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Background Cardiovascular disease is an important driver of the increased mortality associated with chronic kidney disease (CKD). Higher left ventricular mass (LVM) predicts increased risk of adverse cardiovascular outcomes and total mortality, but previous reviews have shown no clear association between intervention-induced LVM change and all-cause or cardiovascular mortality in CKD. Methods The primary objective of this meta-analysis was to investigate whether treatment-induced reductions in LVM over periods ≥12 months were associated with all-cause mortality in patients with CKD. Cardiovascular mortality was investigated as a secondary outcome. Measures of association in the form of relative risks (RRs) with associated variability and precision (95% confidence intervals [CIs]) were extracted directly from each study, when reported, or were calculated based on the published data, if possible, and pooled RR estimates were determined. Results The meta-analysis included 42 trials with duration ≥12 months: 6 of erythropoietin stimulating agents treating to higher vs. lower hemoglobin targets, 10 of renin-angiotensin-aldosterone system inhibitors vs. placebo or another blood pressure lowering agent, 14 of modified hemodialysis regimens, and 12 of other types of interventions. All-cause mortality was reported in 121/2584 (4.86%) subjects in intervention groups and 168/2606 (6.45%) subjects in control groups. The pooled RR estimate of the 27 trials ≥12 months with ≥1 event in ≥1 group was 0.72 (95% CI 0.57 to 0.90, p = 0.005), with little heterogeneity across studies. Directionalities of the associations in intervention subgroups were the same. Sensitivity analyses of ≥6 months (34 trials), ≥9 months (29 trials), and >12 months (10 trials), and including studies with no events in either group, demonstrated similar risk reductions to the primary analysis. The point estimate for cardiovascular mortality was similar to all-cause mortality, but not statistically significant: RR 0.67, 95% CI 0.39 to 1.16. Conclusions These results suggest that LVM regression may be a useful surrogate marker for benefits of interventions intended to reduce mortality risk in patients with CKD.

Pulmonary hypertension (PH) is an important contributor to morbidity and mortality in patients seeking emergency care, resulting in high acuity presentations and resource utilization. The objective was to characterize the rate of intensive care unit (ICU) admission for PH among adult patients presenting to the emergency department (ED) along with other important clinical outcomes.We analyzed data from the State Emergency Department Databases (SEDD) and State Inpatient Databases (SID) from two geographically separated U.S. states (New York and Nebraska). The primary outcome measure was admission to an ICU. Other measures of interest included the hospital admission rate, hospital length of stay (LOS), inpatient mortality, and rate of critical care procedures performed.From 2010 to 2014, in a sample of 34 million ED visits, patients with a diagnosis of PH accounted for 0.71% of all ED visits. Of the PH visits, 20.2% were admitted to the ICU, compared to 2.6% of all other visits (P0.001), with an aOR of 1.74 (95% CI 1. 72-1.76). The vast majority (94.6%) of PH patients were admitted to the hospital, compared to 20.5% for all other ED visits (P0.001). Hospital LOS and hospital-based mortality were higher in the PH group than for other ED patients. With the exception of invasive mechanical ventilation, a significantly higher percentage of patients with PH admitted to the ICU than other patients underwent all critical care procedures evaluated.In this study, patients with PH who sought emergency care in U.S. EDs from 2010 to 2014 were significantly more likely to require ICU admission than all other patients. They were also significantly more likely to be admitted to the hospital than all other patients, had longer hospital LOS, increased risk of inpatient mortality, and underwent more critical care procedures. These findings indicate the high acuity of PH patients seeking emergency care and demonstrate the need for additional research into this population.

Aims Sleep apnoea and congestive heart failure (CHF) commonly co‐exist, but their interaction is unclear. Metabolomics may clarify their interaction and relationships to outcome. Methods and results We assayed 372 circulating metabolites and lipids in 1919 and 1524 participants of the Framingham Heart Study (FHS) (mean age 54 ± 10 years, 53% women) and Women's Health Initiative (WHI) (mean age 67 ± 7 years), respectively. We used linear and Cox regression to relate plasma concentrations of metabolites and lipids to echocardiographic parameters; CHF and its subtypes heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF); and sleep indices. Adenine dinucleotide phosphate (ADP) associated with left ventricular (LV) fractional shortening; phosphocreatine with LV wall thickness; lysosomal storage molecule sphingomyelin 18:2 with LV mass; and nicotine metabolite cotinine with time spent with an oxygen saturation less than 90% (β = 2.3 min, P = 2.3 × 10−5). Pro‐hypertrophic metabolite hydroxyglutarate partly mediated the association between LV wall thickness and HFpEF. Central sleep apnoea was significantly associated with HFpEF (P = 0.03) but not HFrEF (P = 0.5). There were three significant metabolite canonical variates, one of which conferred protection from cardiovascular death [hazard ratio = 0.3 (0.11, 0.81), P = 0.02]. Conclusions Energetic metabolites were associated with cardiac function; energy‐ and lipid‐storage metabolites with LV wall thickness and mass; plasma levels of nicotine metabolite cotinine were associated with increased time spent with a sleep oxygen saturation less than 90%, a clinically significant marker of outcome, indicating a significant hazard for smokers who have sleep apnoea.

Background The AARS2 gene encodes a mitochondrial alanyl-transfer RNA synthetase. Defects in this gene have been linked with autosomal recessive inheritance of a variety of different clinical phenotypes. Case A 13 year-old boy developed behavioral and psychiatric problems following a mild head injury. At age 21 he developed tremor, parkinsonism, and eye nystagmus. MRI revealed white matter changes consistent with a leukoencephalopathy. Genetic studies revealed two pathogenic mutations in the AARS2 gene (c.647dupG and c.595C > T). Literature review Only 47 cases of AARS2-associated disorders have been reported, with equal numbers of males and females, and age at onset ranging from infancy to 44 years. The most common clinical problems include movement disorders (71%), cognitive impairment (67%), corticospinal signs (64%), behavioral or psychiatric features (46%), and eye signs (34%). Imaging evidence suggestive of leukoencephalopathy is common, but not invariant. Premature ovarian failure is frequent in females, but not universal. Conclusions Defects in the AARS2 gene are a rare cause for a variety of movement disorders, often associated with brain imaging evidence suggestive of leukoencephalopathy.

The DUSP22-IRF4 gene rearrangement results in downregulation of DUSP22, a presumed tumor suppressor in T-cell lymphomagenesis. It has been described in some cases of primary cutaneous and systemic anaplastic large-cell lymphoma, lymphomatoid papulosis, and transformed mycosis fungoides. Here we describe two patients with clinical lesions resembling patch/plaque mycosis fungoides that did not meet WHO criteria for large-cell transformation on histopathology yet showed a DUSP22 translocation. One patient who had a history of systemic anaplastic large-cell lymphoma with DUSP22 translocation presented with cutaneous involvement by his systemic lymphoma along with lymphomatoid papulosis and mycosis-fungoides-like lesions, all showing an identical immunophenotype and T-cell clone. These cases expand the spectrum of DUSP22-rearranged lymphomas to include mycosis-fungoides-like presentations without large-cell transformation.

INTRODUCTION In three phase III randomized controlled trials, ceftaroline fosamil was shown to be non-inferior to vancomycin plus aztreonam for the treatment of complicated skin and soft tissue infections (cSSTIs). This exploratory analysis evaluated the impact of underlying comorbidities on clinical outcomes in patients with cSSTI pooled from these three studies. METHODS CANVAS 1 and 2 and COVERS evaluated ceftaroline fosamil (600 mg every 12 h [q12h]; 600 mg every 8 h [q8h; COVERS]) versus vancomycin plus aztreonam (1 g q12h each [CANVAS 1 and 2]; vancomycin 15 mg/kg q12h and aztreonam 1 g q8h [COVERS]) in hospitalized adults with cSSTI. The primary efficacy variable in each trial was clinical response at the test-of-cure (TOC) visit. Subgroup analyses were performed on the pooled clinically evaluable (CE) population, exploring the impact of age and various baseline comorbidities. RESULTS Overall, 1808 patients were included in the CE population (1005 ceftaroline fosamil; 803 vancomycin plus aztreonam). Clinical cure rates at TOC were 89.7% (ceftaroline fosamil) and 90.8% (vancomycin plus aztreonam) (difference [95% confidence interval] - 1.13 [- 3.87, 1.67]). Clinical response rates were similar between treatment groups, regardless of age (≤ 65 years or > 65 years), and in subgroups of patients with and without diabetes mellitus, peripheral vascular disease, cancer/malignancy, renal impairment, and obesity; within these subgroups, efficacy and safety results were generally consistent with those of the overall cSSTI population. CONCLUSIONS This analysis provides supportive evidence of the efficacy of ceftaroline fosamil in patients with cSSTI and underlying comorbidities. TRIAL REGISTRATION CANVAS 1, NCT00424190 and CANVAS 2, NCT00423657 (both trials first posted on ClinicalTrials.gov 18/01/2007); COVERS, NCT01499277 (first posted on ClinicalTrials.gov 26/12/2011).

Objective Infection with Theiler's Murine Encephalomyelitis Virus (TMEV) in C57Bl/6J mice results in handling-induced seizures and is useful for evaluating compounds effective against infection-induced seizures. However, to date only a few compounds have been evaluated in this model, and a comprehensive study of antiseizure medications (ASMs) has not yet been performed. Furthermore, as the TMEV infection produces marked neuroinflammation, an evaluation of prototype anti-inflammatory compounds is needed as well. Methods Male C57Bl/6J mice were inoculated with TMEV (day 0) followed by daily administrations of test compounds (day 3-7) and subsequent handling sessions (day 3-7). Doses of ASMs, comprising several mechanistic classes, were selected based on previously published data demonstrating the effect of these compounds in reducing seizures in the 6 Hz model of pharmacoresistant seizures. Doses of anti-inflammatory compounds, comprising several mechanistic classes, were selected based on published evidence of reduction of inflammation or inflammation-related endpoints. Results Several prototype ASMs reduced acute seizures following TMEV infection: lacosamide, phenytoin, ezogabine, phenobarbital, tiagabine, gabapentin, levetiracetam, topiramate, and sodium valproate. Of these, phenobarbital and sodium valproate had the greatest effect (>95% seizure burden reduction). Prototype anti-inflammatory drugs celecoxib, dexamethasone, and prednisone also moderately reduced seizure burden. Significance The TMEV model is utilized by the Epilepsy Therapy Screening Program (ETSP) as a tool for evaluation of novel compounds. Compounds reducing seizures in the TMEV comprise distinct mechanistic classes, some with mechanisms of action that extend beyond traditional ASMs.

Factitious gastrointestinal bleeding (GIB) is a manifestation of factitious disorder (FD) wherein patients feign GIB in the absence of external gain. As it can be a challenging diagnosis to make, factitious GIB often leads to multiple tests, exposure to contrast agents and radiation, invasive endoscopic and surgical procedures, an increased risk of iatrogenic complications, and increased healthcare costs. Patients who feign GIB often demonstrate characteristic behaviors that may go unnoticed unless they are explicitly addressed. We report a series of patients admitted to our institution for further evaluation of obscure overt GIB with an eventual diagnosis of factitious GIB and review of the epidemiology and development of FD, a diagnostic approach to factitious GIB, and current management strategies.

BackgroundOver 400 variants in the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) are CF-causing. CFTR modulators target variants to improve lung function, but marked variability in response exists and current therapies do not address all CF-causing variants highlighting unmet needs. Alternative epithelial ion channel/transporters such as SLC26A9 could compensate for CFTR dysfunction, providing therapeutic targets that may benefit all individuals with CF.MethodWe investigate the relationship between rs7512462, a marker ofSLC26A9activity, and lung function pre- and post-treatment with CFTR modulators in Canadian and US CF cohorts, in the general population, and in those with chronic obstructive pulmonary disease (COPD).ResultsRs7512462 CC genotype is associated with greater lung function in CF individuals with minimal function variants (for which there are currently no approved therapies; p=0.008); and for gating (p=0.033) and p.Phe508del/ p.Phe508del (p=0.006) genotypes upon treatment with CFTR modulators. In parallel, human nasal epithelia with CC and p.Phe508del/p.Phe508del after Ussing chamber analysis of a combination of approved and experimental modulator treatments show greater CFTR function (p=0.0022). Beyond CF, rs7512462 is associated with lung function in a meta-analysis of the UK Biobank and Spirometa Consortium (min p=2.74×0-44) and provides p=0.0891 in an analysis of COPD case-control status in the UK Biobank defined by spirometry.ConclusionThese findings support SLC26A9 as a therapeutic target to improve lung function for all people with CF and in individuals with other obstructive lung diseases.

BACKGROUND: Rotational thromboelastometry (ROTEM) has been commonly used to assess the viscoelastic properties of the blood clotting process in the clinic for patients with a hemostatic or prothrombotic disorder. OBJECTIVE: To evaluate the capability of ROTEM in assessing hemostatic properties in whole blood from various mouse models with genetic bleeding or clotting disease and the effect of factor VIII (FVIII) therapeutics in FVIII(null) mice. METHODS: Mice with a genetic deficiency in either a coagulation factor or a platelet glycoprotein were used in this study. The properties of platelet- or plasma-FVIII were also assessed. Citrated blood from mice was recalcified and used for ROTEM analysis. RESULTS: We found that blood collected from the vena cava could generate reliable results from ROTEM analysis, but not blood collected from the tail vein, retro-orbital plexus, or submandibular vein. Age and sex did not significantly affect the hemostatic properties determined by ROTEM analysis. Clotting time (CT) and clot formation time (CFT) were significantly prolonged in FVIII(null) (5- and 9-fold, respectively) and FIX(null) (4- and 5.7-fold, respectively) mice compared to wild-type (WT)-C57BL/6J mice. Platelet glycoprotein (GP)IIIa(null) mice had significantly prolonged CFT (8.4-fold) compared to WT-C57BL/6J mice. CT and CFT in factor V (FV) Leiden mice were significantly shortened with an increased α-angle compared to WT-C57BL/6J mice. Using ROTEM analysis, we showed that FVIII expressed in platelets or infused into whole blood restored hemostasis of FVIII(null) mice in a dose-dependent manner. CONCLUSION: ROTEM is a reliable and sensitive assay for assessing therapeutics on hemostatic properties in mouse models with a bleeding or clotting disorder.

SGA (small for gestational age) is widely used to identify high-risk infants, although with inconsistent definitions. Cut points range from 2.5th to 10th percentile of birthweight-for-gestational age. We used receiver operator characteristic curves (ROC) to identify the cut point with maximum sensitivity and specificity (Youden Index), and the area under the curve (AUC), which assesses overall discriminating power. Analysis was conducted on 3,836,034 US births (2015) and 292,279 Norwegian births (2010–14). Birthweight percentiles were calculated using exact birthweights at each week of gestational age, and then summarized across gestational ages. We also conducted a companion analysis of gestational age itself to consider the predictive power of gestational week of birth. Outcomes were neonatal mortality and cerebral palsy, both strongly associated with birthweight. Birthweight percentiles performed poorly in all analyses. The AUC for birthweight percentiles as a discriminator of neonatal mortality was 60% (where 50% is no better than a coin-toss). At such low discrimination, the Youden Index provides no useful SGA cut point. Results in Norway were virtually identical, with an AUC of 58%. The AUC with cerebral palsy as the outcome was even lower, at 54%. In contrast, gestational age had an AUC of 85% as a predictor of neonatal mortality, with

Viral infection of the central nervous system increasingly places people at risk of developing life-threatening and treatment-resistant acute and chronic seizures (epilepsy). The emergence of new human viruses due to ongoing social, political, and ecological changes places people at risk more than ever before. The development of new preventative or curative strategies is critical to address this burden. However, our understanding of the complex relationship between viruses and the brain has been hindered by the lack of animal models that survive the initial infection and are amenable for long-term mechanistic, behavioral, and pharmacological studies in the process of viral-induced epileptogenesis. In this review, we focus on the Theiler’s murine encephalomyelitis virus (TMEV) mouse model of viral infection–induced epilepsy. The TMEV model has a number of important advantages to address the quintessential processes underlying the development of epilepsy following a viral infection, as well as fuel new therapeutic development. In this review, we highlight the contributions of the TMEV model to our current understanding of the relationship between viral infection, inflammation, and seizures.

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.

Vosoritide, an analog of C-type natriuretic peptide, has been developed for the treatment of children with achondroplasia. The pharmacokinetics of vosoritide and relationships between plasma exposure and efficacy, biomarkers, and safety endpoints were evaluated in a phase II, open-label, dose-escalation study (N = 35 patients aged 5–14 years who received daily subcutaneous injections for 24 months) and a phase III, double-blind, placebo-controlled study (N = 60 patients aged 5–18 years randomized to receive daily subcutaneous injections for 52 weeks). Pharmacokinetic parameters for both studies were obtained from non-compartmental analysis. Potential correlations between vosoritide exposure and changes in annualized growth velocity, collagen type X marker (CXM; a biomarker of endochondral ossification), cyclic guanosine monophosphate (cGMP; a biomarker of pharmacological activity), heart rate, and systolic and diastolic blood pressures were then evaluated. The exposure–response relationships for changes in both annualized growth velocity and the CXM biomarker saturated at 15 μg/kg, while systemic pharmacological activity, as measured by urinary cGMP, was near maximal or saturated at exposures obtained at the highest dose studied (i.e. 30 μg/kg). This suggested that the additional bioactivity was likely in tissues not related to endochondral bone formation. In the phase III study, following subcutaneous administration at the recommended dose of 15 μg/kg to patients with achondroplasia aged 5–18 years, vosoritide was rapidly absorbed with a median time to maximal plasma concentration (Cmax) of 15 minutes, and cleared with a mean half-life of 27.9 minutes after 52 weeks of treatment. Vosoritide exposure (Cmax and area under the concentration-time curve [AUC]) was consistent across visits. No evidence of accumulation with once-daily dosing was observed. Total anti-vosoritide antibody (TAb) responses were detected in the serum of 25 of 60 (42%) treated patients in the phase III study, with no apparent impact of TAb development noted on annualized growth velocity or vosoritide exposure. Across the exposure range obtained with 15 µg/kg in the phase III study, no meaningful correlations between vosoritide plasma exposure and changes in annualized growth velocity or CXM, or changes from predose heart rate, and systolic or diastolic blood pressures were observed. The results support the recommended dose of vosoritide 15 µg/kg for once-daily subcutaneous administration in patients with achondroplasia aged ≥ 5 years whose epiphyses are not closed. NCT02055157, NCT03197766, and NCT01603095.

Rebecca Persson,1 Todd Sponholtz,1 Catherine Vasilakis-Scaramozza,1 Katrina Wilcox Hagberg,1 Tim Williams,2 Dipak Kotecha,3 Puja Myles,2 Susan S Jick1,4 1Epidemiology, Boston Collaborative Drug Surveillance Program, Lexington, MA, USA; 2Clinical Practice Research Datalink, Medicines and Healthcare Products Regulatory Agency, London, UK; 3Institute of Cardiovascular Sciences, University of Birmingham & University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK; 4Epidemiology, Boston University School of Public Health, Boston, MA, USACorrespondence: Susan S Jick Email sjick@bu.eduBackground: Validation studies of the Clinical Practice Research Datalink (CPRD) Aurum database in the UK are critical for making decisions about its suitability and validity for research purposes.Objective: To examine data source agreement of myocardial infarction (MI) diagnoses recorded in CPRD Aurum compared with linked Hospital Episode Statistics (HES) data. This comparison provides information on CPRD Aurum data correctness (accuracy, validity) and completeness (presence, missingness).Methods: Patients with MI diagnoses recorded in either data source were selected from a random sample of 50,000 patients in CPRD Aurum with HES linkage (1997– 2017). Correctness was defined as the proportion of MI cases in CPRD Aurum with a concordant MI diagnosis recorded in HES or with strong supporting evidence in either data source. Completeness was defined as the proportion of patients with primary HES-coded MIs with strong supporting evidence that were also present in CPRD Aurum.Results: There were 1260 patients with MI recorded in the CPRD Aurum sample. The overall correctness of the recorded MI diagnoses was 94%: 986 patients (78%) had concordant diagnoses in HES within 90 days; 123 (10%) were concordant with HES, but with an inconclusive date and another 71 (6%) had strong supporting evidence for being a true MI case. There were 1125 patients with MI recorded in HES primary diagnosis fields with strong supporting evidence in either data source. Of these, 880 (78%) were present in CPRD Aurum, with completeness somewhat higher in more recent years.Conclusion: MI diagnoses recorded in CPRD Aurum were highly likely to be correct, supporting its use in clinical research studies. Completeness was lower, indicating the need for data linkage for some studies.Keywords: clinical practice research datalink, CPRD Aurum, data validation, data completeness, data quality

Background Adjustment disorder (AD) is the most common mental health diagnosis in the U.S. military and is more than twice as likely to be diagnosed in active duty servicewomen as compared with male servicemembers. The literature on ADs, particularly in female servicemembers, has not been reviewed yet. We conducted a scoping review of the literature to explore the degree of research activity and summarize current literature gaps. Methods We created a PRISMA-ScR checklist and prospectively registered it in Open Science Framework. The literature search included articles (including studies and reports) published between 2000 and 2018 in either the grey literature or the following databases: Ovid Medline, CINAHL, Embase, PsycINFO, Web of Science, and Ovid Cochrane. We used DistillerSR to conduct title and abstracts screening, full-text screening, and data charting. The social ecological model for military women's health framework was used to organize the results. Results After screening 1,304 records, 29 were included for data charting. Most frequently, studies were descriptive (cross-sectional) (25%), with no randomized controlled studies. The studies primarily focused on ADs’ risk factors in servicewomen (76%), followed by military readiness (38%). Only 14% addressed recommendations for treatments based on expert opinion, although they did not directly test interventions, and 7% focused on health outcomes. Conclusions ADs affect the health of U.S. military women and military readiness, yet little is known about their successful treatment or health outcomes. Additional research in those areas is warranted.

Author(s): Savarirayan, Ravi; Tofts, Louise; Irving, Melita; Wilcox, William R; Bacino, Carlos A; Hoover-Fong, Julie; Font, Rosendo Ullot; Harmatz, Paul; Rutsch, Frank; Bober, Michael B; Polgreen, Lynda E; Ginebreda, Ignacio; Mohnike, Klaus; Charrow, Joel; Hoernschemeyer, Daniel; Ozono, Keiichi; Alanay, Yasemin; Arundel, Paul; Kotani, Yumiko; Yasui, Natsuo; White, Klane K; Saal, Howard M; Leiva-Gea, Antonio; Luna-Gonzalez, Felipe; Mochizuki, Hiroshi; Basel, Donald; Porco, Dania M; Jayaram, Kala; Fisheleva, Elena; Huntsman-Labed, Alice; Day, Jonathan RS | Abstract: PurposeAchondroplasia is caused by pathogenic variants in the fibroblast growth factor receptor 3 gene that lead to impaired endochondral ossification. Vosoritide, an analog of C-type natriuretic peptide, stimulates endochondral bone growth and is in development for the treatment of achondroplasia. This phase 3 extension study was conducted to document the efficacy and safety of continuous, daily vosoritide treatment in children with achondroplasia, and the two-year results are reported.MethodsAfter completing at least six months of a baseline observational growth study, and 52 weeks in a double-blind, placebo-controlled study, participants were eligible to continue treatment in an open-label extension study, where all participants received vosoritide at a dose of 15.0 μg/kg/day.ResultsIn children randomized to vosoritide, annualized growth velocity increased from 4.26 cm/year at baseline to 5.39 cm/year at 52 weeks and 5.52 cm/year at week 104. In children who crossed over from placebo to vosoritide in the extension study, annualized growth velocity increased from 3.81 cm/year at week 52 to 5.43 cm/year at week 104. No new adverse effects of vosoritide were detected.ConclusionVosoritide treatment has safe and persistent growth-promoting effects in children with achondroplasia treated daily for two years.

Ventilator-induced lung injury remains a key contributor to the morbidity and mortality of the acute respiratory distress syndrome. Efforts to minimize this injury are typically limited by the need to preserve adequate gas exchange. In the most severe forms of the syndrome, extracorporeal life support is increasingly being deployed for severe hypoxemia or hypercapnic acidosis refractory to conventional ventilator management strategies. Data from a recent randomized controlled trial, a post-hoc analysis of that trial, a meta-analysis, and a large, international, multicenter observational study, all suggest that extracorporeal life support, when combined with lower tidal volumes and airway pressures than the current standard of care, may improve outcomes compared with conventional management in patients with the most severe forms of the acute respiratory distress syndrome. These findings raise important questions not only about the optimal ventilator strategies for patients receiving extracorporeal support, but how various mechanisms of lung injury in the acute respiratory distress syndrome may potentially be mitigated by ultra-lung-protective ventilation strategies when gas exchange is sufficiently managed with the extracorporeal circuit. Additional studies are needed to more precisely delineate the best strategies for optimizing invasive mechanical ventilation in this patient population.

Summary Background Carbapenemase-producing Enterobacterales (CPE) can colonize the gut and are of major clinical concern. Identification of CPE colonization is problematic; there is no gold-standard detection method, and the effects of antibiotic exposure and microbiota dysbiosis on detection are unknown. Aim Based on a national survey we selected four CPE screening assays in common use. We used a clinically reflective in vitro model of human gut microbiota to investigate the performance of each test to detect three different CPE strains under different, clinically relevant antibiotic exposures. Methods Twelve gut models were seeded with a pooled faecal slurry and exposed to CPE either before, after, concomitant with, or in the absence of piperacillin-tazobactam (358 mg/L, 3 × daily, seven days). Total Enterobacterales and CPE populations were enumerated daily. Regular screening for CPE was performed using Cepheid Xpert® Carba-R molecular test, and with Brilliance™ CRE, Colorex™ mSuperCARBA and CHROMID® CARBA SMART agars. Findings Detection of CPE when the microbiota are intact is problematic. Antibiotic exposure disrupts microbiota populations and allows CPE proliferation, increasing detection. The performances of assays varied, particularly with respect to different CPE strains. The Cepheid assay performed better than the three agar methods for detecting a low level of CPE within an intact microbiota, although performance of all screening methods was comparable when CPE populations increased in a disrupted microbiota. Conclusion CPE strains differed in their dynamics of colonization in an in vitro gut model and in their subsequent response to antibiotic exposure. This affected detection by molecular and screening methods, which has implications for the sensitivity of CPE screening in healthcare settings.

ObjectiveTo assess whether clinical and/or laboratory-confirmed diagnosis of maternal influenza during pregnancy increases the risk of seizures in early childhood.DesignAnalysis of prospectively collected registry data for children born between 2009 and 2013 in three high-income countries. We used Cox regression to estimate country-level adjusted HRs (aHRs); fixed-effects meta-analyses were used to pool adjusted estimates.SettingPopulation-based.Participants1 360 629 children born between 1 January 2009 and 31 December 2013 in Norway, Australia (New South Wales) and Canada (Ontario).ExposureClinical and/or laboratory-confirmed diagnosis of maternal influenza infection during pregnancy.Main outcome measuresWe extracted data on recorded seizure diagnosis in secondary/specialist healthcare between birth and up to 7 years of age; additional analyses were performed for the specific seizure outcomes ‘epilepsy’ and ‘febrile seizures’.ResultsAmong 1 360 629 children in the study population, 14 280 (1.0%) were exposed to maternal influenza in utero. Exposed children were at increased risk of seizures (aHR 1.17, 95% CI 1.07 to 1.28), and also febrile seizures (aHR 1.20, 95% CI 1.07 to 1.34). There was no strong evidence of an increased risk of epilepsy (aHR 1.07, 95% CI 0.81 to 1.41). Risk estimates for seizures were higher after influenza infection during the second and third trimester than for first trimester.ConclusionsIn this large international study, prenatal exposure to influenza infection was associated with increased risk of childhood seizures.

Background Tourette syndrome and OCD are disorders that frequently occur in children and cause a high level of disability. In Alberta there is a huge delivery gap in providing healthcare services for children with TS and OCD. A stakeholder consultation was performed to ascertain how service delivery could be improved across the province and to inform the development of a provincial information and support organization, the Tourette OCD Alberta Network. Methods A mixed-methods study was employed: 10 parents were recruited for interview and 140 parents responded to a survey. Results Qualitative data showed there was often an absence of a clear pathway to access healthcare for people with TS and OCD. The negative impact of not receiving treatment, information, and resources in a timely and prompt manner was also revealed. Good clinical practice existed across the province but too often it was hindered by a shortage of knowledge about TS and OCD. In schools, learning for students with TS and OCD was also impaired by educators’ lack of knowledge and preparedness in relation to the disorders. Conclusions This study identified ways that challenges with healthcare access, school learning, and seeking information can be overcome. Skills-based training webinars, educational outreach in schools, and peer support were recognized as actions for improving healthcare outcomes for people with TS and OCD. The aim of the Tourette OCD Alberta Network is to provide services and support that directly address the healthcare service delivery shortfalls shown in this study.

Patients who present with atrial fibrillation (AF) or flutter with rapid ventricular response (RVR) and hemodynamic stability may be managed with either an intravenous (IV) nondihydropyridine calcium channel blocker (CCB) or a beta-blocker (BB). Patients without improved heart rates may need to switch to, or add, a second AV nodal blocker.To evaluate the incidence of rate control achievement and bradycardia in patients in AF or atrial flutter with RVR who receive both an intravenous CCB and a BB.A retrospective chart review of patients who received concomitant intravenous CCB or BB for the treatment of rapid AF or atrial flutter from April 2016 through July 2018 in the emergency department. Patients were excluded if the second agent was ordered but not administered, or if they received IV amiodarone or digoxin.A total of 136 patients were included in the analysis, and of those, 46% (n = 62) of patients achieved a heart rate110 bpm without bradycardia, and 3.7% (n = 5) developed bradycardia. Age, initial heart rate, time between CCB and BB administration, addition of an oral CCB or BB administration, or administration of IV magnesium did not impact target heart rate achievement.Adding a second nodal blocker in patients who did not achieve rate control with the first agent resulted in heart rate control 46% of the time. The development of symptomatic bradycardia was uncommon.

OBJECTIVES/HYPOTHESIS Evaluate swallowing and airway outcomes following laryngotracheoplasty with posterior grafting (LTP PCCG). METHODS Retrospective review of pediatric patients undergoing LTP PCCG from 2016 to 2019 at a tertiary care pediatric hospital. We included demographics, indications, approach, and revision status. We evaluated preoperative and postoperative instrumental and functional swallow evaluations, and we also gathered information on airway outcomes. RESULTS Thirty-one patients were included in the study. Median (interquartile range [IQR]) age was 4.0 (2.0, 7.0) years old. Primary indication for surgery was bilateral vocal cord immobility (BVCI) in 11 (35.5%) and posterior glottic stenosis (PGS) in 20 (64.5%). Mean (standard deviation) length of follow-up was 11.0 (8.3) months. Twelve patients had gastrostomy tubes (GT) before surgery, and no patients required placement of GT after surgery. Of the remaining 19 patients, 6 required nasogastric feeding for >4 weeks (average length 1.8 months, longest 3.5 months). At last follow-up, 25 (80.6%) patients were primarily orally fed. Eighteen patients had tracheotomies prior to surgery. No patients without a tracheostomy required placement of tracheostomy before or after surgery and only 1 patient had a tracheostomy at last follow-up. Average time to decannulation was 3.7 months, with surgery-specific success of 87.1% and overall success of 96.8%. Four (12.9%) patients required a major intervention to achieve decannulation. CONCLUSION LTP PCCG is an effective surgical technique to address PGS and BVCI with high decannulation rates. It may cause temporary swallowing dysfunction, but in this series a majority of children were orally fed at last follow-up. LEVEL OF EVIDENCE 4 Laryngoscope, 131:2798-2804, 2021.

Background Preterm birth is an important risk factor for neurodevelopmental disabilities. The vast majority of these disabilities occur, however, among term births. The role of fetal growth restriction specifically among term babies has been incompletely described. Methods We conducted a population-based study of term birth weight and its link to a range of neurodevelopmental outcomes using Norwegian health registries. To remove the influence of preterm birth, we restricted our analyses to 1.8 million singleton babies born during a narrow range of term gestational age (39-41 weeks). Babies with malformations were excluded. We adjusted analyses simply for year of birth, as further adjustments for sex, parity, maternal age, smoking, marital status, immigrant status, and parental education had trivial influence. An additional sibling analysis controlled for unmeasured family-based confounding. Results The risk of neurodevelopmental disabilities at term steadily increased at birth weights lower than 3.5 kg. Using the category of 3.5-3.9 kg as the reference, the odds reached 25-fold for cerebral palsy at the smallest weights (95% confidence interval 8.0-79), 16-fold for vision/hearing disability (4.0-65), 11-fold for intellectual impairment (6.9-17), 7-fold for schizophrenia (1.0-50), 5.4-fold for epilepsy (2.6-12), and 3.5-fold for autism spectrum (1.3-9.4) and behavioral disorders including attention deficit hyperactivity disorder (ADHD) (2.1-5.4). Associations remained robust with sibling controls. Conclusions Reduced fetal growth is a powerful predictor of a wide variety of neurodevelopmental disabilities independent of preterm delivery.

OBJECTIVES: Blood pressure (BP) abstracted from electronic medical records (EMR) is moderately correlated to BP in non-pregnant adults with limited agreement. Little is known about the agreement of research versus EMR BP measured during pregnancy or associations of EMR BP with hypertensive disorder of pregnancy (HDP) diagnoses. METHODS: BP was measured according to guidelines at in-person research study visits in 214 women with pre-pregnancy overweight or obesity (44.4% African American, mean age=29.8±4.8 yrs) at week 16 and 32 of pregnancy. Clinic BP readings that occurred within 1 week of the study visit were abstracted from the EMR. We assessed correlations between sources using Pearson’s coefficients; agreement was evaluated with Bland-Altman plots. We compared differences in the proportion of women with an HDP diagnosis in the EMR between women with versus without a hypertensive EMR BP measurement. RESULTS: Systolic and diastolic BP from study visits and the EMR were modestly-moderately correlated at both time points; 0.20

Given recent advances in both pharmacologic and nonpharmacologic strategies for improving outcomes related to chronic systolic heart failure, heart failure with recovered ejection fraction (HFrecEF) is now recognized as a distinct clinical entity with increasing prevalence. In many patients who once had an indication for active implantable cardioverter-defibrillator (ICD) therapy, questions remain regarding the usefulness of this primary prevention strategy to protect against syncope and cardiac arrest after they have achieved myocardial recovery. Early, small studies provide convincing evidence for continued guideline-directed medical therapy (GDMT) in segments of the HFrecEF population to promote persistent left ventricular myocardial recovery. Retrospective data suggest that the risk of sudden cardiac death is lower, but still present, in HFrecEF as compared with HF with reduced ejection fraction, with reports of up to 5 appropriate ICD therapies delivered per 100 patient-years. The usefulness of continued ICD therapy is weighed against the unfavorable effects of this strategy, which include a cumulative risk of infection, inappropriate discharge, and patient-level anxiety. Historically, many surrogate measures for risk stratification have been explored, but few have demonstrated efficacy and widespread availability. We found that the available data to inform decisions surrounding the continued use of active ICD therapies in this population are incomplete, and more advanced tools such as genetic testing, evaluation of high-risk structural cardiomyopathies (such as noncompaction), and cardiac magnetic resonance imaging have emerged as vital in risk stratification. Clinicians and patients should engage in shared decision-making to evaluate the appropriateness of active ICD therapy for any given individual. In this article, we explore the definition of HFrecEF, data underlying continuation of guideline-directed medical therapy in patients who have achieved left ventricular ejection fraction recovery, the benefits and risks of active ICD therapy, and surrogate measures that may have a role in risk stratification.

Epilepsy is one of the most common chronic brain diseases and is often associated with cognitive, behavioral, or other medical conditions. The need for therapies that would prevent, ameliorate, or cure epilepsy and the attendant comorbidities is a priority for both epilepsy research and public health. In 2018, the National Institute of Neurological Disease and Stroke (NINDS) convened a workshop titled “Accelerating the Development of Therapies for Antiepileptogenesis and Disease Modification” that brought together preclinical and clinical investigators and industry and regulatory bodies’ representatives to discuss and propose a roadmap to accelerate the development of antiepileptogenic (AEG) and disease‐modifying (DM) new therapies. This report provides a summary of the discussions and proposals of the Preclinical Science working group. Highlights of the progress of collaborative preclinical research projects on AEG/DM of ongoing research initiatives aiming to improve infrastructure and translation to clinical trials are presented. Opportunities and challenges of preclinical epilepsy research, vis‐à‐vis clinical research, were extensively discussed, as they pertain to modeling of specific epilepsy types across etiologies and ages, the utilization of preclinical models in AG/DM studies, and the strategies and study designs, as well as on matters pertaining to transparency, data sharing, and reporting research findings. A set of suggestions on research initiatives, infrastructure, workshops, advocacy, and opportunities for expanding the borders of epilepsy research were discussed and proposed as useful initiatives that could help create a roadmap to accelerate and optimize preclinical translational AEG/DM epilepsy research.

Purpose Cystic fibrosis (CF), caused by pathogenic variants in the CF transmembrane conductance regulator (CFTR), affects multiple organs including the exocrine pancreas, which is a causal contributor to cystic fibrosis–related diabetes (CFRD). Untreated CFRD causes increased CF-related mortality whereas early detection can improve outcomes. Methods Using genetic and easily accessible clinical measures available at birth, we constructed a CFRD prediction model using the Canadian CF Gene Modifier Study (CGS; n = 1,958) and validated it in the French CF Gene Modifier Study (FGMS; n = 1,003). We investigated genetic variants shown to associate with CF disease severity across multiple organs in genome-wide association studies. Results The strongest predictors included sex, CFTR severity score, and several genetic variants including one annotated to PRSS1, which encodes cationic trypsinogen. The final model defined in the CGS shows excellent agreement when validated on the FGMS, and the risk classifier shows slightly better performance at predicting CFRD risk later in life in both studies. Conclusion We demonstrated clinical utility by comparing CFRD prevalence rates between the top 10% of individuals with the highest risk and the bottom 10% with the lowest risk. A web-based application was developed to provide practitioners with patient-specific CFRD risk to guide CFRD monitoring and treatment.

Covid-19 Vaccination in Early Pregnancy and Miscarriage In this case–control study performed with the use of registry data in Norway, there was no evidence of an increased risk of first-trimester p...

Background Perinatal depression is estimated to affect ~ 12% of pregnancies and is linked to numerous negative outcomes. There is currently no model to predict perinatal depression at multiple time-points during and after pregnancy using variables ascertained early into pregnancy. Methods A prospective cohort design where 858 participants filled in a baseline self-reported survey at week 4–10 of pregnancy (that included social economics, health history, various psychiatric measures), with follow-up until 3 months after delivery. Our primary outcome was an Edinburgh Postnatal Depression Score (EPDS) score of 12 or more (a proxy for perinatal depression) assessed during each trimester and again at two time periods after delivery. Five gradient boosting machines were trained to predict the risk of having EPDS score > = 12 at each of the five follow-up periods. The predictors consisted of 21 variables from 3 validated psychometric scales. As a sensitivity analysis, we also investigated different predictor sets that contained: i) 17 of the 21 variables predictors by only including two of the psychometric scales and ii) including 143 additional social economics and health history predictors, resulting in 164 predictors. Results We developed five prognostic models: PND-T1 (trimester 1), PND-T2 (trimester 2), PND-T3 (trimester 3), PND-A1 (after delivery 1) and PND-A2 (delayed onset after delivery) that calculate personalised risks while only requiring that women be asked 21 questions from 3 validated psychometric scales at weeks 4–10 of pregnancy. C-statistics (also known as AUC) ranged between 0.69 (95% CI 0.65–0.73) and 0.77 (95% CI 0.74–0.80). At 50% sensitivity the positive predictive value ranged between 30%-50% across the models, generally identifying groups of patients with double the average risk. Models trained using the 17 predictors and 164 predictors did not improve model performance compared to the models trained using 21 predictors. Conclusions The five models can predict risk of perinatal depression within each trimester and in two post-natal periods using survey responses as early as week 4 of pregnancy with modest performance. The models need to be externally validated and prospectively tested to ensure generalizability to any pregnant patient.

Primary cutaneous T-cell lymphoma (CTCL) comprises a heterogeneous group of neoplasms with variable clinical behavior. Immunophenotypic switch (IS) is a phenomenon that occurs during lymphoma progression and is defined by an alteration in the immunophenotypic expression of a tumor with retention of its genotypic signature. This has been well-recognized in hematopoietic neoplasms; however, it has been rarely reported in CTCL and its clinical implications are not well understood. We present the clinical, histopathologic, immunophenotypic, and genetic findings of three cases of CTCL that demonstrated IS post treatment with variable outcomes. We add our cases to the small number previously reported to increase awareness of this phenomenon and its diagnostic challenge.

Background and Purpose: Early detection of large vessel occlusion (LVO) stroke optimizes endovascular therapy and improves outcomes. Clinical stroke severity scales used for LVO identification have variable accuracy. We investigated a portable LVO-detection device (PLD), using electroencephalography and somatosensory-evoked potentials, to identify LVO stroke. Methods: We obtained PLD data in suspected patients with stroke enrolled prospectively via a convenience sample in 8 emergency departments within 24 hours of symptom onset. LVO discriminative signals were integrated into a binary classifier. The National Institutes of Health Stroke Scale was documented, and 4 prehospital stroke scales were retrospectively calculated. We compared PLD and scale performance to diagnostic neuroimaging. Results: Of 109 patients, there were 25 LVO (23%), 38 non-LVO ischemic (35%), 14 hemorrhages (13%), and 32 stroke mimics (29%). The PLD had higher sensitivity (80% [95% CI, 74–85]) and similar specificity (80% [95% CI, 77–83]) to all prehospital scales at their predetermined high probability LVO thresholds. The PLD had high discrimination for LVO ( C -statistic=0.88). Conclusions: The PLD identifies LVO with superior accuracy compared with prehospital stroke scales in emergency department suspected stroke. Future studies need to validate the PLD’s potential as an LVO triage aid in prehospital undifferentiated stroke populations.

Perioperative cardiovascular events are a leading cause of morbidity and mortality after noncardiac surgery. We propose a simplified method for perioperative risk stratification.In a retrospective cohort study we identified patients who underwent noncardiac surgery between 2009 and 2015 in the US National Surgical Quality Improvement Program. Multivariable logistic regression models adjusted for age, sex, race, and surgery type were generated to estimate the effect of traditional cardiovascular risk factors (hypertension, diabetes mellitus, current smoking) on odds of perioperative myocardial infarction (MI). Time to event analysis was conducted using competing risk analysis, with MI as the outcome event and death as the competing risk.A total of 3,848,501 noncardiac surgeries were identified. Postoperative MI occurred in 0.37% of patients and 1.04% of patients died. The 30-day event rate of perioperative MI increased in a stepwise fashion with additional risk factors (0.42% for 1, 0.82% for 2, and 1.08% for 3; P for trend0.001) after accounting for the competing risk of death. Compared with those with no risk factors, patients with 1, 2, and 3 risk factors had increased odds of MI (adjusted odds ratio [aOR], 2.07 [95% confidence interval (CI), 1.96-2.19]; aOR, 3.63 [95% CI, 3.43-3.85]; and aOR, 5.54 [95% CI, 5.09-6.04], respectively). Perioperative MI was rare (0.10%) in patients without risk factors.Patients with cardiovascular risk factors are at increased risk of perioperative MI, those without risk factors are at low risk. Further evaluation is needed to determine the effect of a simplified risk score in the perioperative setting.

Background & Aims Idiopathic chronic pancreatitis (ICP) is the second most common subtype of CP. In 1994, researchers reported the bimodal age at onset of ICP symptoms: early onset ICP (EO-ICP; median age, 19.2 y) and late-onset ICP (LO-ICP; median age, 56.2 y). Ages of onset and clinical features of ICP differed from those of alcohol-related CP (ACP). However, variants in PRSS1 had not yet been associated with ICP. We reexamined ages of onset of ICP in a large, North American cohort of patients, and investigated the effects of genetic factors and alcohol use in patients with EO-ICP, LO-ICP, and ACP. Methods We performed a cross-sectional analysis of patients with CP of European ancestry enrolled in the North American Pancreatitis Study 2, a prospective study of 1195 patients with CP from 26 centers in the United States from August 2000 through December 2014. We compared age at onset of symptoms for 130 patients with CP who were lifetime abstainers from alcohol (61 patients with early onset and 69 patients with late onset), 308 light to moderate alcohol drinkers with CP, and 225 patients with ACP and heavy to very heavy alcohol use. DNA from available patients was analyzed for variants associated with CP in SPINK1, CFTR, and CTRC. The Kruskal–Wallis test was used to compare continuous variables across groups and based on genetic variants. Results Median ages at onset of symptoms were 20 years for patients with EO-ICP and no alcohol use, 58 years for patients with LO-ICP and no alcohol use, 47 years for light to moderate alcohol drinkers with CP, and 44 years for patients with ACP. A higher proportion of patients with EO-ICP had constant pain (65%) than patients with LO-ICP (31%) (P = .04). A higher proportion of patients with ACP had pseudocysts (43%) than patients with EO-ICP (11%) (P = .001). A higher proportion of patients with EO-ICP had pathogenic variants in SPINK1, CFTR, or CTRC (49%) than patients with LO-ICP (23%), light to moderate alcohol drinking with CP (26%), or ACP (23%) (P = .001). Among patients with variants in SPINK1, those with EO-ICP had onset of symptoms at a median age of 12 years, and light to moderate alcohol drinkers with CP had an age at onset of 24 years. Among patients with variants in CFTR, light to moderate alcohol drinkers had an age at onset of symptoms of 41 years, but this variant did not affect age at onset of EO-ICP or ACP. Conclusions We confirmed previously reported ages at onset of symptoms for EO-ICP and LO-ICP in a North American cohort. We found differences in clinical features among patients with EO-ICP, LO-ICP, and ACP. Almost half of patients with EO-ICP have genetic variants associated with CP, compared with approximately one quarter of patients with LO-CP or ACP. Genetic variants affect ages at onset of symptoms in some groups.

Follicular lymphoma (FL) is the 2nd most common lymphoma in the USA/Western Europe. While incurable, the majority of patients are able to survive at least a decade with this disease. Response duration though varies, and subset of patients will relapse within 24 months of initial therapy (POD24). These patients have shortened survival compared to those who achieve more durable responses. Treatment interventions for patients are varied and include observation, radiation, or systemic therapies. Treatment outcomes have improved considerably over the last several decades with the introduction of new agents such as the CD 20 antibody rituximab and more recently with the advent of more targeted therapy. Most of the newer agents work differently from cytotoxic chemotherapy and either inhibit tumor-specific mutations, survival pathways, or harness the immune systems. While outcomes with traditional cytotoxic agents have been historically poor in certain subtypes such as POD24 and rituximab refractory disease, the reported outcomes with the newer agents have been encouraging as evident by several new drug approvals in FL. The biggest impact has been in the relapsed/refractory setting where we have approval of the immunomodulatory agent lenalidomide given in combination with rituximab. Based on the AUGMENT study, this agent has been approved for patients with R/R FL after one previous line of therapy. The EZH2 inhibitor, tazemetostat, was approved recently for patients with a known EZH2 mutation after one prior line of therapy or for FL patients who are deemed intolerant to other agents given the impressive safety profile in all patients. Finally, there is a plethora of agents that are designed to harness the immune system to combat this lymphoma. The data for these agents is still very early but nonetheless very impressive. In summary, FL is an incurable lymphoma without any standard of care options but has numerous treatments that have demonstrated some degree of efficacy. Recently we have made enormous strides in the understanding of some of the biological drivers of this disease which has allowed for refinement of treatment options. Moving forward, I would anticipate that we will continue to explore the use of agents that target specific mutations or utilize the immune system to hopefully one day achieve a cure.

Objective Examine the association and moderating effect of residential location (urban/rural) on the relationship between neighborhood healthy food density and diet quality. Design Cross-sectional analysis of baseline data from the Health in Pregnancy and Postpartum study, a randomized trial designed to prevent excessive gestational weight gain. Participants Pregnant women in South Carolina with prepregnancy overweight/obesity (n = 228). Main Outcome Measures Healthy Eating Index–2015 (HEI) was used to measure diet quality from 2 24-hour dietary recalls. The HEI total scores and 11 binary HEI components (those that met the standard for maximum component score vs those that did not) were calculated as dependent variables. Analysis Multiple linear and logistic regression models were used to examine the association between healthy food density and HEI total scores and meeting the standards for maximum component scores. Healthy food density × residential location tested for moderation. P Results Participants’ diet quality was suboptimal (mean, 52.0; SD, 11.7; range, 27–85). Healthy food density was not significantly related to HEI total scores or components, and residential location was not a moderator. Conclusions and Implications Diet quality was suboptimal, and there was no relationship between healthy food density and diet quality among Health in Pregnancy and Postpartum study participants. These data support examining behavioral factors that could influence diet quality.

Background High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements is an aggressive lymphoma, mostly occurring in elderly patients, that frequently has poor response to therapy. We report a unique case of MYC/BCL2 double-hit lymphoma (DHL) in a 35-year-old male that spontaneously regressed without therapy. Methods Biopsy specimen was evaluated morphologically, by immunohistochemistry, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). Spontaneous regression was assessed with sequential positron emission tomography (PET)/computed tomography (CT) scans. Results Morphologically, lymphoma cells showed a diffuse, “starry-sky” pattern and were intermediate-sized with finely dispersed chromatin and several nucleoli. By immunohistochemistry, they were positive for CD20, CD10, BCL6, BCL2, C-MYC (60-70%), and Ki67 (80%). FISH study showed MYC and IGH/BCL2 rearrangements. NGS showed mutations of MYC, BCL2, and KMT2D, among others, in keeping with mutational profile of MYC/BCL2 DHL. PET/CT scans, performed at diagnosis, as well as 1 month and 7 months after diagnosis, demonstrated complete spontaneous regression of this lymphoma. Patient remains in remission 28 months after diagnosis. Conclusions Spontaneous regression of a higher grade B-cell lymphoma is a rare occurrence, and the reasons for it are unclear. Our case is a first documented MYC/BCL2 DHL that spontaneously regressed without therapy.

Case presentation: A 33-year-old male presented to the emergency department following a motor vehicle collision with complaints of right eye pain after hitting his head on the steering wheel. Point-of-care ultrasound (POCUS) revealed retinal detachment and an anterior lens dislocation. Discussion: Lens dislocations following blunt head trauma can often be diagnosed using POCUS. Anterior ocular lens dislocation is a rare but vision-threatening result of head trauma. This case highlights how POCUS can facilitate early detection of ocular pathology, such as lens dislocation, and improves patient outcomes.

Vaginoplasty with colon is a common technique for vaginal replacement in patients with cloaca. Malignancy in the neovagina is a rare outcome and typically presents decades after reconstruction. We present a case of an adolescent female with history of cloaca, ulcerative colitis, and high-grade dysplasia of the sigmoid neovagina.

New findings What is the central question of this study? Cachexia causes severe changes in skeletal muscle metabolism and function and is a key predictor of negative outcomes in cancer patients: what are the changes in whole animal energy metabolism and mitochondria in skeletal muscle? What is the main finding and its importance? There is decreased whole animal energy expenditure in mice with cachexia. They displayed highly dysmorphic mitochondria and mitophagy in skeletal muscle. Abstract Cachexia causes changes in skeletal muscle metabolism. Mice with MDA-MB-231 breast cancer bone metastases and cachexia have decreased whole animal energy metabolism and increased skeletal muscle mitophagy. We examined whole animal energy metabolism by indirect calorimetry in mice with MDA-MB-231 breast cancer bone metastases, and showed decreased energy expenditure. We also examined skeletal muscle mitochondria and found that mitochondria in mice with MDA-MB-231 bone metastases are highly dysmorphic and have altered protein markers of mitochondrial biogenesis and dynamics. In addition, LC3B protein was increased in mitochondria of skeletal muscle from cachectic mice, and colocalized with the mitochondrial protein Tom20. Our data demonstrate the importance of mitophagy in cachexia. Understanding these changes will help contribute to defining treatments for cancer cachexia.

Bladder and bowel dysfunction (BBD) is a common yet underdiagnosed paediatric entity that describes lower urinary tract symptoms (LUTS) accompanied by abnormal bowel patterns manifested as constipation and/or encopresis. LUTS usually manifest as urgency, urinary frequency, incontinence, and urinary tract infections (UTI). Despite increasing recognition of BBD as a risk factor for long-term urinary tract problems including recurrent UTI, vesicoureteral reflux, and renal scarring, the mechanisms underlying BBD have been unclear, and treatment remains empirical. We investigated how constipation affects the lower urinary tract function using a juvenile murine model of functional constipation. Following four days of functional constipation, animals developed LUTS including urinary frequency and detrusor overactivity evaluated by awake cystometry. Physiological examination of detrusor function in vitro using isolated bladder strips, demonstrated a significant increase in spontaneous contractions without affecting contractile force in response to electrical field stimulation, carbachol, and KCl. A significant upregulation of serotonin receptors, Htr2a and Htr2c, was observed in the bladders from mice with constipation, paralleled with augmented spontaneous contractions after pre-incubation of the bladder strips with 0.5 µM of serotonin. These results suggest that constipation induced detrusor overactivity and increased excitatory serotonin receptor activation in the urinary bladder, which contributes to the development of BBD.

Background: Inadequate and excessive gestational weight gain (GWG) is associated with adverse health outcomes for mother and child. Health care providers are well positioned to help women achieve appropriate GWG. This systematic review examined associations between women's report of provider advice on GWG and women's compliance with the Institute of Medicine (IOM) GWG guidelines. Materials and Methods: In March 2019, PubMed, EMBASE, and Cochrane CENTRAL databases were searched. Observational studies were eligible if published from 1990 to 2019, described provider advice on GWG, and determined whether women's target or actual GWG was consistent with the 1990 or 2009 IOM guidelines. Heterogeneity across studies precluded the use of meta-analytic methods. Results: Seventeen cross-sectional and cohort studies of poor to good quality, representing 20,717 women were included. Approximately 69% of women reported provider advice on GWG during pregnancy; however, only 50% reported provider advice consistent with IOM guidelines. Eleven studies found that provider advice on GWG was significantly associated with women's compliance with IOM guidelines, and six studies found no association. Conclusions: While a high percentage of women report provider advice on GWG, accuracy of reported advice is less than optimal. The evidence examining associations of provider advice and women's compliance with guidelines is mixed and limited by methodological concerns. Future studies using more robust methods in diverse populations are needed to confirm the role of provider advice in optimizing GWG. Intervention studies are also necessary to increase the proportion of providers who accurately counsel their patients on appropriate GWG to improve health outcomes.

Objectives The objectives of this post-hoc analysis were to examine the safety and efficacy of omadacycline by BMI categories and diabetes history in adults with acute bacterial skin and skin structure infections (ABSSSI) from two pivotal Phase III studies. Patients and methods OASIS-1 (ClinicalTrials.gov identifier NCT02378480): patients were randomized 1:1 to IV omadacycline or linezolid for 7–14 days, with optional transition to oral medication. OASIS-2 (ClinicalTrials.gov identifier NCT02877927): patients received once-daily oral omadacycline or twice-daily oral linezolid for 7–14 days. Early clinical response (ECR) was defined as ≥20% reduction in lesion size 48–72 h after the first dose. Clinical success at post-treatment evaluation (PTE; 7–14 days after the last dose) was defined as symptom resolution such that antibacterial therapy was unnecessary. Safety was assessed by treatment-emergent adverse events and laboratory measures. Between-treatment comparisons were made with regard to WHO BMI categories and diabetes history. Results Patients were evenly distributed among healthy weight, overweight and obese groups. Clinical success for omadacycline-treated patients at ECR and PTE was similar across BMI categories. Outcomes by diabetes status were similar in omadacycline- and linezolid-treated patients: at ECR, clinical success rates were lower for those with diabetes; at PTE, clinical success was similar between treatment groups regardless of diabetes history. The safety of omadacycline and linezolid was largely similar across BMI groups and by diabetes history. Conclusions Omadacycline efficacy in patients with higher BMI and in patients with diabetes was consistent with results from two pivotal Phase III ABSSSI trials. Fixed-dose omadacycline is an appropriate treatment for ABSSSI in adults regardless of BMI.

Cystic fibrosis (CF) pulmonary exacerbations (PEx) remain underdiagnosed by CF clinicians. Serum C-reactive protein (CRP) and calprotectin are inflammatory biomarkers that have the potential to aid in the diagnosis of PEx. 19 subjects (56 stable, 46 PEx visits) from a longitudinal study were included and the diagnostic performance of absolute and fold-change CRP and calprotectin cut-offs to discriminate stable and PEx visits was assessed. Based on Youden's index, optimal absolute and fold-change thresholds to identify PEx were 9.5 mg/L (Sn 76%, Sp 73%; AUC 0.76) and 2.2-fold (Sn 50%, Sp 96%; AUC 0.78) for CRP and 8.1 mg/L (Sn 61%, Sp 79%; AUC 0.72) and 1.3-fold (Sn 57%, Sp 88%; AUC 0.74) for calprotectin. A step-wise algorithm was able to improve diagnostic performance (Sn 80%; Sp 88%). CRP and calprotectin could discriminate stable vs. PEx visits with good performance and appear promising as diagnostic biomarkers but further validation studies are required prior to implementing these diagnostic thresholds.

BACKGROUND/OBJECTIVES: Black Americans are at increased risk of chronic pancreatitis (CP) compared to their White counterparts. We aimed to describe the race-specific smoking history and lifetime drinking in patients diagnosed with CP. METHODS: We analyzed data on 334 Black and White CP participants of the North American Pancreatitis Study 2 Continuation and Validation Study and Ancillary Study. Lifetime drinking history and lifetime smoking history were collected through in-person interviews. Intensity, frequency, duration and current status of drinking and smoking were compared between Black and White CP participants, stratified by physician-defined alcohol etiology. In addition, drinking levels at each successive decades in life (20s, 30s, 40s) were compared by race and graphically portrayed as heat diagrams. RESULTS: Among patients with alcoholic CP, current smoking levels were not different by race (67-70%), but a smaller proportion of Black patients reported having smoked 1 or more packs per day in the past (32%) as compared to White patients (58%, p

Follicle center lymphomas, including primary cutaneous follicle center lymphoma, may rarely show plasmacytic differentiation. Such cases can pose a diagnostic challenge and can be mistaken for other lymphomas that more commonly include plasma cells. Here, we report four cases of PCFCL and one case of systemic follicular lymphoma involving the skin with associated monotypic plasma cells, including the clinical, morphologic and immunophenotypic features. This article is protected by copyright. All rights reserved.