested on day 10 after symptom onset to a low of 8.1% (1686 of 20 719 [95% CI, 7.7%-8.5%]) among patients presenting within the first 24 hours of symptom onset.Conclusions and RelevanceThis study suggests that the diagnostic sensitivity was high for the first SARS-CoV-2 NAAT performed in the hospital and did not vary significantly by symptom duration. Repeated testing of patients with negative test results should be avoided unless their pretest probability of disease is high.

Background Numerous scoring tools have been developed for assessing the probability of SARS-COV-2 test positivity, though few being suitable or adapted for outpatient triage of health care workers. Methods We retrospectively analysed 3069 patient records of health care workers admitted to the COVID-19 Testing Unit of the Ludwig-Maximilians-Universität of Munich between January 27 and September 30, 2020, for real-time polymerase chain reaction analysis of naso- or oropharyngeal swabs. Variables for a multivariable logistic regression model were collected from self-completed case report forms and selected through stepwise backward selection. Internal validation was conducted by bootstrapping. We then created a weighted point-scoring system from logistic regression coefficients. Results 4076 (97.12%) negative and 121 (2.88%) positive test results were analysed. The majority were young (mean age: 38.0), female (69.8%) and asymptomatic (67.8%). Characteristics that correlated with PCR-positivity included close-contact professions (physicians, nurses, physiotherapists), flu-like symptoms (e.g., fever, rhinorrhoea, headache), abdominal symptoms (nausea/emesis, abdominal pain, diarrhoea), less days since symptom onset, and contact to a SARS-COV-2 positive index-case. Variables selected for the final model included symptoms (fever, cough, abdominal pain, anosmia/ageusia) and exposures (to SARS-COV-positive individuals and, specifically, to positive patients). Internal validation by bootstrapping yielded a corrected Area Under the Receiver Operating Characteristics Curve of 76.43%. We present sensitivity and specificity at different prediction cut-off points. In a subgroup with further workup, asthma seems to have a protective effect with regard to testing result positivity and measured temperature was found to be less predictive than anamnestic fever. Conclusions We consider low threshold testing for health care workers a valuable strategy for infection control and are able to provide an easily applicable triage score for the assessment of the probability of infection in health care workers in case of resource scarcity.

We evaluated the safety and efficacy of a resveratrol-paclitaxel-coated peripheral balloon catheter in an all-comer patient cohort undergoing endovascular treatment of above-the-knee and below-the-knee peripheral artery disease. CONSEQUENT ALL COMERS (Clinical Post-Market Clinical Follow-up [PMCF] on Peripheral Arteries treated with SeQuent Please OTW [Over-the Wire]) is a prospective, single-arm, multicenter observational study (ClinicalTrials Identifier: NCT02460042). The primary end point was the 12-month target lesion revascularization (TLR) rate. Secondary end points included vessel patency, target vessel revascularization, and all-cause mortality. A total of 879 lesions in 784 consecutive patients (71.3 ± 10.4 years old, 57.7% male) were analyzed; 53.3% had claudication, whereas the remaining 46.7% exhibited critical limb ischemia (CLI). Substantial comorbidities were present, including diabetes mellitus (41.2%), smoking (66.1%), and coronary artery disease (33.9%). Lesion length (879 lesions) was 12.0 ± 9.3 cm and 31.8% were Transatlantic Inter-Society Consensus II C/D lesions. The overall technical success rate of the 1269 drug-coated balloon (DCB)’s used was 99.6% (1.60 ± 0.79 DCB’s/patient). At 12 months, the TLR rates were 6.3% in patients with CLI and 9.6% in claudicants, with a primary patency rate of 89.9% and 87.1%, respectively. All-cause mortality was 4.3% (28/658). The most important predictors for TLR were female gender, in-stent restenosis at baseline and lesion length.

Aims Obesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the ‘NACHT, LRR, and PYD Domains-containing Protein 3’ (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF. Methods and results Western blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of obese patients, sheep, and diet-induced obese (DIO) mice. The increased body weight in patients, sheep, and mice was associated with enhanced NLRP3-inflammasome activation. To determine whether NLRP3 contributes to the obesity-induced atrial arrhythmogenesis, wild-type (WT) and NLRP3 homozygous knockout (NLRP3−/−) mice were subjected to high-fat-diet (HFD) or normal chow (NC) for 10 weeks. Relative to NC-fed WT mice, HFD-fed WT mice were more susceptible to pacing-induced AF with longer AF duration. In contrast, HFD-fed NLRP3−/− mice were resistant to pacing-induced AF. Optical mapping in DIO mice revealed an arrhythmogenic substrate characterized by abbreviated refractoriness and action potential duration (APD), two key determinants of reentry-promoting electrical remodeling. Upregulation of ultra-rapid delayed-rectifier K+-channel (Kv1.5) contributed to the shortening of atrial refractoriness. Increased profibrotic signaling and fibrosis along with abnormal Ca2+ release from sarcoplasmic reticulum (SR) accompanied atrial arrhythmogenesis in DIO mice. Conversely, genetic ablation of Nlrp3 (NLRP3−/−) in HFD-fed mice prevented the increases in Kv1.5 and the evolution of electrical remodeling, the upregulation of profibrotic genes, and abnormal SR Ca2+ release in DIO mice. Conclusion These results demonstrate that the atrial NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmogenesis and establishes a mechanistic link between obesity-induced AF and NLRP3-inflammasome activation.

Background Substance use is common among people who visit emergency departments (EDs) frequently. We aimed to characterize subgroups within this cohort to better understand care needs/gaps, and generalizability of characteristics in three Canadian provinces. Methods This was a retrospective cohort study (April 1st, 2013 to March 31st, 2016) of ED patients in Ontario, Alberta, and British Columbia (B.C.) We included patients ≥ 18 years with substance use-related healthcare contact during the study period and frequent ED visits, defined as those in the top 10% of ED utilization when all patients were ordered by annual ED visit number. We used linked administrative databases including ED visits and hospitalizations (all provinces); mental heath-related hospitalizations (Ontario and Alberta); and prescriptions, physician services, and mortality (B.C.). We compared to cohorts of people with (1) frequent ED visits and no substance use, and (2) non-frequent ED visits and substance use. We employed cluster analysis to identify subgroups with distinct visit patterns and clinical characteristics during index year, April 1st, 2014 to March 31st, 2015. Results In 2014/15, we identified 19,604, 7,706, and 9,404 people with frequent ED visits and substance use in Ontario, Alberta, and B.C (median 37–43 years; 60.9–63.0% male), whose ED visits and hospitalizations were higher than comparison groups. In all provinces, cluster analyses identified subgroups with “extreme” and “moderate” frequent visits (median 13–19 versus 4–6 visits/year). “Extreme” versus “moderate” subgroups had more hospitalizations, mental health-related ED visits, general practitioner visits but less continuity with one provider, more commonly left against medical advice, and had higher 365-day mortality in B.C. (9.3% versus 6.6%; versus 10.4% among people with frequent ED visits and no substance use, and 4.3% among people with non-frequent ED visits and substance use). The most common ED diagnosis was acute alcohol intoxication in all subgroups. Conclusions Subgroups of people with “extreme” (13–19 visits/year) and “moderate” (4–6 visits/year) frequent ED visits and substance use had similar utilization patterns and characteristics in Ontario, Alberta, and B.C., and the “extreme” subgroup had high mortality. Our findings suggest a need for improved evidence-based substance use disorder management, and strengthened continuity with primary and mental healthcare.

Background Frequent emergency department users disproportionately account for rising health care costs. We aimed to characterize frequent emergency department users in British Columbia, Canada. Methods We performed a retrospective analysis using health administrative databases. We included patients aged 18 years or more with at least 1 emergency department visit from 2012/13 to 2015/16, linked to hospital, physician billing, prescription and mortality data. We used annual emergency department visits made by the top 10% of patients to define frequent users (≥ 3 visits/year). Results Over the study period, 13.8%-15.3% of patients seen in emergency departments were frequent users. We identified 205 136 frequent users among 1 196 353 emergency department visitors. Frequent users made 40.3% of total visits in 2015/16. From 2012/13 to 2015/16, their visit rates per 100 000 BC population showed a relative increase of 21.8%, versus 13.1% among all emergency department patients. Only 1.8% were frequent users in all study years. Mental illness accounted for 8.2% of visits among those less than 60 years of age, and circulatory or respiratory diagnoses for 13.3% of visits among those aged 60 or more. In 2015/16, frequent users were older and had lower household incomes than nonfrequent users; the sex distribution was similar. Frequent users had more prescriptions (median 9, interquartile range [IQR] 5-14 v. 1, IQR 1-3), primary care visits (median 15, IQR 9-27 v. 7, IQR 4-12) and hospital admissions (median 2, IQR 1-3 v. 1, IQR 1-1), and higher 1-year mortality (10.2% v. 3.5%) than nonfrequent users. Interpretation Emergency department use by frequent users increased in BC between 2012/13 and 2015/16; these patients were heterogenous, had high mortality and rarely remained frequent users over multiple years. Our results suggest that interventions must account for heterogeneity and address triggers of frequent use episodes.

As of 10 April 2020, New York State had 180,458 cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 9,385 reported deaths. Patients with cancer comprised 8.4% of deceased individuals1. Population-based studies from China and Italy suggested a higher coronavirus disease 2019 (COVID-19) death rate in patients with cancer2,3, although there is a knowledge gap as to which aspects of cancer and its treatment confer risk of severe COVID-194. This information is critical to balance the competing safety considerations of reducing SARS-CoV-2 exposure and cancer treatment continuation. From 10 March to 7 April 2020, 423 cases of symptomatic COVID-19 were diagnosed at Memorial Sloan Kettering Cancer Center (from a total of 2,035 patients with cancer tested). Of these, 40% were hospitalized for COVID-19, 20% developed severe respiratory illness (including 9% who required mechanical ventilation) and 12% died within 30 d. Age older than 65 years and treatment with immune checkpoint inhibitors (ICIs) were predictors for hospitalization and severe disease, whereas receipt of chemotherapy and major surgery were not. Overall, COVID-19 in patients with cancer is marked by substantial rates of hospitalization and severe outcomes. The association observed between ICI and COVID-19 outcomes in our study will need further interrogation in tumor-specific cohorts.

Background Identifying individuals at highest risk maximizes efficacy of prevention programs in decreasing recidivist gunshot wound (GSW) injury. Characteristics of GSW recidivists may identify this population. Hospital-based violence intervention programs (HVIPs) are one effective strategy; however, programs are expensive, therefore, when possible, epidemiologic data should guide inclusion criteria. Methods Seventeen years of all GSW patients presenting to an urban Level I trauma center were reviewed. Countywide murders were reviewed from the same timeframe. Recidivists were any patient presenting twice, either to the hospital or once to the hospital and subsequently dying by firearm. Demographics and characteristics of future recidivists were compared with nonfuture recidivists. Results There were 9,699 unique intentional, GSW cases reviewed and 1,426 died, leaving 8,273 at risk of recidivism. Five hundred fourteen (6.2%) became recidivists. Most recidivists were African-American men and were younger at first GSW. Median time between incidents was 2.5 years, with a range of 0 days to 16 years. Nearly half were treated and released from the emergency department at their first episode of GSW. For recidivists who died, 128 died at the second incident, 29 at later incidents. Mortality from a second incident of firearm injury is 10% higher than first injuries, second hospitalizations are US $5,000 more expensive, and loss of life has a societal cost of US $167 billion in this community alone. Conclusion The most appropriate population for inclusion in HVIPs at our hospital are young black men. The HVIP services are needed in the emergency department to address those treated and released at first GSW. Recidivists have higher mortality, and hospitalizations are significantly more expensive at the second injury. The investment in prevention is justified and may lead to a decrease in recidivism. Level of evidence Therapeutic/Care Management level III.

BackgroundOne in nine emergency department (ED) visits in Canada are caused by adverse drug events, the unintended and harmful effects of medication use. Medication reviews by clinical pharmacists are interventions designed to optimize medications and address adverse drug events to impact patient outcomes. However, the effect of medication reviews on long-term outpatient health services utilization is not well understood. This research studied the effect of medication review performed by clinical pharmacists on long-term outpatient health services utilization.MethodsData included information from 10,783 patients who were part of a prospective, multi-centre quality improvement evaluation from 2011 to 2013. Outpatient health services utilization was defined as total ED visits and physician contacts, aggregated to four physician specialty groups: general and family practitioners (GP); medical specialists; surgical specialists; and imaging and laboratory specialists. During triage, patients deemed high-risk based on their medical history, were systematically allocated to receive either a medication review (n = 6403) or the standard of care (n = 4380). Medication review involved a critical examination of a patient’s medications to identify and resolve medication-related problems and communicate these results to community care providers. Interrupted time series analysis compared the effect of the intervention on health services utilization relative to the standard of care controlling for pre-intervention differences in utilization.ResultsED-based pharmacist-led medication review did not result in a significant level or trend change in the primary outcome of total outpatient health services utilization. There were also no differences in the secondary outcomes of primary care physician visits or ED visits relative to the standard of care in the 12 months following the intervention. Our findings were consistent when stratified by age, hospital site, and whether patients were discharged on their index visit.ConclusionThis was the first study to measure long-term trends of physician visits following an ED-based medication review. The lack of differences in level and trend of GP and ED visits suggest that pharmacist recommendations may not have been adequately communicated to community-based providers, and/or recommendations may not have affected health care delivery. Future studies should evaluate physician acceptance of pharmacist recommendations and should encourage patient follow-up to community providers.

To assess the course of the COVID-19 pandemic and the impact of non-pharmaceutical interventions, the number of reported positive test results is frequently used as an estimate of the true number of population-wide infections. We conducted a retrospective observational analysis of patient data of the Corona Testing Unit (CTU) in Munich, Bavaria, Germany between January 27th, and September 30th, 2020. We analyzed the course of daily patient numbers over time by fitting a negative binomial model with multiple breakpoints. Additionally, we investigated possible influencing factors on patient numbers and characteristics by literature review of policy papers and key informant interviews with individuals involved in the set-up of the CTU. The 3,963 patients included were mostly young (median age: 34, interquartile range: 27–48), female (66.2%), and working in the healthcare sector (77%). For these, 5,314 real-time RT-PCR tests were conducted with 157 (2.94%) positive results. The overall curve of daily tests and positive results fits the re-ported state-wide incidence in large parts but shows multiple breakpoints with considerable trend changes. These can be most fittingly attributed to testing capacities and -strategies and individual risk behavior, rather than public health measures. With the large impact on patient numbers and pre-test probabilities of various strategic and operational factors, we consider the derived re-ported incidence as a poor measurement to base policy decisions on. Testing units should be prepared to encounter these fluctuations with a quickly adaptable structure.

To understand the health needs and challenges experienced by the patient population served by a student-run free clinic in Jackson, Mississippi.A retrospective chart review was conducted on all patients who presented between 2017 and 2019. Data collected included age, race, sex, hometown, number of visits, chief complaint, lab utilization, blood pressure, and body mass index.The patient population was 73.3% African American and 55.5% female and came from 88 different towns across Mississippi. Most patients (54.1%) came only once. Nearly half (46.7%) of African American patients and 50.0% of White patients were obese. The top three chief complaints were health management (40.3%), STI/UTI (9.3%), and musculoskeletal (7.5%).The data indicate a need for the development of programs to improve patient access to care and resources: a community health outreach program, a social health services program, and further studies to determine the effectiveness of care provided.

DUSP22 gene rearrangements are recurrent in systemic and cutaneous ALK-negative anaplastic large cell lymphomas, rarely encountered in other cutaneous CD30+ lymphoproliferations, and typically absent in other peripheral T-cell lymphomas. We report the case of a 51-year-old woman, with longstanding celiac disease and a rapidly enlarging leg ulcer, due to a DUSP22-rearranged CD30+ T-cell lymphoproliferation. Subsequent history revealed an intestinal enteropathy-associated T-cell lymphoma (EATL). Identical monoclonal TR gene rearrangements and mutations in STAT3 and JAK1 typical of EATL were present in the cutaneous and intestinal lesions. No DUSP22 rearrangement was detected in the patient's intestinal tumour, nor in 15 additional EATLs tested. These findings indicate that DUSP22 rearrangements are not entirely specific of ALCLs, may rarely occur as a secondary aberration in EATL, and expand the differential diagnosis of DUSP22-rearranged cutaneous CD30+ lymphoproliferative disorders.

Candida albicans is a pathobiont that colonizes multiple niches in the body including the gastrointestinal (GI) tract, but is also responsible for both mucosal and systemic infections. Despite its prevalence as a human commensal, the murine GI tract is generally refractory to colonization with the C. albicans reference isolate SC5314. Here, we identify two C. albicans isolates, 529L and CHN1, that stably colonize the murine GI tract in three different animal facilities under conditions where SC5314 is lost from this niche. Analysis of the bacterial microbiota did not show notable differences between mice colonized with the three C. albicans strains. We compared the genotypes and phenotypes of these three strains and identified thousands of SNPs and multiple phenotypic differences, including their ability to grow and filament in response to nutritional cues. Despite striking filamentation differences under laboratory conditions, however, analysis of cell morphology in the GI tract revealed that the three isolates exhibited similar filamentation properties in this in vivo niche. Notably, we found that SC5314 is more sensitive to the antimicrobial peptide CRAMP, and the use of CRAMP-deficient mice increased the ability of SC5314 to colonize the GI tract relative to CHN1 and 529L. These studies provide new insights into how strain-specific differences impact C. albicans traits in the host and advance CHN1 and 529L as relevant strains to study C. albicans pathobiology in its natural host niche.IMPORTANCEUnderstanding how fungi colonize the GI tract is increasingly recognized as highly relevant to human health. The animal models used to study Candida albicans commensalism commonly rely on altering the host microbiome (via antibiotic treatment or defined diets) to establish successful GI colonization by the C. albicans reference isolate SC5314. Here, we characterize two C. albicans isolates that can colonize the murine GI tract without antibiotic treatment and can therefore be used as tools for studying fungal commensalism. Importantly, experiments were replicated in three different animal facilities and utilized three different mouse strains. Differential colonization between fungal isolates was not associated with alterations in the bacterial microbiome but rather with distinct responses to CRAMP, a host antimicrobial peptide. This work emphasizes the importance of C. albicans intra-species variation as well as host anti-microbial defense mechanisms in defining commensal interactions.

Thymic epithelial cells (TECs) are essential in supporting the development of mature T cells from hematopoietic progenitor cells and facilitate their lineage-commitment, proliferation, T-cell receptor repertoire selection and maturation. While animal model systems have greatly aided in elucidating the contribution of stromal cells to these intricate processes, human tissue has been more difficult to study, partly due to a lack of suitable surface markers comprehensively defining human TECs. Here, we conducted a flow cytometry based surface marker screen to reliably identify and quantify human TECs and delineate medullary from cortical subsets. These findings were validated by transcriptomic and histologic means. The combination of EpCAM, podoplanin (pdpn), CD49f and CD200 comprehensively identified human TECs and not only allowed their reliable distinction in medullary and cortical subsets but also their detailed quantitation. Transcriptomic profiling of each subset in comparison to fibroblasts and endothelial cells confirmed the identity of the different stromal cell subsets sorted according to the proposed strategy. Our dataset not only demonstrated transcriptional similarities between TEC and cells of mesenchymal origin but furthermore revealed a subset-specific distribution of a specific set of extracellular matrix-related genes in TECs. This indicates that TECs significantly contribute to the distinct compartmentalization – and thus function – of the human thymus. We applied the strategy to quantify TEC subsets in 31 immunologically healthy children, which revealed sex-specific differences of TEC composition early in life. As the distribution of mature CD4- or CD8-single-positive thymocytes was correspondingly altered, the composition of the thymic epithelial compartment may directly impact on the CD4-CD8-lineage choice of thymocytes. We prove that the plain, reliable strategy proposed here to comprehensively identify human TEC subpopulations by flow cytometry based on surface marker expression is suitable to determine their frequency and phenotype in health and disease and allows sorting of live cells for downstream analysis. Its use reaches from a reliable diagnostic tool for thymic biopsies to improved phenotypic characterization of thymic grafts intended for therapeutic use., Frontiers in Immunology, 12, ISSN:1664-3224

Shedding of SARS-CoV-2 after Immunosuppression The prolonged contagious period after viral infection in immunocompromised patients may affect how long precautions will be necessary to reduce furthe...

The lack of stable housing can impair access and continuity of care for patients living with human immunodeficiency virus (HIV). This study investigated the relationship between housing status assessed at multiple time points and several core HIV-related outcomes within the same group of HIV patients experiencing homelessness. Patients with consistently stable housing (CSH) during the year were compared to patients who lacked CSH (non-CSH group). The study outcomes included HIV viral load (VL), CD4 counts, and health care utilization. Multivariable and propensity weighted analyses were used to assess outcomes adjusting for potential group differences. Of 208 patients, 88 (42%) had CSH and 120 (58%) were non-CSH. Patients with CSH had significantly higher proportion of VL suppression and higher mean CD4 counts. The frequency of nurse visits in the CSH group was less than a half of that in the non-CSH group. Patients with CSH were less likely to be admitted to the medical respite facility, and if admitted, their length of stay was about a half of that for the non-CSH group. Our study findings show that patients with CSH had significantly better HIV virologic control and immune status as well as improved health care utilization.

Macrophages are important in mounting an innate immune response to injury as well as in repair of injury. Gene expression of Rho proteins is known to be increased in fibrotic models; however, the role of these proteins in idiopathic pulmonary fibrosis (IPF) is not known. Here, we show that BAL cells from patients with IPF have a profibrotic phenotype secondary to increased activation of the small GTPase Rac1. Rac1 activation requires a posttranslational modification, geranylgeranylation, of the C-terminal cysteine residue. We found that by supplying more substrate for geranylgeranylation, Rac1 activation was substantially increased, resulting in profibrotic polarization by increasing flux through the mevalonate pathway. The increased flux was secondary to greater levels of acetyl-CoA from metabolic reprogramming to β oxidation. The polarization mediated fibrotic repair in the absence of injury by enhancing macrophage/fibroblast signaling. These observations suggest that targeting the mevalonate pathway may abrogate the role of macrophages in dysregulated fibrotic repair.

Summary Decitabine is a DNA‐hypomethylating agent that has been widely applied for the treatment of acute myeloid leukaemia (AML) patients who are elderly or unfit for intensive therapy. Although effective, the complete response rate to decitabine is only around 30% and the overall survival remains poor. Emerging data support that regulation of DNA methylation is critical to control immune cell development, differentiation and activation. We hypothesize that defining how decitabine influences the immune responses in AML will facilitate the development of novel immune‐based leukaemia therapeutics. Here, we performed phenotypic and functional immune analysis on clinical samples from AML patients receiving decitabine treatment and demonstrated a significant impact of decitabine on the immune system. T‐cell expression of inhibitory molecules was upregulated and the ability of CD8 T cells to produce cytokines was decreased upon decitabine treatment. Importantly, in an unbiased comprehensive analysis, we identified a unique immune signature containing a cluster of key immune markers that clearly separate patients who achieved complete remission after decitabine from those who failed to do so. Therefore, this immune signature has a strong predictive value for clinical response. Collectively, our study suggests that immune‐based analyses may predict clinical response to decitabine and provide a therapeutic strategy to improve the treatment of AML.

Background Overall time spent in moderate-to-vigorous intensity physical activity (MVPA) and sedentary behavior are both correlated in couples. Knowledge about the nature and psychosocial correlates of such dyadic covariation could inform important avenues for physical activity promotion. Purpose The present study investigates hour-by-hour covariation between partners (i.e., synchrony) in MVPA and sedentary behavior as partners engage in their daily lives and links it with person-level MVPA/sedentary behavior, temporal characteristics, and relationship variables. Methods We used 7-day accelerometer data from two couple studies (Study 1, n = 306 couples, aged 18–80 years; Study 2, n = 108 couples, aged 60–87 years) to estimate dyadic covariation in hourly MVPA and sedentary behavior between partners. Data were analyzed using coordinated multilevel modeling. Results In both studies, hourly MVPA and sedentary behavior exhibited similarly sized dyadic covariation between partners in the low-to-medium range of effects. Higher MVPA synchrony between partners was linked with higher individual weekly MVPA and higher individual weekly sedentary levels, whereas higher sedentary synchrony between partners was associated with higher individual weekly MVPA but lower individual weekly sedentary levels. MVPA and sedentary synchrony were higher in the morning and evening, more pronounced on weekends, and associated with more time spent together, longer relationship duration, and time-varying perceptions of higher partner closeness. Conclusions This study demonstrates that MVPA and sedentary behaviors do not occur in a social vacuum. Instead, they are linked with close others such as partners. Thus, capitalizing on social partners may increase the effectiveness of individual-level physical activity interventions.

Summary Background HER2-positive breast cancers usually contain large amounts of T-cell infiltrate. We hypothesised that trastuzumab resistance in HER2-positive breast cancer could be mediated by immune mechanisms. We assessed the safety and anti-tumour activity of pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, added to trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer. Methods We did this single-arm, multicentre, phase 1b–2 trial in 11 centres based in five countries. Eligible participants were women aged 18 years or older, who had advanced, histologically confirmed, HER2-positive breast cancer; documented progression during previous trastuzumab-based therapy; an Eastern Cooperative Oncology Group performance status of 0 or 1; and a formalin-fixed, paraffin-embedded metastatic tumour biopsy for central assessment of programmed cell death 1 ligand 1 (PD-L1) status. In phase 1b, we enrolled patients with PD-L1-positive tumours in a 3 + 3 dose-escalation of intravenous pembrolizumab (2 mg/kg and 10 mg/kg, every 3 weeks) plus 6 mg/kg of intravenous trastuzumab. The primary endpoint of the phase 1b study was the incidence of dose-limiting toxicity and recommended phase 2 dose; however, a protocol amendment on Aug 28, 2015, stipulated a flat dose of pembrolizumab of 200 mg every 3 weeks in all Merck-sponsored trials. In phase 2, patients with PD-L1-positive and PD-L1-negative tumours were enrolled in parallel cohorts and received the flat dose of pembrolizumab plus standard trastuzumab. The primary endpoint of the phase 2 study was the proportion of PD-L1-positive patients achieving an objective response. This trial is registered in ClinicalTrials.gov, number NCT02129556, and with EudraCT, number 2013-004770-10, and is closed. Findings Between Feb 2, 2015, and April 5, 2017, six patients were enrolled in phase 1b (n=3 received 2 mg/kg pembrolizumab, n=3 received 10 mg/kg pembrolizumab) and 52 patients in phase 2 (n=40 had PD-L1-positive tumours, n=12 had PD-L1-negative tumours). The data cutoff for this analysis was Aug 7, 2017. During phase 1b, there were no dose-limiting toxicities in the dose cohorts tested. Median follow-up for the phase 2 cohort was 13·6 months (IQR 11·6–18·4) for patients with PD-L1-positive tumours, and 12·2 months (7·9–12·2) for patients with PD-L1-negative tumours. Six (15%, 90% CI 7–29) of 40 PD-L1-positive patients achieved an objective response. There were no objective responders among the PD-L1-negative patients. The most common treatment-related adverse event of any grade was fatigue (12 [21%] of 58 patients). Grade 3–5 adverse events occurred in 29 (50%) of patients, treatment-related grade 3–5 adverse events occurred in 17 (29%), and serious adverse events occurred in 29 (50%) patients. The most commonly occurring serious adverse events were dyspnoea (n=3 [5%]), pneumonitis (n=3 [5%]), pericardial effusion (n=2 [3%]), and upper respiratory infection (n=2 [3%]). There was one treatment-related death due to Lambert-Eaton syndrome in a PD-L1-negative patient during phase 2. Interpretation Pembrolizumab plus trastuzumab was safe and showed activity and durable clinical benefit in patients with PD-L1-positive, trastuzumab-resistant, advanced, HER2-positive breast cancer. Further studies in this breast cancer subtype should focus on a PD-L1-positive population and be done in less heavily pretreated patients. Funding Merck, International Breast Cancer Study Group.

Background: Massage therapy (MT) is a holistic procedure that includes hand pressure (HP), therapeutic communication (TC), and attentive care (AC); together, these procedures could decrease symptoms of depression. Purpose: To study the influence of TC and AC during MT. Methods: Within-subject experimental design with counterbalancing order of treatment. Comparison analysis of the effect of a typical Swedish massage session (SM) with a “sham” massage (ShM; without HP) on the heart rate variability (HRV) mood and affective responses of patients with major depressive disorder ( N = 11). During the ShM, clay stones were randomly placed on the body, and the patients were informed about the (sham) therapeutic effect of stones. Findings: A main effect of time showed that after intervention, both SM and ShM increased the HRV (high-frequency power; F[1, 10] = 7.58, p = .02) and reduced scores for anxiety ( F[1, 10] = 37.57, p < .001), other feelings ( F[1, 10] = 22.64, p = .001), and physical sedation ( F[1, 10] = 10.72, p = .008). The SM was associated with more positive affective responses than ShM (qualitative analysis). Conclusions: AC and TC included in MT session improved mood and HRV in the absence of HP. Additional effect on affective responses was observed owing to the HP.

BackgroundIn previous studies, we reported the beneficial impact of two lipoxygenase-inhibitors, Baicalein and Zileuton, on osteoporotic bone in a postmenopausal rat model. Whereas subcutaneous Baicalein predominantly improved cortical bone, Zileuton enhanced vertebral and femoral trabecular bone. In this study, we aimed to reveal whether the oral administration of Baicalein caused similar effects on bone and whether a combined administration of Baicalein and Zileuton could act synergistically to ameliorate the formerly reported effects in the musculoskeletal system.MethodsWe treated ovariectomized (OVX) female Sprague-Dawley rats either with Baicalein (10mg/kg BW), Zileuton (10mg/kg BW) or a combination of both (each 10mg/kg BW) for 13 weeks and compared with untreated OVX and NON-OVX groups (n=12-16 rats per group). Lumbar vertebral bodies and femora were analyzed. Tibiae were osteotomized, plate-stabilized (at week 8 after OVX) and likewise analyzed by biomechanical, histological, micro-computed tomographical and ashing tests. The skeletal muscle structure was analyzed.ResultsOral administration of Baicalein did not confirm the reported favorable cortical effects in neither vertebra nor femur. Zileuton showed a beneficial effect on trabecular vertebra, while the femur was negatively affected. Callus formation was enhanced by all treatments; however, its density and biomechanical properties were unaltered. Lipoxygenase inhibition did not show a beneficial effect on skeletal muscle. The combination therapy did not ameliorate OVX-induced osteoporosis but induced even more bone loss.ConclusionsThe preventive anti-osteoporotic treatments with two lipoxygenase inhibitors applied either alone or in combination showed no benefit for the musculoskeletal system in estrogen deficient rats.

Background The human leucocyte antigen (HLA) complex controls adaptive immunity by presenting defined fractions of the intracellular and extracellular protein content to immune cells. Understanding the benign HLA ligand repertoire is a prerequisite to define safe T-cell-based immunotherapies against cancer. Due to the poor availability of benign tissues, if available, normal tissue adjacent to the tumor has been used as a benign surrogate when defining tumor-associated antigens. However, this comparison has proven to be insufficient and even resulted in lethal outcomes. In order to match the tumor immunopeptidome with an equivalent counterpart, we created the HLA Ligand Atlas, the first extensive collection of paired HLA-I and HLA-II immunopeptidomes from 227 benign human tissue samples. This dataset facilitates a balanced comparison between tumor and benign tissues on HLA ligand level. Methods Human tissue samples were obtained from 16 subjects at autopsy, five thymus samples and two ovary samples originating from living donors. HLA ligands were isolated via immunoaffinity purification and analyzed in over 1200 liquid chromatography mass spectrometry runs. Experimentally and computationally reproducible protocols were employed for data acquisition and processing. Results The initial release covers 51 HLA-I and 86 HLA-II allotypes presenting 90,428 HLA-I- and 142,625 HLA-II ligands. The HLA allotypes are representative for the world population. We observe that immunopeptidomes differ considerably between tissues and individuals on source protein and HLA-ligand level. Moreover, we discover 1407 HLA-I ligands from non-canonical genomic regions. Such peptides were previously described in tumors, peripheral blood mononuclear cells (PBMCs), healthy lung tissues and cell lines. In a case study in glioblastoma, we show that potential on-target off-tumor adverse events in immunotherapy can be avoided by comparing tumor immunopeptidomes to the provided multi-tissue reference. Conclusion Given that T-cell-based immunotherapies, such as CAR-T cells, affinity-enhanced T cell transfer, cancer vaccines and immune checkpoint inhibition, have significant side effects, the HLA Ligand Atlas is the first step toward defining tumor-associated targets with an improved safety profile. The resource provides insights into basic and applied immune-associated questions in the context of cancer immunotherapy, infection, transplantation, allergy and autoimmunity. It is publicly available and can be browsed in an easy-to-use web interface at https://hla-ligand-atlas.org ., Journal for ImmunoTherapy of Cancer, 9 (4), ISSN:2051-1426

Aspergillus fumigatus is a filamentous fungus which can cause multiple diseases in humans. Allergic broncho-pulmonary aspergillosis (ABPA) is a disease diagnosed primarily in cystic fibrosis patients caused by a severe allergic response often to long-term A. fumigatus colonization in the lungs. Mice develop an allergic response to repeated inhalation of A. fumigatus spores; however, no strains have been identified that can survive long-term in the mouse lung and cause ABPA-like disease. We characterized A. fumigatus strain W72310, which was isolated from the expectorated sputum of an ABPA patient, by whole-genome sequencing and in vitro and in vivo viability assays in comparison to a common reference strain, CEA10. W72310 was resistant to leukocyte-mediated killing and persisted in the mouse lung longer than CEA10, a phenotype that correlated with greater resistance to oxidative stressors, hydrogen peroxide, and menadione, in vitro. In animals both sensitized and challenged with W72310, conidia, but not hyphae, were viable in the lungs for up to 21 days in association with eosinophilic airway inflammation, airway leakage, serum IgE, and mucus production. W72310-sensitized mice that were recall challenged with conidia had increased inflammation, Th1 and Th2 cytokines, and airway leakage compared to controls. Collectively, our studies demonstrate that a unique strain of A. fumigatus resistant to leukocyte killing can persist in the mouse lung in conidial form and elicit features of ABPA-like disease. IMPORTANCE Allergic broncho-pulmonary aspergillosis (ABPA) patients often present with long-term colonization of Aspergillus fumigatus. Current understanding of ABPA pathogenesis has been complicated by a lack of long-term in vivo fungal persistence models. We have identified a clinical isolate of A. fumigatus, W72310, which persists in the murine lung and causes an ABPA-like disease phenotype. Surprisingly, while viable, W72310 showed little to no growth beyond the conidial stage in the lung. This indicates that it is possible that A. fumigatus can cause allergic disease in the lung without any significant hyphal growth. The identification of this strain of A. fumigatus can be used not only to better understand disease pathogenesis of ABPA and potential antifungal treatments but also to identify features of fungal strains that drive long-term fungal persistence in the lung. Consequently, these observations are a step toward helping resolve the long-standing question of when to utilize antifungal therapies in patients with ABPA and fungal allergic-type diseases.

The gut microbiota produces metabolites that regulate host immunity, thereby impacting disease resistance and susceptibility. The extent to which commensal bacteria reciprocally respond to immune activation, however, remains largely unexplored. Herein, we colonized mice with four anaerobic symbionts and show that acute immune responses result in dramatic transcriptional reprogramming of these commensals with minimal changes in their relative abundance. Transcriptomic changes include induction of stress-response mediators and downregulation of carbohydrate-degrading factors such as polysaccharide utilization loci (PULs). Flagellin and anti-CD3 antibody, two distinct immune stimuli, induced similar transcriptional profiles, suggesting that commensal bacteria detect common effectors or activate shared pathways when facing different host responses. Immune activation altered the intestinal metabolome within 6 hours, decreasing luminal short-chain fatty acid and increasing aromatic metabolite concentrations. Thus, intestinal bacteria, prior to detectable shifts in community composition, respond to acute host immune activation by rapidly changing gene transcription and immunomodulatory metabolite production.

Background Adverse drug events are unintended and harmful effects of medication use. Using existing information and communication technologies (ICTs) to increase information sharing about adverse drug events may improve patient care but can introduce concerns about data privacy. Objective This study aims to examine the views of patients and their caregivers about data protection when using ICTs to communicate adverse drug event information to improve patient safety. Methods We conducted an exploratory qualitative study. A total of 4 focus groups were held among patients who had experienced or were at risk of experiencing an adverse drug event, their family members, and their caregivers. We recruited participants through multiple avenues and iteratively analyzed the data using situational analysis. Results Of the 47 participants recruited, 28 attended our focus groups. We identified 3 primary themes. First, participants felt that improved information sharing about adverse drug events within their circle of care would likely improve care. Second, participants were concerned about data handling and inappropriate access but believed that the benefits of information sharing outweighed the risks of privacy breaches. Finally, participants were more concerned about data privacy in the context of stigmatized health conditions. Conclusions Current conditions for maintaining health data privacy are consistent with participants’ preferences, despite the fact that health data are susceptible to breaches and mismanagement. Information sharing that increases patient safety may justify potential privacy risks. Greater attention to patient concerns and the effect of social and contextual concerns in the design and implementation of health information technologies may increase patient confidence in the privacy of their information.

Clinicians in resource-limited settings commonly use the World Health Organization criteria to diagnose pneumonia in children.The aim of this study was to prospectively evaluate the diagnostic accuracy of the WHO criteria compared with chest radiograph for the diagnosis of pneumonia in children under 5 years of age presenting to an emergency department (ED) in Nepal.A prospective cross-sectional study of children presenting to an ED with respiratory complaints in Nepal was conducted. It included all children under 5 years of age with cough or difficulty breathing who received a chest radiograph. Paediatric pneumonia was diagnosed according to WHO criteria when a child presented with a cough or difficulty breathing and met the age-related WHO-defined respiratory rate for tachypnoea. The criterion standard was radiographic pneumonia. The primary outcome was the sensitivity and specificity of the WHO criteria for diagnosis of pneumonia.Of 324 patients enrolled, 72 had radiographic pneumonia. The median (IQR) age was 17 (23) months. Overall, WHO criteria had a sensitivity of 71% (95% CI 59-81) and specificity of 57% (95% CI 50-63). Respiratory rate had poor diagnostic accuracy for pneumonia with an area under the curve of 0.65.The WHO criteria had poor sensitivity and specificity for the diagnosis of pneumonia in children presenting to the ED in a resource-limited setting.

Background/objectives Micro-induction is a novel buprenorphine induction approach that seeks to avoid withdrawal and minimize precipitated withdrawal, both barriers to standard inductions. We aimed to synthesize evidence on micro-induction effectiveness, and regimens described. Methods We searched scientific databases and grey literature for studies including adolescents or adults with opioid use disorder who received buprenorphine micro-induction. Study selection, data extraction and quality assessments occurred in duplicate. We narratively synthesized results. Results We screened 4,752 citations and included 19 case studies/series and one feasibility study (n = 57 patients; mean age 38 years [SD 12.0]; 57.9% male [33/57]). Studies described 26 regimens; starting and maintenance doses ranged from 0.03 to 1.0 mg, and 8 to 32 mg, respectively. We calculated rate of increase to 8 mg. All patients achieved the desired maintenance dose. Among 54 patients in whom precipitated withdrawal was not reported, mean increases were 1.36 mg/day (SD 0.41). For three patients in whom precipitated withdrawal was specifically reported, mean increase was 1.17 mg/day (SD 0.11). All studies were low quality. Discussion Described regimens are highly variable. Inconsistent reporting, selection bias, and poor quality evidence limit conclusions regarding optimal dosing, and patient characteristics and clinical settings in which micro-induction is likely beneficial. Conclusions This systematic review provides the most up-to-date synthesis on buprenorphine micro-induction regimens. Rigorous studies evaluating effectiveness and safety of micro-induction, and patient and clinical factors influencing its success, are needed.

Chronic granulomatous disease (CGD) is a primary immunodeficiency resulting in life-threatening infections and inflammatory complications. Allogeneic hematopoietic cell transplantation (allo-HCT) can cure the disease, but the indication to transplant remains controversial. We performed a retrospective multicenter study of 712 patients with CGD who underwent allo-HCT transplantation from March 1993 through December 2018. We studied 635 children (aged 1 antigen mismatch. Choice of conditioning regimen did not influence OS or EFS. In summary, we report an excellent outcome after allo-HCT in CGD, with low incidence of graft failure and mortality in all ages. Older patients and recipients of 1-antigen-mismatched grafts had a less favorable outcome. Transplantation should be strongly considered at a younger age and particularly in the presence of a well-matched donor.

Summary Fast synaptic transmission relies upon the activation of ionotropic receptors by neurotransmitter release to evoke postsynaptic potentials. Glutamate and GABA play dominant roles in driving highly dynamic activity in synaptically connected neuronal circuits, but ionotropic receptors for other neurotransmitters are also expressed in the neocortex, including nicotinic receptors, which are non-selective cation channels gated by acetylcholine. To study the function of non-glutamatergic excitation in neocortex, we used two-photon microscopy to target whole-cell membrane potential recordings to different types of genetically defined neurons in layer 2/3 of primary somatosensory barrel cortex in awake head-restrained mice combined with pharmacological and optogenetic manipulations. Here, we report a prominent nicotinic input, which selectively depolarizes a subtype of GABAergic neuron expressing vasoactive intestinal peptide leading to disinhibition during active sensorimotor processing. Nicotinic disinhibition of somatosensory cortex during active sensing might contribute importantly to integration of top-down and motor-related signals necessary for tactile perception and learning., Highlights • Acetylcholine is released in the mouse barrel cortex during active whisker sensing • Acetylcholine depolarizes inhibitory cells expressing vasoactive intestinal peptide • Excitation of vasoactive intestinal peptide-expressing neurons causes disinhibition • Cholinergic-driven disinhibition could gate sensorimotor integration and plasticity, Gasselin et al. report that acetylcholine released in the mouse barrel cortex during active whisker sensing selectively excites a class of inhibitory neurons characterized by expression of vasoactive intestinal peptide through nicotinic receptors causing disinhibition of sensory processing in nearby excitatory neurons.

BACKGROUND: Understanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell (CAR T) therapy at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations. METHODS: We retrospectively investigated patients diagnosed between March 15, 2020, and May 7, 2020. In a subset of patients, lymphocyte immunophenotyping, quantitative real-time PCR from nasopharyngeal swabs, and SARS-CoV-2 antibody status were available. RESULTS: We identified 77 patients with SARS-CoV-2 who were recipients of cellular therapy (Allo, 35; Auto, 37; CAR T, 5; median time from cellular therapy, 782 days; IQR, 354–1611 days). Overall survival at 30 days was 78%. Clinical variables significantly associated with the composite endpoint of nonrebreather or higher oxygen requirement and death (n events = 25 of 77) included number of comorbidities (HR 5.41, P = 0.004), infiltrates (HR 3.08, P = 0.032), and neutropenia (HR 1.15, P = 0.04). Worsening graft-versus-host disease was not identified among Allo recipients. Immune profiling revealed reductions and rapid recovery in lymphocyte populations across lymphocyte subsets. Antibody responses were seen in a subset of patients. CONCLUSION: In this series of Allo, Auto, and CAR T recipients, we report overall favorable clinical outcomes for patients with COVID-19 without active malignancy and provide preliminary insights into the lymphocyte populations that are key for the antiviral response and immune reconstitution. FUNDING: NIH grant P01 CA23766 and NIH/National Cancer Institute grant P30 CA008748.

Highlights • Prospective space-time statistics are particularly useful for COVID-19 surveillance. • Daily cluster detection can track the evolution of key hotspots of COVID-19. • Temporal trend towards smaller but more numerous clusters. • Time-periodic surveillance of COVID-19 facilitates decision-making in public health. • Web application for live results http://covid19scan.net., Graphical abstract, The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first discovered in late 2019 in Wuhan City, China. The virus may cause novel coronavirus disease 2019 (COVID-19) in symptomatic individuals. Since December of 2019, there have been over 7,000,000 confirmed cases and over 400,000 confirmed deaths worldwide. In the United States (U.S.), there have been over 2,000,000 confirmed cases and over 110,000 confirmed deaths. COVID-19 case data in the United States has been updated daily at the county level since the first case was reported in January of 2020. There currently lacks a study that showcases the novelty of daily COVID-19 surveillance using space-time cluster detection techniques. In this paper, we utilize a prospective Poisson space-time scan statistic to detect daily clusters of COVID-19 at the county level in the contiguous 48 U.S. and Washington D.C. As the pandemic progresses, we generally find an increase of smaller clusters of remarkably steady relative risk. Daily tracking of significant space-time clusters can facilitate decision-making and public health resource allocation by evaluating and visualizing the size, relative risk, and locations that are identified as COVID-19 hotspots.

PURPOSE: To examine the emotional experience of African American breast cancer survivors (BCS), and the information exchange between providers and patients, during transitioning to post-treatment survivorship RESEARCH APPROACH: We conducted a qualitative study using interviews and focus groups. PARTICIPANTS: We sought perspectives of oncology providers (n = 27) and African-American breast cancer survivors (BCS) (n = 45) who provided and received care in three counties in Washington State. METHODS: African-American community consultants conducted interviews and focus groups. Thematic coding and constant comparison were applied to identify emergent themes. FINDINGS: Participants reported emotional health information and support were needed but not consistently provided, resulting in a sense of survivor isolation. Systemic challenges limited providers’ ability to deliver emotional support information. Survivors and providers expressed similar understandings of the emotional impact of transition, but each group highlighted different, yet complementary priorities to address emotional needs of African-American BCS. CONCLUSIONS: There is congruence between African-American BCS and oncology providers perceptions of the emotional experience of transitioning to post-treatment survivorship, but patients are not receiving adequate information and resources to help them adequately address their emotional needs. IMPLICATIONS FOR POLICY: Improved care continuity, team-based approaches, and partnerships between health systems and community organization partnerships may help patients and providers recognize and address emotional needs during the transition.

BACKGROUND Circulating cholesterol levels have been linked to PD, but not directly to brain physiology. OBJECTIVE To assess whether brain cholesterol metabolism is related to PD. METHODS Sixty PD patients and 64 controls were recruited from an academic movement disorder clinic (2009-2012). Thirty-five PD patients and 33 controls returned approximately 36 months later. Fasting plasma (S)24-OH-cholesterol (brain-derived cholesterol metabolite) and 27-OH-cholesterol (peripheral cholesterol metabolite) were quantified. Odds ratios for PD were derived from logistic regression models, adjusting for potential confounders. Relationships between the oxysterols and clinical measurements were explored using Spearman correlation coefficients. RESULTS Mean age of PD subjects was 63.8 ± 8.3 years and disease duration was 5.0 ± 5.4 years. Plasma (S)24-OH-cholesterol levels were inversely associated with the odds of having PD, with an odds ratio of 0.92 (95% confidence interval: 0.87-0.97) for each 1-ng/mL increase (P = 0.004). Compared to the lowest tertile, the odds ratio was 0.34 (0.12-0.98) for the second tertile (P = 0.045) and 0.08 (0.02-0.31) for the highest tertile (P < 0.001). Higher (S)24-OH-cholesterol levels also were correlated with better sense of smell (r = 0.35; P = 0.01). No significant associations were found between clinical measures and 27-OH-cholesterol, a peripheral cholesterol metabolite. Furthermore, (S)24-OH-cholesterol levels were stable over time, whereas 27-OH-cholesterol decreased with time in both cases and controls. CONCLUSIONS Results indicate that plasma (S)24-OH-cholesterol (possibly reflecting brain cholesterol metabolism) is inversely linked to PD, is relatively stable over time, and may serve as a new biomarker for PD. Further investigation is necessary to determine the mechanistic and clinical implications. © 2019 International Parkinson and Movement Disorder Society.

Aims Atrial fibrillation is the most prevalent sustained arrhythmia associated with arrhythmic ventricular contractions, incident heart failure, increased morbidity and mortality. The relationship between arrhythmic contractions and ventricular remodelling is incompletely understood. The aim of this study was to characterize the influence of irregular contractions on pro-fibrotic signalling in neonatal rat ventricular cardiomyocytes (NRVM). Methods and results Neonatal rat ventricular cardiomyocytes were paced via field stimulation at 3 Hz for 24 h. Irregularity was created by pseudorandomized variation of stimulation intervals and compared to regular pacing. Treatment of neonatal cardiac fibroblasts (NCF) with medium of irregularly paced NRVM increased protein expression of collagen I (206 ± 62%, P = 0.0121) and collagen III (51 ± 37%, P = 0.0119). To identify the underlying mechanism, expression of pro-fibrotic connective tissue growth factor (CTGF) and transforming growth factor beta (TGF-β) was assessed. In irregularly paced NRVM, increased protein expression of CTGF (80 ± 22%, P = 0.0035) and TGF-β (122 ± 31%, P = 0.0022) was associated with enhanced excretion of both proteins into the medium. Electron paramagnetic resonance spectroscopy revealed an increased production of reactive oxygen species (46 ± 21%, P = 0.0352) after irregular pacing accompanied by increased 8-hydroxydeoxyguanosine staining (214 ± 53%, P = 0.0011). Irregular pacing was associated with elevated mRNA levels of anti-oxidative superoxide dismutase 1 (25 ± 7%, P = 0.0175), superoxide dismutase 3 (20 ± 7%, P = 0.0309), and catalase (20 ± 7%, P = 0.046). Conclusion These data demonstrate that irregular pacing is an important inductor of pro-fibrotic signalling in NRVM involving paracrine effects of CTGF and TGF-β as well as increased oxidative stress. Thus, irregularity of the heart beat might directly be involved in the progression of maladaptive remodelling processes in atrial fibrillation.

Objectives This study provides an insight into associations between: (1) parental and child perceptions of parental strategies restricting screen use among children, (2) child perceptions of the presence and availability of screen-based equipment at home, (3) child sedentary screen use behaviours, and (4) child body fat. Design A prospective study with two assessment periods (Time 1, T1; Time 2, T2), spanning 7-8 months. Methods At T1, 879 parent-child dyads (83.3% mothers; 52.3% girls) were enrolled and provided parental and child (5-11 years old) self-report data. T2 data were obtained from 603 dyads. Child body fat was measured with bioimpedance method (T1 and T2). Path analysis was used to test models calculated with and without additional covariates, such as parental and child age and gender, parental education, and economic status. Results Path analysis indicated indirect effects of the presence and availability of screen-based equipment at home (T1) on child body fat (T2), with screen use among children (T1) mediating this association. Parental perceptions of restrictions (T1) were unrelated to child body fat (T2). In contrast, child perceptions of parental restrictions (T1) predicted child body fat (T2). Children who perceived that their parents applied a higher level of restrictions (T1) had a lower body fat at the 7- to 8-month follow-up. These associations were found after controlling for baseline levels of child body fat, across models calculated with and without additional covariates. Conclusions Child, not parental perceptions of parental restrictions, predicted better obesity-related outcomes in children, such as lower body fat. Statement of contribution What is already known on this subject? Little is known about effects of parental restrictions of screen use on child body fat. Evidence is mostly cross-sectional, except from a recent investigation by Sleddens, Gubbels, Kremers, van der Plas, and Thijs (). To date, effects of parental (not children's) reports of screen use restrictions were investigated. What does this study add? Children reporting more parental restrictions of screen use have less body fat at a follow-up. Parental reports of screen use restrictions are unrelated to child screen use and body fat. Frequent screen use mediate between the number of screen devices at home and higher child body fat.

Objective To summarize current evidence regarding testosterone treatment for women with low sexual desire. Materials and methods The Female Endocrinology and Andrology Department of the Brazilian Society of Endocrinology and Metabolism invited nine experts to review the physiology of testosterone secretion and the use, misuse, and side effects of exogenous testosterone therapy in women, based on the available literature and guidelines and statements from international societies. Results Low sexual desire is a common complaint in clinical practice, especially in postmenopausal women, and may negatively interfere with quality of life. Testosterone seems to exert a positive effect on sexual desire in women with sexual dysfunction, despite a small magnitude of effect, a lack of long-term safety data, and insufficient evidence to make a broad recommendation for testosterone therapy. Furthermore, there are currently no testosterone formulations approved for women by the relevant regulatory agencies in the United States, Brazil, and most other countries, and testosterone formulations approved for men are not recommended for use by women. Conclusion Therefore, testosterone therapy might be considered if other strategies fail, but the risks and benefits must be discussed with the patient before prescription. Arch Endocrinol Metab. 2019;63(3):190-8

ObjectivesThe primary objective of this study was to ascertain the reasons for emergency department (ED) attendance among patients with a history of atrial fibrillation (AF).DesignAppropriate ED attendance was defined by the requirement for an electrical or chemical cardioversion and/or an attendance resulting in hospitalisation or administration of intravenous medications for ventricular rate control. Quantitative and qualitative responses were recorded and analysed using descriptive statistics and content analysis, respectively. Random effects logistic regression was performed to estimate the OR of inappropriate ED attendance based on clinically relevant patient characteristics.ParticipantsParticipants ≥18 years with a documented history of AF were approached in one of eight centres partaking in the study across Canada (Ontario, Nova Scotia, Alberta and British Columbia).ResultsOf the 356 patients enrolled (67±13, 45% female), the majority (271/356, 76%) had inappropriate reasons for presentation and did not require urgent ED treatment. Approximately 50% of patients(172/356, 48%) were driven to the ED due to symptoms, while the remainder presented on the basis of general fear or anxiety (67/356, 19%) or prior medical advice (117/356, 33%). Random effects logistic regression analysis showed that patients with a history of congestive heart failure were significantly more likely to seek urgent care for appropriate reasons (p=0.03). Likewise, symptom-related concerns for ED presentation were significantly less likely to result in inappropriate visitation (p=0.02). When patients were surveyed on alternatives to ED care, the highest proportion of responses among both groups was in favour of specialised rapid assessment outpatient clinics (186/356, 52%). Qualitative content analysis confirmed these results.ConclusionsImproved education focused on symptom management and alleviating disease-related anxiety as well as the institution of rapid access arrhythmias clinics may reduce the need for unnecessary healthcare utilisation in the ED and subsequent hospitalisation.Trial registration numberNCT03127085

OBJECTIVE: To determine whether higher frequency of GP visits among insulin-dependent patients with type 2 diabetes is associated with reduced hospitalizations. DESIGN: Nationally representative study using data from the 2013–2014 cycle of the Canadian Community Health Survey. SETTING: Canada. PARTICIPANTS: A study sample comprising 2203 insulin-dependent Canadians with type 2 diabetes. MAIN OUTCOME MEASURES: The relationship between GP visits (no visits, 1–5 visits, ≥ 6 visits) in the past year and the number of nights spent in-hospital. Zero-inflated negative binomial Poisson regression models were used to account for overdispersion and excess zeros. RESULTS: Higher numbers of GP visits were associated with spending fewer nights in-hospital. Patients with 1 to 5 GP visits had a significantly lower number of nights spent in-hospital (rate ratio of 0.38, 95% CI 0.25 to 0.56), as did those with 6 or more GP visits (rate ratio of 0.57, 95% CI 0.38 to 0.84) despite having reduced odds of not being hospitalized (odds ratio of 0.62, 95% CI 0.39 to 0.95), compared with those who did not see a GP in the past year, after adjusting for confounders. CONCLUSION: We found that insulin-dependent patients with diabetes who saw GPs more frequently were hospitalized less commonly compared with those who did not see a GP in the past year. Further research is needed to examine relationships with other types of follow-up, ideally using a longitudinal design.