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Background: The “crescent sign” is a hyperattenuating crescent-shaped region on CT within the mural thrombus or wall of an aortic aneurysm. Although it has previously been associated with aneurysm instability or impending rupture, the literature is largely based on retrospective analyses of urgently repaired aneurysms. We strove to more rigorously assess the association between an isolated “crescent sign” and risk of impending aortic rupture. Methods: Patients were identified by querying a single health system PACS database for radiology reports noting a crescent sign. Adult patients with a CT demonstrating a descending thoracic, thoracoabdominal, or abdominal aortic aneurysm and “crescent sign” between 2004 and 2019 were included, with exclusion of those showing definitive signs of aortic rupture on imaging. Results: A total of 82 patients were identified. Aneurysm size was 7.1 ± 2.0 cm. Thirty patients had emergent or urgent repairs during their index admission (37%), 19 had elective repairs at a later date (23%), and thirty-three patients had no intervention due to either patient choice or prohibitive medical comorbidities (40%). Patients without intervention had a median follow up of 275 days before death or loss to follow up. In patients undergoing elective intervention, 6,968 patient-days elapsed between presentation and repair, with zero episodes of acute rupture (median 105 days). Patients undergoing elective repair had smaller aneurysms compared to those who underwent emergent/urgent repair (6.2 ± 1.3 vs 7.7 ± 2.1 cm, p = 0.008). No surgical candidate with an aneurysm smaller than 8 cm ruptured. There were 31 patients with previous axial imaging within 2 years prior to presentation with a “crescent sign”, with mean aneurysm growth rate of 0.85 ± 0.62 cm per 6 months [median 0.65, range 0 – 2.6]. Those with aneurysms sized below 5.5 cm displayed decreased aneurysm growth compared to patients with aneurysm's sized 5.5 – 6.5 cm or patients with aneurysms greater than 6.5 cm (0.12 vs 0.64 vs 1.16 cm per 6 months, p = 0.002). Conclusions: The finding of an isolated radiographic “crescent sign” without other signs of definitive aortic rupture (i.e. hemothorax, aortic wall disruption, retroperitoneal bleeding) is not necessarily an indicator of impending aortic rupture, but may be found in the setting of rapid aneurysm growth. Many factors, including other associated radiographic findings, aneurysm size and growth rate, and patient symptomatology, should guide aneurysm management in these patients. We found that patients with minimal symptoms, aneurysm sizes below 6.5 cm, and no further imaging findings of aneurysm instability, such as peri-aortic fat stranding, can be successfully managed with elective intervention after optimization of comorbid factors with no evidence of adverse outcomes.

BACKGROUND: Repair of complete atrioventricular canal (CAVC) is often complicated by atrioventricular valve regurgitation, particularly of the left-sided valve. Understanding the three-dimensional (3D) structure of the atrioventricular canal annulus prior to repair may help to inform optimized repair. However, the 3D shape and movement of the CAVC annulus has yet to be quantified nor has it been rigorously compared to a normal mitral valve annulus. METHODS: The complete annuli of 43 patients with CAVC were modeled in 4 cardiac phases using transthoracic 3D echocardiograms and custom code. The annular structure was compared to the annuli of 20 normal pediatric mitral valves using 3D metrics and statistical shape analysis (Procrustes analysis). RESULTS: The unrepaired CAVC annulus varied in shape significantly throughout the cardiac cycle. Procrustes analysis visually demonstrated that the average normalized CAVC annular shape is more planar than the normal mitral annulus. Quantitatively, the annular height to valve width ratio of the native left CAVC atrioventricular valve was significantly lower than that of a normal mitral valve in all systolic phases(p

Background: Despite advances in surgery and pharmacotherapy, there remains significant residual ischemic risk after coronary artery bypass grafting surgery. Methods: In REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial), a multicenter, placebo-controlled, double-blind trial, statin-treated patients with controlled low-density lipoprotein cholesterol and mild to moderate hypertriglyceridemia were randomized to 4 g daily of icosapent ethyl or placebo. They experienced a 25% reduction in risk of a primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina) and a 26% reduction in risk of a key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) when compared with placebo. The current analysis reports on the subgroup of patients from the trial with a history of coronary artery bypass grafting. Results: Of the 8179 patients randomized in REDUCE-IT, a total of 1837 (22.5%) had a history of coronary artery bypass grafting, with 897 patients randomized to icosapent ethyl and 940 to placebo. Baseline characteristics were similar between treatment groups. Randomization to icosapent ethyl was associated with a significant reduction in the primary end point (hazard ratio [HR], 0.76 [95% CI, 0.63–0.92]; P =0.004), in the key secondary end point (HR, 0.69 [95% CI, 0.56–0.87]; P =0.001), and in total (first plus subsequent or recurrent) ischemic events (rate ratio, 0.64 [95% CI, 0.50–0.81]; P =0.0002) compared with placebo. This yielded an absolute risk reduction of 6.2% (95% CI, 2.3%–10.2%) in first events, with a number needed to treat of 16 (95% CI, 10–44) during a median follow-up time of 4.8 years. Safety findings were similar to the overall study: beyond an increased rate of atrial fibrillation/flutter requiring hospitalization for at least 24 hours (5.0% vs 3.1%; P =0.03) and a nonsignificant increase in bleeding, occurrences of adverse events were comparable between groups. Conclusions: In REDUCE-IT patients with a history of coronary artery bypass grafting, treatment with icosapent ethyl was associated with significant reductions in first and recurrent ischemic events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01492361.

Background Acne is a chronic disease with a varying presentation that requires long-term management. Despite this, the clinical guidelines for acne offer limited guidance to facilitate personalized or longitudinal management of patients. Objectives To generate recommendations to support comprehensive, personalized, long-term patient management that address all presentations of acne and its current and potential future burden. Methods The Personalising Acne: Consensus of Experts panel consisted of 13 dermatologists who used a modified Delphi approach to reach consensus on statements related to longitudinal acne management. The consensus was defined as ≥75% voting "agree" or "strongly agree." All voting was electronic and blinded. Results Key management domains, consisting of distinct considerations, points to discuss with patients, and "pivot points" were identified and incorporated into the Personalised Acne Care Pathway. Long-term treatment goals and expectations and risk of (or fears about) sequelae are highlighted as particularly important to discuss frequently with patients. Limitations Recommendations are based on expert opinion, which could potentially differ from patients' perspectives. Regional variations in health care systems may not have been captured. Conclusions The Personalised Acne Care Pathway provides practical recommendations to facilitate the longitudinal management of acne, which can be used by health care professionals to optimize and personalize care throughout the patient journey.

Purpose To investigate clinical and morphologic characteristics of serous retinal disturbances in patients taking extracellular signal-regulated kinase (ERK) inhibitors. Design Single-center retrospective study of prospectively collected data. Participants Of 61 patients receiving ERK inhibitors for treatment of metastatic cancer, this study included 40 eyes of 20 patients with evidence of retinopathy confirmed by OCT. Methods Clinical examination, fundus photography, and OCT were used to evaluate ERK inhibitor retinopathy. The morphologic features, distribution, and location of fluid foci were evaluated serially. Visual acuity (VA) and choroidal thickness measurements were compared at baseline, fluid accumulation, and resolution. Main Outcome Measures Characteristics of treatment-emergent choroid and retinal OCT abnormalities as compared with baseline OCT findings and the impact of toxicity on VA. Results Of 20 patients with retinopathy, most showed fluid foci that were bilateral (100%), multifocal in each eye (75%), and with at least 1 focus involving the fovea (95%). All subretinal fluid foci occurred between the interdigitation zone and an intact retinal pigment epithelium. No statistical difference was found in choroidal thickness at fluid accumulation and resolution compared with baseline. Forty-five percent of eyes showed evidence of concomitant intraretinal edema localized to the outer nuclear layer. At the time of fluid accumulation, 57.5% eyes showed a decline in VA (mainly by 1–2 lines from baseline). For all eyes with follow-up, the subretinal fluid and intraretinal edema were reversible and resolved without medical intervention, and best-corrected VA at fluid resolution was not statistically different from baseline. Concomitant intraretinal fluid was not associated with worsening of VA. No patient discontinued or decreased drug dose because of retinopathy. Conclusions This study showed that ERK inhibitors may cause subretinal fluid foci with unique clinical and morphologic characteristics. The observed foci were similar to mitogen-activated protein kinase kinase (MEK) inhibitor–associated retinopathy and distinct from central serous chorioretinopathy. However, unlike with MEK inhibitors, an increased occurrence of concomitant intraretinal fluid without significant additive visual impact seems to occur with ERK inhibitors. In this series, ERK inhibitors did not cause irreversible loss of vision or serious eye damage; retinopathy was self-limited and did not require medical intervention.

INTRODUCTION: The leishmaniases represent a group of parasitic diseases caused by infection with one of several species of Leishmania parasites. Disease presentation varies because of differences in parasite and host genetics and may be influenced by additional factors such as host nutritional status or co-infection. Studies in experimental models of Leishmania infection, vaccination of companion animals and human epidemiological data suggest that many forms of leishmaniasis could be prevented by vaccination, but no vaccines are currently available for human use. AREAS COVERED: We describe some of the existing roadblocks to the development and implementation of an effective leishmaniasis vaccine, based on a review of recent literature found on PubMed, BioRxiv and MedRxiv. In addition to discussing scientific unknowns that hinder vaccine candidate identification and selection, we explore gaps in knowledge regarding the commercial and public health value propositions underpinning vaccine development and provide a route map for future research and advocacy. EXPERT OPINION: Despite significant progress, leishmaniasis vaccine development remains hindered by significant gaps in understanding that span the vaccine development pipeline. Increased coordination and adoption of a more holistic view to vaccine development will be required to ensure more rapid progress in the years ahead.

PURPOSE Low-grade serous carcinoma (LGSC) is a rare type of ovarian cancer, which commonly arises from serous borderline tumor (SBT) and is characterized by frequent activating mutations in the mitogen-activated protein kinase pathway, including BRAF. The BRAFV600E mutation is associated with improved prognosis in SBT and LGSC, and responses to BRAF inhibitor therapy have been reported. We sought to characterize the clinicopathologic and molecular features of BRAF-driven tubo-ovarian and primary peritoneal serous tumors. METHODS Retrospective analysis of our institutional cohort of SBTs (n = 22), LGSCs (n = 119) and high-grade serous carcinomas (HGSCs, n = 1,290) subjected to targeted massively parallel sequencing was performed to identify cases with BRAF genetic alterations. Putative BRAF rearrangements were confirmed using targeted RNA sequencing and/or fluorescence in situ hybridization (FISH). BRAFV600E oncoprotein expression was assessed by immunohistochemistry on selected cases. RESULTS BRAF somatic genetic alterations were identified in 29 of 1,431 (2%) serous tumors and included mutations (n = 24), gene rearrangements (n = 3), and amplification (n = 2). BRAF mutations were more frequent in SBTs (7 of 22; 32%) compared with LGSCs (11 of 119; 9%, P = .009) and HGSCs (6 of 1,290; 0.5%; P < .0001, SBT/LGSC v HGSC). The BRAFV600E hotspot mutation was most common (n = 16); however, other BRAF driver mutations were also detected (n = 8). BRAF mutations were often clonal or truncal in SBTs and LGSCs, but subclonal in most HGSCs. Pathogenic BRAF gene fusions were identified in LGSCs (n = 2) and HGSC (n = 1) and involved distinct fusion partners ( AGK, MKRN1, and AGAP3). Three patients with BRAF-mutant LGSC were treated with targeted mitogen-activated protein kinase inhibitors, one of whom was maintained on therapy for over 3 years with clinical benefit. CONCLUSION Recognition of BRAF alterations beyond V600E mutation in LGSC may have clinical implications for appropriate targeted therapy selection.

Individuals with personality disorders often experience romantic relationship dysfunction and have an insecure attachment style. Here, we examined attachment dynamics in dyadic interactions, focusing specifically on the role of physiological coregulation in state attachment processes in couples oversampled for personality pathology. A total of 121 couples completed a 10-minute discussion about an area of disagreement in their relationship and a 5-minute discussion in which they planned an event together. We used a dynamical model of heart rate changes to estimate coregulation. We found that (a) increases in state attachment avoidance were associated with contrarian coregulation (heart rate becoming misaligned with the partner's physiology) and (b) conversely, increases in state attachment anxiety were associated with dependent coregulation (heart rate becoming aligned with the partners' physiology). Dispositional attachment insecurity moderated the effects of state attachment insecurity on physiological coregulation. Whereas dispositional anxiety predicted individuals exhibiting dependent coregulation in response to state insecurity, dispositional avoidance predicted contrarian coregulation in response to state insecurity. This work provides insight into the role of physiological coregulation in attachment dynamics among couples oversampled for personality pathology, suggesting that disruptions to coregulation contribute to impaired emotion regulation during romantic conflicts. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

INTRODUCTION: Leishmaniasis is a neglected tropical disease that is defined by the World Health Organization as vaccine preventable. Although several new candidate vaccines are in development, no vaccine has successfully reached the market for human use. Several species of Leishmania cause human disease and have co-evolved with their respective sand fly vectors. These unique relationships have implications for initiation of infection and vaccine development. An approach to vaccine development for many infectious diseases is the use of controlled human infection models (CHIMs). AREAS COVERED: We describe the history and recent development of experimental and deliberate infection using Leishmania in humans and the rationale for developing a new sand fly-initiated CHIM to progress leishmaniasis vaccine development. Examples from other infectious diseases are discussed in the context of the development of a new leishmaniasis CHIM. We also reflect upon the manufacture of the challenge agent, practical considerations, safety, ethics, and regulatory issues. EXPERT OPINION: A new cutaneous Leishmania CHIM is being developed to enable testing of vaccines in the development pipeline. Questions remain about the use of such CHIMs to determine effectiveness of vaccines against visceral leishmaniasis. However, such a CHIM will be invaluable in expediting time to market for vaccines.

BackgroundMethamphetamine is a stimulant drug of abuse with increasing prevalence of use worldwide leading to public health concern. While previous research by our group a decade ago found no evidence of increasing harms associated with methamphetamine use in the UK, there are conflicting data on whether or not this is still the case. This paper aims to identify trends in methamphetamine-related harms and characterise the clinical features of ED presentations involving methamphetamine with gamma-hydroxybutyrate/gamma-butyrolactone (GHB/GBL).MethodsWe retrospectively interrogated a database of all toxicology-related presentations to two central London EDs, extracting data on drugs involved for presentations relating to methamphetamine between 2005 and 2018 to enable analysis of trends. Further clinical data were extracted for presentations between 2014 and 2018 to give a 4-year case series.ResultsA total of 1244 presentations involving the use of methamphetamine were identified. The number of presentations rose from 4 in 2005 (1.9% of all recreational drug presentations) to 294 (16.2%) in 2018. A total of 850 cases were identified for the 2014–2018 case series, 94.9% were male with a median (range) age of 35.1 (16–67) years. The most common clinical features in the methamphetamine presentations were neuropsychiatric: agitation (41.5%), anxiety (35.2%), hallucinations (16.5%) and psychosis (14.8%). GHB/GBL was co-used in 54.2% of presentations and appeared to attenuate the neuropsychiatric features seen. Use of GHB/GBL was associated with a higher Poisoning Severity Score and requirement for level 2/3 (high dependency unit/intensive care unit (ICU)) care.ConclusionED attendances in central London relating to methamphetamine use have risen over the last decade. Combining methamphetamine with GHB/GBL is common and is associated with a higher Poisoning Severity Score and need for ICU level care. Further work is required to establish whether further resources need to be directed at this clinical and public health problem.

Altered approach motivation is hypothesized to be critical for the maintenance of depression. Computer-administered approach-avoidance training programs to increase approach action tendencies toward positive stimuli produce beneficial outcomes. However, there have been few studies examining neural changes following approach-avoidance training. Participants with major depressive disorder were randomized to an approach-avoidance training (AAT) manipulation intended to increase approach tendencies for positive social cues (n = 13) or a control procedure (n = 15). We examined changes in neural activation (primary outcome) and connectivity patterns using Group Iterative Multiple Model Estimation during a social reward anticipation task (exploratory). A laboratory-based social affiliation task was also administered following the manipulation to measure affect during anticipation of real-world social activity. Individuals in the AAT group demonstrated increased activation in reward processing regions during social reward anticipation relative to the control group from pre- to post-training. Following training, connectivity patterns across reward regions were observed in the full sample and connectivity between the medial prefrontal cortex and caudate was associated with anticipatory positive affect before the social interaction. Preliminary evidence of differential connectivity patterns between the two groups also emerged. Results support models whereby modifying approach-oriented behavioral tendencies with computerized training lead to alterations in reward circuitry (NCT02330744).

OBJECTIVE: To examine the association between preconception diet quality, sedentary behavior, and physical activity with gestational weight gain (GWG) among Hispanic/Latina women METHODS: This was a prospective cohort study of participants from visits 1 (2008–2011) and 2 (2014–2017) of the Hispanic Community Health Study/Study of Latinos and singleton pregnancies between the 2 visits. Diet quality (alternative healthy eating index/AHEI-2010), sedentary behaviors, and physical activity (Global Physical Activity Questionnaire) were measured at visit 1 and accounted for preconception health behaviors. GWG was evaluated as a continuous and categorical variable according to the 2009 Institute of Medicine guidelines (inadequate, adequate, excessive). Linear and generalized logit survey regressions were used to study the association between health behaviors and GWG, using adequate GWG as the reference. RESULTS: Of the 457 women included, deliveries occurred at 3.2 years (mean) from visit 1; 48.7% of women had excessive GWG. Mean AHEI-2010 scores were

BACKGROUND: Aortic root evaluation is conventionally based on two-dimensional measurements at a single phase of the cardiac cycle. This work presents an image analysis method for assessing dynamic three-dimensional changes in the aortic root of minimally calcified bicuspid aortic valves (BAVs) with and without moderate to severe aortic regurgitation. METHODS: The aortic root was segmented over the full cardiac cycle in three-dimensional transesophageal echocardiographic images acquired from 19 patients with minimally calcified BAVs and from 16 patients with physiologically normal tricuspid aortic valves (TAVs). The size and dynamics of the aortic root were assessed using the following image-derived measurements: absolute mean root volume and mean area at the level of the ventriculoaortic junction, sinuses of Valsalva, and sinotubular junction, as well as normalized root volume change and normalized area change of the ventriculoaortic junction, sinuses of Valsalva, and sinotubular junction over the cardiac cycle. RESULTS: Normalized volume change over the cardiac cycle was significantly greater in BAV roots with moderate to severe regurgitation than in normal TAV roots and in BAV roots with no or mild regurgitation. Aortic root dynamics were most significantly different at the mid-level of the sinuses of Valsalva in BAVs with moderate to severe regurgitation than in competent TAVs and BAVs. CONCLUSIONS: Echocardiographic reconstruction of the aortic root demonstrates significant differences in dynamics of BAV roots with moderate to severe regurgitation relative to physiologically normal TAVs and competent BAVs. This finding may have implications for risk of future dilatation, dissection, or rupture, which warrant further investigation.

In the United States, mental health conditions are the most common complications of pregnancy and childbirth, and suicide and overdose combined are the leading cause of death for new mothers. Although awareness of and action on perinatal mental health is increasing, significant gaps remain. Screening and treatment are widely recommended but unevenly implemented, and policies and funding do not adequately support the mental health of childbearing people. As a result, treatable perinatal mental health conditions can have long-term, multigenerational negative consequences. This article provides an overview of the perinatal mental health landscape in the United States by identifying serious gaps in screening, education, and treatment; describing recent federal and state policy efforts; highlighting successful models of care; and offering recommendations for robust and integrated perinatal mental health care.

Objective To improve prostate cancer screening for high-risk men, we developed an early detection clinic for patients at high genetic risk of developing prostate cancer. Despite the rapidly growing understanding of germline variants in driving aggressive prostate cancer and the increased availability of genetic testing, there is little evidence surrounding how best to screen these men. Methods We are reporting on the first 45 patients enrolled, men between the ages of 35–75, primarily with known pathogenic germline variants in prostate cancer susceptibility genes. Screening consists of an intake lifestyle survey, PSA, DRE, and SelectMDx urine assay. A biopsy was recommended for any of the following indications: 1) abnormal DRE, 2) PSA above threshold, or 3) SelectMDx above threshold. The primary outcomes were number needed to screen, and number needed to biopsy to diagnose a patient with prostate cancer. Results Patients enrolled in the clinic included those with BRCA1 (n=7), BRCA2 (n=16), Lynch Syndrome (n=6), and CHEK2 (n = 4) known pathogenic germline variants. The median age and PSA were 58 (range 35–71) and 1.4 ng/ml (range 0.1–11.4 ng/ml), respectively. 12 patients underwent a prostate needle biopsy and there were 4positive biopsies for prostate cancer. Conclusion These early data support the feasibility of opening a dedicated clinic for men at high genetic risk of prostate cancer. This early report on the initial enrollment of our long-term study will help optimize early detection protocols and provide evidence for personalized prostate cancer screening in men with key pathogenic germline variants.

OBJECTIVES: Early placental volume (PV) has been associated with small-for-gestational-age infants born under the 10(th)/5(th) centiles (SGA10/SGA5). Manual or semi-automated PV quantification from 3DUS is time-intensive, limiting its incorporation into clinical care. We devised a novel convolutional neural network (CNN) pipeline for fully-automated placenta segmentation from 3DUS images, exploring the association between the calculated PV and SGA. METHODS: 3DUS volumes obtained from singleton pregnancies at 11–14 weeks’ gestation were automatically segmented by our CNN pipeline trained and tested on 99/25 images, combining two 2D and one 3D models with downsampling/upsampling architecture. The PVs derived from the automated segmentations (PV(CNN)) were used to train multi-variable logistic-regression classifiers for SGA10/SGA5. The test performance for predicting SGA was compared to PVs obtained via the semi-automated VOCAL (GE-Healthcare) method (PV(VOCAL)). RESULTS: We included 442 subjects with 37 (8.4%) and 18 (4.1%) SGA10/SGA5 infants, respectively. Our segmentation pipeline achieved a mean Dice score of 0.88 on an independent test-set. Adjusted models including PV(CNN) or PV(VOCAL) were similarly predictive of SGA10 (AUCs: PV(CNN)=0.780, PV(VOCAL)=0.768). The addition of PV(CNN) to a clinical model without any PV included (AUC=0.725) yielded statistically significant improvement in AUC (P

Objective To characterize longitudinal changes in blood biomarkers, leukocyte composition, and gene expression following laparoscopic sleeve gastrectomy (LSG). Background LSG is an effective treatment for obesity, leading to sustainable weight loss and improvements in obesity-related comorbidities and inflammatory profiles. However, the effects of LSG on immune function and metabolism remain uncertain. Methods Prospective data were collected from 23 enrolled human subjects from a single institution. Parameters of weight, comorbidities, and trends in blood biomarkers and leukocyte subsets were observed from preoperative baseline to 1 year postsurgery in 3-month follow-up intervals. RNA sequencing was performed on pairs of whole blood samples from the first 6 subjects of the study (baseline and 3 months postsurgery) to identify genome-wide gene expression changes associated with undergoing LSG. Results LSG led to a significant decrease in mean total body weight loss (18.1%) at 3 months and among diabetic subjects a reduction in hemoglobin A1c. Improvements in clinical inflammatory and hormonal biomarkers were demonstrated as early as 3 months after LSG. A reduction in neutrophil-lymphocyte ratio was observed, driven by a reduction in absolute neutrophil counts. Gene set enrichment analyses of differential whole blood gene expression demonstrated that after 3 months LSG induced transcriptomic changes not only in inflammatory cytokine pathways but also in several key metabolic pathways related to energy metabolism. Conclusions LSG induces significant changes in the composition and metabolism of immune cells as early as 3 months postoperatively. Further evaluation is required of bariatric surgery’s effects on immunometabolism and the consequences for host defense and metabolic disease.

Background Activating fusions of the NTRK1, NTRK2 and NTRK3 genes are drivers of carcinogenesis and proliferation across a broad range of tumour types in both adult and paediatric patients. Recently, the FDA granted tumour-agnostic approvals of TRK inhibitors, larotrectinib and entrectinib, based on significant and durable responses in multiple primary tumour types. Unfortunately, testing rates in clinical practice remain quite low. Adding plasma next-generation sequencing of circulating tumour DNA (ctDNA) to tissue-based testing increases the detection rate of oncogenic drivers and demonstrates high concordance with tissue genotyping. However, the clinical potential of ctDNA analysis to identify NTRK fusion-positive tumours has been largely unexplored. Methods We retrospectively reviewed a ctDNA database in advanced stage solid tumours for NTRK1 fusions. Results NTRK1 fusion events, with nine unique fusion partners, were identified in 37 patients. Of the cases for which clinical data were available, 44% had tissue testing for NTRK1 fusions; the NTRK1 fusion detected by ctDNA was confirmed in tissue in 88% of cases. Here, we report for the first time that minimally-invasive plasma NGS can detect NTRK fusions with a high positive predictive value. Conclusion Plasma ctDNA represents a rapid, non-invasive screening method for this rare genomic target that may improve identification of patients who can benefit from TRK-targeted therapy and potentially identify subsequent on- and off-target resistance mechanisms.

Predicció de risc de càncer de mama; Dones europees; Variant patògena heterozigota Predicción del riesgo de cáncer de mama; Mujeres europeas; Variante patógena heterocigota Breast cancer risk prediction; European women; Heterozygous pathogenic variant Purpose To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC

Rickettsial diseases (RDs) are transmitted to humans by ectoparasites, including ticks and fleas. Symptoms range from mild febrile illness, to severe disease or death. Doxycycline is the treatment of choice for patients of all ages; early treatment based on clinical diagnosis is critical to prevent severe outcomes. We conducted a descriptive analysis using insurance claims data captured by IBM MarketScan® research databases to describe demographics, treatment patterns, and outcomes of patients diagnosed with RDs in the United States during 2005–2017. Overall, 14,830 patients had a RD diagnosis during 2005–2017; 7,517 (50.7%) spotted fever rickettsiosis (SFR), 4,571 ( 30.8%) ehrlichiosis, 1,362 (9.2%) typhus group rickettsiosis (TGR), and 1,193 (8.0%) other rickettsial diseases. Among all patients diagnosed, 53.1% received doxycycline. Prescription rates varied by diagnosis and age; 24.1% of TGR and 61.1% of SFR patients received doxycycline; 23.9% of persons

Our study describes breast cancer risk loci using a cross-ancestry GWAS approach. We first identify variants that are associated with breast cancer at P, GWAS have enhanced our understanding for the genetic basis of breast cancer, but the majority of them were performed for European ancestry populations. Here, the authors use a cross-ancestry approach and report seven new variants associated with breast cancer risk among women of African ancestry.

Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies ~7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis., In breast cancer the contribution of different genetic variants to disease heritability is complex and not fully understood. Here, the authors present a network-based analysis in 84,567 patients studying ~7.3 million variants, identifying gene modules associated with breast cancer survival.

The lungs are exposed to a range of environmental toxins (including cigarette smoke, air pollution, asbestos) and pathogens (bacterial, viral and fungal), and most respiratory diseases are associated with local or systemic hypoxia. All of these adverse factors can trigger endoplasmic reticulum (ER) stress. The ER is a key intracellular site for synthesis of secretory and membrane proteins, regulating their folding, assembly into complexes, transport and degradation. Accumulation of misfolded proteins within the lumen results in ER stress, which activates the unfolded protein response (UPR). Effectors of the UPR temporarily reduce protein synthesis, while enhancing degradation of misfolded proteins and increasing the folding capacity of the ER. If successful, homeostasis is restored and protein synthesis resumes, but if ER stress persists, cell death pathways are activated. ER stress and the resulting UPR occur in a range of pulmonary insults and the outcome plays an important role in many respiratory diseases. The UPR is triggered in the airway of patients with several respiratory diseases and in corresponding experimental models. ER stress has been implicated in the initiation and progression of pulmonary fibrosis, and evidence is accumulating suggesting that ER stress occurs in obstructive lung diseases (particularly in asthma), in pulmonary infections (some viral infections and in the setting of the cystic fibrosis airway) and in lung cancer. While a number of small molecule inhibitors have been used to interrogate the role of the UPR in disease models, many of these tools have complex and off-target effects, hence additional evidence (eg, from genetic manipulation) may be required to support conclusions based on the impact of such pharmacological agents. Aberrant activation of the UPR may be linked to disease pathogenesis and progression, but at present, our understanding of the context-specific and disease-specific mechanisms linking these processes is incomplete. Despite this, the ability of the UPR to defend against ER stress and influence a range of respiratory diseases is becoming increasingly evident, and the UPR is therefore attracting attention as a prospective target for therapeutic intervention strategies.

Objectives This study aimed to explore the impact of the coronavirus disease 2019 (COVID‐19) pandemic on self‐care of individuals living with rheumatoid arthritis (RA). Methods Guided by a constructivist, qualitative design, we conducted one‐to‐one in‐depth telephone interviews between March and October 2020 with participants with RA purposively sampled for maximum variation in age, sex and education, who were participating in one of two ongoing randomized‐controlled trials. An inductive, reflexive thematic analysis approach was used. Results Twenty‐six participants (aged 27–73 years; 23 females) in British Columbia, Canada were interviewed. We identified three themes: (1) Adapting to maintain self‐care describes how participants took measures to continue self‐care activities while preventing virus transmissions. While spending more time at home, some participants reported improved self‐care. (2) Managing emotions describes resilience‐building strategies such as keeping perspective, positive reframing and avoiding negative thoughts. Participants described both letting go and maintaining a sense of control to accommodate difficulties and emotional responses. (3) Changing communication with health professionals outlined positive experiences of remote consultations with health professionals, particularly if good relationships had been established prepandemic. Conclusion The insights gained may inform clinicians and researchers on ways to support the self‐care strategies of individuals with RA and other chronic illnesses during and after the COVID‐19 pandemic. The findings reveal opportunities to further examine remote consultations to optimize patient engagement and care. Patient or Public Contribution This project is jointly designed and conducted with patient partners in British Columbia, Canada. Patient partners across the United Kingdom also played in a key role in providing interpretations of themes during data analysis.

Purpose: To compare outcomes between patients with relapsed follicular lymphoma who received a nonmyeloablative allogeneic stem cell transplant (alloSCT) and those who received an autologous transplant (autoSCT). Patients and Methods: We evaluated 194 patients with follicular lymphoma who received an alloSCT (n = 98) or autoSCT (n = 96) at MD Anderson Cancer Center (Houston, TX). The transplant type used was based on donor availability and by Medicare reimbursement guidelines. Patients who received an alloSCT were enrolled in four consecutive trials in which they received fludarabine, cyclophosphamide (or bendamustine), and rituximab conditioning. autoSCT patients received R-BEAM (rituximab, carmustine, etoposide, cytarabine, and melphalan). Results: The median follow-up of survivors was 108 months for the alloSCT group and 102 months for the autoSCT group. Overall survival was significantly better for patients who received an alloSCT compared with those who received an autoSCT (62% vs. 46%; P = 0.048). Similarly, progression-free survival rates were 52% in patients who received an alloSCT and 31% in those who received an autoSCT (P < 0.001), and the 8-year relapse rates were 11% and 43%, respectively (P < 0.0001). Only three patients in the alloSCT group relapsed beyond 3.5 years. In the alloSCT group, the rates for grade 2 to 4 acute graft-versus-host disease (GVHD), grade 3 to 4 acute GVHD, and extensive chronic GVHD were 22%, 9%, and 38%, respectively. In the autoSCT group, the 8-year incidence of secondary myelodysplasia was 11%. Nonrelapse mortality was similar between the two groups (15% vs. 11% at 8 years; P = 0.27). Conclusions: This study shows that alloSCT is curative and confers superior survival compared with autoSCT in patients with follicular lymphoma.

Background The physical sequelae of acne include erythema, hyperpigmentation, and scarring, which are highly burdensome for patients. Early, effective treatment can potentially limit and prevent sequelae development, but there is a need for guidance for and evidence of prevention-oriented management to improve patient outcomes. Objective To identify unmet needs of acne sequelae and generate expert recommendations to address gaps in clinical guidance. Methods The Personalizing Acne: Consensus of Experts panel of 13 dermatologists used a modified Delphi approach to achieve a consensus on the clinical aspects of acne sequelae. A consensus was defined as ≥75% of the dermatologists voting "agree" or "strongly agree." All voting was electronic and blinded. Results The panel identified gaps in current guidance and made recommendations related to acne sequelae. These included identification and classification of sequelae, pertinent points to consider for patient consultations, and management aimed at reducing the development of sequelae. Limitations The recommendations are based on expert opinion and made in the absence of high-quality evidence. Conclusions The identified gaps should help inform future research and guideline development for acne sequelae. The consensus-based recommendations should also support the process of consultations throughout the patient journey, helping to reduce the development and burden of acne sequelae through improved risk factor recognition, early discussion, and appropriate management.

BACKGROUND Acne is the commonest inflammatory dermatosis seen worldwide. Atrophic acne scarring is a frequent complication, which can arise from acne of any severity. Micro (mi)RNAs are noncoding RNA molecules of 19-25 nucleotides that function as post-transcriptomic mediators of gene expression. They have demonstrated differential expression in various pathologies, such as eczema and psoriasis, allowing for a unique miRNA 'signature' profile to be established for different disease states. AIM To establish a miRNA signature for acne, and acne-associated atrophic scarring and to identify if a pattern of circulating miRNA is evident in patients who are prone to scarring. METHODS In total, 41 participants were consecutively recruited to this study. Circulating miRNA was quantified from plasma samples in all 41 patients, while in 8 patients, and in a further validation cohort of 9 patients, whole miRNAome was undertaken from tissue specimens, which included lesional, normal and where present, scarred skin. RESULTS Three miRNAs, miR-223, miR-21 and miR-150, were statistically significantly overexpressed in acne lesions, and notably, in clinically uninvolved skin in participants prone to scarring. In this subgroup, we also found statistically significantly elevated levels of circulating miRNA-21 and miRNA-150. CONCLUSION The presence of elevated levels of these specific miRNAs in the serum of patients with acne raises the potential of a blood test to identify those at risk of scarring, allowing for earlier intervention with effective therapy.

With the increasing use of magnetic resonance imaging in the assessment of acute intracerebral hemorrhage, diffusion-weighted imaging hyperintense lesions have been recognized to occur at sites remote to the hematoma in up to 40% of patients. We investigated whether blood pressure reduction was associated with diffusion-weighted imaging hyperintense lesions in acute intracerebral hemorrhage and whether such lesions are associated with worse clinical outcomes by analyzing imaging data from a randomized trial. We performed exploratory subgroup analyses in an open-label randomized trial that investigated acute blood pressure lowering in 1000 patients with intracerebral hemorrhage between May 2011 and September 2015. Eligible participants were assigned to an intensive systolic blood pressure target of 110–139 mm Hg versus 140–179 mm Hg with the use of intravenous nicardipine. Of these, 171 patients had requisite magnetic resonance imaging sequences for inclusion in these subgroup analyses. The primary outcome was the presence of diffusion-weighted imaging hyperintense lesions. Secondary outcomes included death or disability and serious adverse event at 90 days. Diffusion-weighted imaging hyperintense lesions were present in 25% of patients (mean age 62 years). Hematoma volume > 30 cm3 was an adjusted predictor (adjusted relative risk 2.41, 95% confidence interval 1.00–5.80) of lesion presence. Lesions occurred in 25% of intensively treated patients and 24% of standard treatment patients (relative risk 1.01, 95% confidence interval 0.71–1.43, p = 0.97). Patients with diffusion-weighted imaging hyperintense lesions had similar frequencies of death or disability at 90 days, compared with patients without lesions. Randomized assignment to intensive acute blood pressure lowering did not result in a greater frequency of diffusion-weighted imaging hyperintense lesion. Alternative mechanisms of diffusion-weighted imaging hyperintense lesion formation other than hemodynamic fluctuations need to be explored. Clinical trial registration ClinicalTrials.gov (Ref. NCT01176565; https://clinicaltrials.gov/ct2/show/NCT01176565 ).

AIMS Fibrous cephalic plaques (FCPs) in individuals with tuberous sclerosis complex (TSC) may be excised for cosmetic reasons or biopsied to confirm lesion identification and TSC diagnosis. The aim of this study was to determine the range of histopathological features of FCPs. METHODS AND RESULTS A retrospective analysis was conducted on 119 adults with TSC. Twenty-one lesions from 16 individuals were evaluated by a dermatopathologist. Additionally, we assessed whether lesion colour or histology varied by anatomical location. Seventy-six lesions were observed in 36 of 119 individuals. Erythematous lesions were more commonly found on the forehead, face or neck than on the scalp (odds ratio = 12.6, P = 0.0001). Thickened and disorganised collagen fibre bundles were present in 95% (20/21) of lesions. Perifollicular fibrosis was observed in 95% (20/21) of lesions, enhanced vascularity was observed in 52% (11/21) of lesions, and features of fibrofolliculoma were observed in 43% (9/21) of lesions. Other abnormalities included features similar to trichofolliculoma, follicular-derived, infundibular-type cysts, and abnormally arranged primitive hair follicles. CONCLUSIONS FCPs in TSC show thickened bundles of collagen, and hamartomatous changes involving hair follicles. Recognition of these histopathological features may raise the possibility of unsuspected TSC or confirm FCP identification.

While being in a committed relationship is associated with a better prostate cancer prognosis, little is known about how marital status relates to its incidence. Social support provided by marriage/relationship could promote a healthy lifestyle and an increased healthcare seeking behavior. We investigated the association between marital status and prostate cancer risk using data from the PRACTICAL Consortium. Pooled analyses were conducted combining 12 case–control studies based on histologically-confirmed incident prostate cancers and controls with information on marital status prior to diagnosis/interview. Marital status was categorized as married/partner, separated/divorced, single, or widowed. Tumours with Gleason scores ≥ 8 defined high-grade cancers, and low-grade otherwise. NCI-SEER’s summary stages (local, regional, distant) indicated the extent of the cancer. Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CI) for the association between marital status and prostate cancer risk, adjusting for potential confounders. Overall, 14,760 cases and 12,019 controls contributed to analyses. Compared to men who were married/with a partner, widowed men had an OR of 1.19 (95% CI 1.03–1.35) of prostate cancer, with little difference between low- and high-grade tumours. Risk estimates among widowers were 1.14 (95% CI 0.97–1.34) for local, 1.53 (95% CI 1.22–1.92) for regional, and 1.56 (95% CI 1.05–2.32) for distant stage tumours. Single men had elevated risks of high-grade cancers. Our findings highlight elevated risks of incident prostate cancer among widowers, more often characterized by tumours that had spread beyond the prostate at the time of diagnosis. Social support interventions and closer medical follow-up in this sub-population are warranted.

Prior research demonstrated large increased risk for maternal mortality among women with epilepsy. The objective of this study was to estimate risk for adverse maternal outcomes during delivery hospitalizations among women with epilepsy. Truven Health MarketScan databases were used to compare risk for adverse maternal outcomes during delivery hospitalizations based upon whether there was diagnosis of epilepsy and receipt of anti-epileptic drugs prior to delivery. Outcomes included: (i) death during delivery hospitalization, (ii) severe maternal morbidity, (iii) cesarean delivery, (iv) postpartum hemorrhage, (v) placental abruption, (vi) preeclampsia, (vii) preterm delivery, (viii) premature rupture of membranes, and (ix) stillbirth. Adjusted models including hospital and demographic factors were performed with adjusted risk ratios (aRR) with 95% CIs as measures of effect. Women with epilepsy prior to delivery who received antiepileptic drugs (n = 6019) during pregnancy were not at increased risk for mortality with no deaths occurring in this group (p = .27). Risk for severe maternal morbidity in this group was approximately double (aRR 2.16, 95% CI 1.86–2.51) with risks for other outcomes including placental abruption (aRR 1.29, 95% CI 1.04–1.60), cesarean delivery (aRR 1.14, 95% CI 1.10–1.18), and preterm delivery (aRR 1.25, 95% CI 1.15–1.35) slightly increased compared to women without seizures. No significant difference in mortality risk was found for women with epilepsy. Increased risk for other adverse maternal outcomes for women with epilepsy on antiepileptics was modest.

Previous approaches to acne management have focused on the four main factors implicated in acne, namely, androgen-mediated sebogenesis (considered integral to acne), hyperkeratinization, colonization with Cutibacterium acnes, and inflammation related to both innate and adaptive mechanisms. Recent advances have facilitated potential novel approaches to acne management, as the pathophysiology and the immunological aspects related to acne and wound healing have evolved. Particular targets that have been shown to be closely involved in acne pathophysiology and wound healing include interleukin (IL)-1β, IL-17, IL-23, and tumor necrosis factor alpha (TNFα). Biological antibodies targeting IL-1β, IL-17, IL-23, and TNFα could provide novel approaches for treating severe acne and related disorders. Acne is primarily a disease associated with sebogenesis. Monosaturated free acids are important components. Insulin growth factor 1 (IGF-1) promotes the proliferation and differentiation of sebocytes and IL-1β. Research into the microbiome may also provide insights into potential future therapeutic options for acne. Scars, both atrophic and hypertrophic, are common sequelae to acne. Risk factors associated with the development of acne scars include genetic, systemic, local, and lifestyle factors. Pro-inflammatory cytokines have been shown to play a crucial role in the development of acne-induced hypertrophic scars. Treatment for extensive inflammatory keloid scarring is limited. Surgery and postoperative radiotherapy are two possible options. Transforming growth factor-β (TGFβ), IL-6, matrix metalloproteinase (MMP), IGF-1, and B cells are found in keloid or hypertrophic scar tissues. Biological antibodies targeting these cytokines may be a potential strategy for the prevention and treatment of this type of scar in the future. Future treatment for acne should embrace approaches that target the main etiological factors of acne. In particular, specific emphasis on aggressive treatment in the acute inflammatory phase to reduce the likelihood of scarring and other clinical sequelae, such as pigmentary changes would be highly desirable. Treatment for established acne-induced sequelae should also be considered.

Background: Improving the mobility of hospitalized patients with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a priority of care. AECOPD-Mob is a clinical decision-making tool for physical therapists, especially those who are newly graduated or are new to caring for patients with AECOPDs in acute care settings. Although this tool has been available for several years, dissemination via publication is not sufficient to implement it in clinical practice. Objective: The primary objective of this study was to develop, implement, and evaluate different formats of AECOPD-Mob in an acute care setting. Methods: We used a mixed-methods, convergent parallel design. In addition to the paper format of AECOPD-Mob, we developed a smartphone app, a web-based learner module, and an in-service learning session. Newly graduated physical therapists (PTs) or PTs new to the practice area were recruited from urban acute care hospitals. Participants used the different formats for 3 weeks and then completed the Post-Study System Usability Questionnaire. User data were retrieved for the learning module. Participants participated in focus groups at 3 weeks and 3 months. Results: Eighteen (72% of eligible PTs, 100% female, 94% graduated within 3 yr) PTs participated. Post-Study System Usability Questionnaire scores for the learning module and smartphone indicated that participants were satisfied with these formats (median score 2.0 on 1–7 Likert Scale for both technology formats, lower scores indicating greater satisfaction). However, the participants reported in the focus group that the paper format was preferred over other formats. Concerns with the smartphone app included infection control and the perception of lack of professionalism when using a smartphone during clinical practice. The learning module and in-service were considered helpful as an introduction but not as an ongoing support. The paper format was seen as the most efficient way to access the necessary information and to facilitate communication between other members of the care team about the importance of mobility for hospitalized patients with AECOPDs. Conclusion: Newly graduated PTs strongly preferred the paper format of the AECOPD-Mob tool in the acute care setting. Future research will focus on knowledge translation strategies for other health disciplines.

Study Objective Provider misconceptions regarding intrauterine device (IUD) safety for adolescents and young women can unnecessarily limit contraceptive options offered; we sought to evaluate rates of Neisseria gonorrhoeae or Chlamydia trachomatis (GC/CT) diagnoses among young women who adopted IUDs. Design Secondary analysis of a cluster-randomized provider educational trial. Setting Forty US-based reproductive health centers. Participants We followed 1350 participants for 12 months aged 18-25 years who sought contraceptive care. Interventions The parent study assessed the effect of provider training on evidence-based contraceptive counseling. Main Outcome Measures We assessed incidence of GC/CT diagnoses according to IUD use and sexually transmitted infection risk factors using Cox regression modeling and generalized estimating equations. Results Two hundred four participants had GC/CT history at baseline; 103 received a new GC/CT diagnosis over the 12-month follow-up period. IUDs were initiated by 194 participants. Incidence of GC/CT diagnosis was 10.0 per 100 person-years during IUD use vs 8.0 otherwise. In adjusted models, IUD use (adjusted hazard ratio [aHR], 1.31; 95% confidence interval [CI], 0.71-2.40), adolescent age (aHR, 1.28; 95% CI, 0.72-2.27), history of GC/CT (aHR, 1.23; 95% CI, 0.75-2.00), and intervention status (aHR, 1.12; 95% CI, 0.74-1.71) were not associated with GC/CT diagnosis; however, new GC/CT diagnosis rates were significantly higher among individuals who reported multiple partners at baseline (aHR, 2.0; 95% CI, 1.34-2.98). Conclusion In this young study population with GC/CT history, this use of IUDs was safe and did not lead to increased GC/CT diagnoses. However, results highlighted the importance of dual sexually transmitted infection and pregnancy protection for participants with multiple partners.

Background Primary care nurses can assist General Practitioner’s to identify cognition concerns and support patient health self-management for those experiencing cognitive impairment or dementia. This support may lead to more appropriate care and better health outcomes for this group. Consequently, there is a need to identify the role of the primary care nurse in dementia care provision, nurse perceptions of this role and to also understand the barriers and enablers that may influence any current or potential primary care nurse role in dementia care provision. Methods Eight focus groups were conducted with a total of 36 primary care nurses. Data was transcribed verbatim and thematically analysed. Results There was a high level of agreement between primary care nurses that they had a role in provision of dementia care. This role was largely attributed to the strong therapeutic relationship between nurses and patients. However, dementia care provision was not without its challenges, including a perceived lack of knowledge, limited resources and the hierarchical nature of general practice. Three main themes were identified: personal attributes of the primary care nurse; professional attributes of the primary care nurse role and the context of practice. Six sub-themes were identified: knowing the person; overcoming stigma; providing holistic care; knowing what to do; team culture and working in the system. Conclusions The findings of this study suggest primary care nurses have a role in dementia care provision and, there is a need to provide support for the nurse to deliver person-centred health care in the context of cognitive impairment. As the demand for good quality primary care for people living with dementia increases, the role of the primary care nurse should be considered in primary care policy discussions. The knowledge gained from this study could be useful in informing dementia training content, to provide better prompts in the health assessment and care planning templates used by primary care nurses to better identify the care needs of people with a cognitive impairment and to develop dementia care guidelines for primary care nurses.

Assessing hospital environment conditions is necessary for healthcare providers and patients to coordinate safe care. The aims of this research included: a) identifying patterns in hospital visit feedback transcripts regarding bathroom doors and lights in the hospital room and b) interpreting the results to make recommendations for more enabling clinical environments. The methods used by the research team included organizing transcript data, assigning codes, and conducting an interrater reliability test to assess codebook efficacy. Finally, working with maternal and infant mortality experts, recommendations for the hospital were developed. We identified four possible interventions to address barriers: a) implement low-height, dimmable lighting along the base of the patient room, b) provide personal lights, such as penlights, to staff for nighttime assessments, c) install and improve on existing grab bars in patient room bathrooms and d) replace the standard patient room bathroom door with a different kind of auditory/visual privacy barrier.

Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values-8 as genome-wide significant, and p-values-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values5. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Background Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim‐Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking. Methods Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer‐related genes. Results Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen‐activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p, Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from the monocytic or dendritic cell lineage. This article presents the molecular characteristics of the four major subtypes of malignant histiocytic and dendritic cell neoplasms, focusing on genomic alterations that could represent therapeutic targets.

For patients diagnosed with a rare musculoskeletal or neuromuscular disease, pain may transition from acute to chronic; the latter yielding additional challenges for both patients and care providers. We assessed the present understanding of pain across a set of ten rare, noninfectious, noncancerous disorders; Osteogenesis Imperfecta, Ehlers-Danlos Syndrome, Achondroplasia, Fibrodysplasia Ossificans Progressiva, Fibrous Dysplasia/McCune-Albright Syndrome, Complex Regional Pain Syndrome, Duchenne Muscular Dystrophy, Infantile- and Late-Onset Pompe disease, Charcot-Marie-Tooth Disease, and Amyotrophic Lateral Sclerosis. Through the integration of natural history, cross-sectional, retrospective, clinical trials, & case studies we described pathologic and genetic factors, pain sources, phenotypes, and lastly, existing therapeutic approaches. We highlight that while rare diseases possess distinct core pathologic features, there are a number of shared pain phenotypes and mechanisms that may be prospectively examined and therapeutically targeted in a parallel manner. Finally, we describe clinical and research approaches that may facilitate more accurate diagnosis, monitoring, and treatment of pain as well as elucidation of the evolving nature of pain phenotypes in rare musculoskeletal or neuromuscular illnesses.

In this systematic review, objectives were to investigate dropout rates, adverse events, and effects of exercise-based therapies on urogenital function and quality of life (QoL) in persons with spinal cord injury (SCI). Database searches were conducted on MEDLINE, EMBASE, and CINAHL for studies examining any form of exercise intervention on urogenital function and/or QoL in adults with SCI. Quality of publications was evaluated using the Joanna Briggs Institute critical evaluation tools. When possible, Hedges'

JAG2 encodes the Notch ligand Jagged2. The conserved Notch signaling pathway contributes to the development and homeostasis of multiple tissues, including skeletal muscle. We studied an international cohort of 23 individuals with genetically unsolved muscular dystrophy from 13 unrelated families. Whole-exome sequencing identified rare homozygous or compound heterozygous JAG2 variants in all 13 families. The identified bi-allelic variants include 10 missense variants that disrupt highly conserved amino acids, a nonsense variant, two frameshift variants, an in-frame deletion, and a microdeletion encompassing JAG2. Onset of muscle weakness occurred from infancy to young adulthood. Serum creatine kinase (CK) levels were normal or mildly elevated. Muscle histology was primarily dystrophic. MRI of the lower extremities revealed a distinct, slightly asymmetric pattern of muscle involvement with cores of preserved and affected muscles in quadriceps and tibialis anterior, in some cases resembling patterns seen in POGLUT1-associated muscular dystrophy. Transcriptome analysis of muscle tissue from two participants suggested misregulation of genes involved in myogenesis, including PAX7. In complementary studies, Jag2 downregulation in murine myoblasts led to downregulation of multiple components of the Notch pathway, including Megf10. Investigations in Drosophila suggested an interaction between Serrate and Drpr, the fly orthologs of JAG1/JAG2 and MEGF10, respectively. In silico analysis predicted that many Jagged2 missense variants are associated with structural changes and protein misfolding. In summary, we describe a muscular dystrophy associated with pathogenic variants in JAG2 and evidence suggests a disease mechanism related to Notch pathway dysfunction.

Placenta accreta spectrum (PAS) is a group of placental invasion pathologies associated with significant morbidity to both mother and fetus. The majority of patients with PAS will require a blood transfusion at time of delivery and subsequent cesarean hysterectomy. The optimal approach to maternal acute blood loss resuscitation is currently unknown.Here, we present a cohort analysis of 34 patients with pathology-confirmed PAS treated with either whole blood (We observed comparable results in post-operative outcomes with fewer overall transfusions and subsequently, lower volumes of resuscitation (Whole blood transfusion may represent a viable option for initial resuscitation with lower resuscitation volumes and transfusion-associated complications without directly effecting post-operative outcomes in cases of PAS.

This review outlines the important oral implications of tobacco use. The lining of the mouth (oral mucosa), if exposed to tobacco and its products in a susceptible individual, can develop benign, potentially malignant, and malignant tumours. Treatment and prognosis depend on tumour type, how early it is detected, its size and site in the oral cavity and whether it has spread. Advanced oral squamous cell carcinoma (OSCC) has a 20% 5-year survival rate. Tobacco use also increases the risk of periodontitis, peri-implantitis, caries, alveolar osteitis and halitosis. Although less life threatening than OSCC, these tobacco related conditions create a substantial financial and health burden for individuals and society. Dental practitioners routinely examine the oral cavity for signs of mucosal and tooth changes, are experienced in recognising variations from normal and have established management and referral pathways. They are also ideally positioned to provide brief interventions to assist their patients to quit smoking.

The reasons for the positive association between anxiety disorders and asthma are unknown. We investigated the possible role of shared exposures in early life.We conducted a case–control study among adolescents (age 12–17 years) with and without asthma in urban Uganda, as part of a larger asthma case–control study. Anxiety disorders were diagnosed by psychiatric clinical officers. We focused on generalised anxiety disorder (GAD), panic disorder and social anxiety disorder. Asthma was doctor-diagnosed by study clinicians. We used questionnaires to collect data on early-life exposures. The data were analysed using multiple logistic regression.We enrolled 162 adolescents; 73 of them had asthma. Adolescents with asthma were more likely to have any of the three anxiety disorders studied (46.6%) than adolescents without asthma (21.4%) (adjusted OR (aOR) 2.68, 95% CI 1.30–5.53). The association was strong for GAD (aOR 4.49, 95% CI 1.48–13.56) and panic disorder (aOR 5.43, 95% CI 2.11–14.02), but not for social anxiety disorder. The early-life risk factors associated with anxiety disorders among adolescents were similar to asthma risk factors previously published, including urban residence at birth (aOR 3.42, 95% CI 1.29–9.09) and during most of the first 5 years of life (aOR 2.87, 95% CI 1.07–7.66), father's tertiary education (aOR 2.09, 95% CI 1.00–4.37), and adolescent's history of other allergy-related diseases (aOR 4.64, 95% CI 1.66–13.00).We confirm a positive association between anxiety disorders and asthma among adolescents in urban Uganda. The early-life risk factors associated with anxiety disorders among adolescents were similar to those for asthma in the same age group, suggesting shared underlying environmental exposures.

This is a single-center randomized open label active-controlled crossover trial comparing efficacy and safety of fast acting insulin aspart (FA) (FIASP®) versus insulin aspart (IAsp) (NovoLog®) when used in the Medtronic 670G system in auto mode in patients with type 1 diabetes. Forty patients were randomized to either IAsp or FA. Each treatment period was 7 weeks and a standardized meal test was administered 6 weeks after the start of each treatment period. The primary endpoint was postprandial glucose (PPG) increment after the meal test at 1 h. Treatment with FA using the MiniMed 670G hybrid closed loop (HCL) led to a greater reduction in 1-h postprandial glucose increase compared with treatment with IAsp during the standardized mixed meal test. Change in glucose: [estimated treatment difference (ETD ± standard deviation [SD]); 95% confidence interval]: 70.27 (±17.36) mg/dL (3.9 ± 1.0 mmol/L) with FA versus 98.42 (±17.36) mg/dL (5.5 ± 1.0 mmol/L) with IAsp (P = 0.008). Patients spent 1.81% (P = 0.016) more time (equivalent to 26 min per day) in the 70–180 mg/dL (3.89–9.99 mmol/L) range with FA than with IAsp. The entire sample spent only 0.5% of time

Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co­mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.

Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj > 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus 0– Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

Denosumab has been advocated as a potential treatment for the rare skeletal disorder fibrous dysplasia (FD); however, there is limited data to support safety and efficacy, particularly after drug discontinuation. We report a case of successful treatment of aggressive craniofacial FD with denosumab, highlighting novel insights into the duration of efficacy, surrogate treatment markers, and discontinuation effects. A 13-year-old girl presented with persistent pain and expansion of a maxillary FD lesion, which was not responsive to repeated surgical procedures or bisphosphonates. Pre-treatment biopsy showed high RANKL expression and localization with proliferation markers. Denosumab therapy was associated with improved pain, decreased bone turnover markers, and increased lesion density on computed tomography scan. During 3.5 years of treatment, the patient developed increased non-lesional bone density, and after denosumab discontinuation, she developed hypercalcemia managed with bisphosphonates. Pain relief and lesion stability continued for 2 years following treatment, and symptom recurrence coincided with increased bone turnover markers and decreased lesion density back to pre-treatment levels. This case highlights the importance of considering the duration of efficacy when treating patients with FD and other nonresectable skeletal neoplasms that require long-term management.

Objectives Individuals with major depressive disorder (MDD) have problems with engaging in approach behaviour to potentially rewarding encounters, which contributes to the maintenance of depressive symptoms. Approach-avoidance training (AAT) retrains implicit approach tendencies, and behavioural activation (BA) promotes explicit approach behaviour in MDD. As a novel MDD treatment strategy, this study aimed to implement a brief, computerized version of BA integrated with implicit AAT. Design Adults with a principal diagnosis of MDD (N = 25) were randomly assigned to complete one of two versions of AAT - approach-positive faces (n = 12) or balanced approach of positive and neutral faces (n = 13) - concurrently with self-guided BA twice weekly for 2 weeks. Methods Outcomes included treatment completion rates; bias scores for automatic approach towards positive social cues; and symptom scales for depression, positive affect, social relationship functioning, anhedonia, and anxiety. Results Feasibility and acceptability of computerized BA + AAT were supported by moderate pre-treatment credibility and expectancy ratings and 80% treatment completion. Participants across both conditions displayed significant and large sized reductions in depression from pre- to post-assessment (Cohen's d = -1.23) that maintained three months later, as well as decreased anxiety and anhedonia and increased positive affect and social relationship functioning (medium to large effects). Conclusion Results support the feasibility and potential efficacy of brief, computerized BA + AAT. Research is needed to determine whether AAT is additive to BA, and what AAT parameters best enhance treatment outcomes. Practitioner points Brief, computerized behavioral activation plus approach/avoidance training (BA + AAT) may be acceptable and beneficial for some patients with moderate-to-severe major depression. Computer-delivered BA + AAT can be implemented as a largely self-guided program for MDD and could be administered remotely and/or with minimal clinician interaction. As this was a small proof of concept study, it cannot be determined which treatment components - AAT, BA, or both - contributed to positive clinical outcomes. Because BA + AAT was implemented in a research clinic, it remains unknown what treatment engagement and response would look like in community settings.