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Liver transplantation is associated with significant blood loss, often requiring massive blood product transfusion. Transfusion-related acute lung injury (TRALI) is a devastating cause of transfusion-related deaths. While reports have investigated the general incidence of TRALI, the incidence of TRALI specifically following transfusion during liver transplant remains unclear. This scoping review summarizes existing literature regarding TRALI during the liver transplantation perioperative period. Databases were searched for all articles and abstracts reporting on TRALI after liver transplantation. Data collected included number of patients studied, patient characteristics, incidences of TRALI, TRALI characteristics, and patient outcomes. The primary outcome investigated was the incidence of TRALI in the setting of liver transplantation. Thirteen full-text citations were included in this review. The incidence of TRALI post-liver transplant was 0.68% (65 of 9,554). Based on reported transfusion data, patients diagnosed with TRALI received an average of 10.92 ± 10.81 units of packed red blood cells (pRBC), 20.05 ± 15.72 units of fresh frozen plasma, and 5.75 ± 10.00 units of platelets. Common interventions following TRALI diagnosis included mechanical ventilation with positive end-expiratory pressure, inhaled high-flow oxygen, inhaled pulmonary vasodilator, and pharmacologic treatment using pressors or inotropes, corticosteroids, or diuretics. Based on reported mortality data, 26.67% of patients (12 of 45) diagnosed with TRALI died during the postoperative period. This scoping review underscores the importance of better understanding the incidence and presentation of TRALI after liver transplant surgery. The clinical implications of these results warrant the development of identification and management strategies for liver transplant patients at increased risk for developing TRALI.

Diagnosis of LM is limited by low sensitivity of cerebrospinal fluid (CSF) cytopathology. Detecting tumor cells in CSF (CSF-TCs) might be more sensitive. We evaluated if CNSide (CNSide), a novel assay for tumor cell detection in CSF, can detect CSF-TCs better than conventional CSF cytology.We enrolled adults with metastatic breast cancer and clinical suspicion for LM to undergo lumbar puncture (LP) for CSF cytopathology and CNSide. CNSide captured CSF-TCs using a primary 10-antibody mixture, streptavidin-coated microfluidic channel, and biotinylated secondary antibodies. CSF-TCs were assessed for estrogen receptor (ER) expression by fluorescent antibody and HER2 amplification by fluorescent in situ hybridization (FISH). CSF cell-free DNA (cfDNA) was extracted for next-generation sequencing (NGS). Leptomeningeal disease was defined as positive CSF cytology and/or unequivocal MRI findings. We calculated sensitivity and specificity of CSF cytology and CNSide for the diagnosis of LM.Ten patients, median age 51 years (range, 37-64), underwent diagnostic LP with CSF evaluation by cytology and CNSide. CNSide had sensitivity of 100% (95% Confidence Interval [CI], 40%-100%) and specificity of 83% (95% CI, 36%-100%) for LM. Among these patients, concordance of ER and HER2 status between CSF-TCs and metastatic biopsy were 60% and 75%, respectively. NGS of CSF cfDNA identified somatic mutations in three patients, including one with PIK3CA p.H1047L in blood and CSF.CNSide may be a viable platform to detect CSF-TCs, with potential use as a diagnostic tool for LM in patients with metastatic breast cancer. Additional, larger studies are warranted.

PURPOSE: Increasing usage of multigene panel testing has identified more patients with pathogenic or likely pathogenic (P or LP) variants in low-moderate penetrance genes or variants of uncertain significance (VUS). Our study evaluates the association between genetic test results and contralateral prophylactic mastectomy (CPM) among patients with breast cancer. METHODS: We conducted a retrospective cohort study among women diagnosed with unilateral stage 0-III breast cancer between 2013 and 2020 who underwent genetic testing. We examined whether genetic test results were associated with CPM using multivariable logistic regression models. RESULTS: Among 707 racially or ethnically diverse women, most had benign or likely benign (B or LB) variants, whereas 12.5% had P or LP and 17.9% had VUS. Racial or ethnic minorities were twice as likely to receive VUS. Patients with P or LP variants had higher CPM rates than VUS or B or LB (64.8% v 25.8% v 25.9%), and highest among women with P or LP variants in high-penetrance genes (74.6%). On multivariable analysis, P or LP compared with B or LB variants were significantly associated with CPM (odds ratio = 4.24; 95% CI, 2.48 to 7.26). CONCLUSION: Women with P or LP variants on genetic testing were over four times more likely to undergo CPM than B or LB. Those with VUS had similar CPM rates as B or LB. Our findings suggest appropriate genetic counseling and communication of cancer risk to multiethnic breast cancer survivors.

Introduction Cognitive impairment is common in Parkinson's Disease, but the impact of predictive factors on incidence and rate of cognitive decline is incompletely understood. We aimed to determine the effects of sex and APOE allele status on cognitive performance in patients with Parkinson's Disease (PD). Material and methods We conducted a retrospective analysis of 325 clinically diagnosed PD patients who underwent one or more cognitive screenings with a Mini-Mental Status Examination (MMSE) or Mattis Dementia Rating Scale (DRS-2). We used proportional odds regression models to estimate odds ratios for higher versus lower cognitive scores in association with age, sex, education, disease duration, and APOE allele status. Results Higher cognitive scores were independently associated with female sex on the MMSE (OR 2.43; 95% CI 1.14, 5.14) and DRS-2 total (OR 4.14; 95% CI 2.01, 8.53). APOE e4 dose was associated with lower DRS-2 totals (OR 0.42; 95% CI 0.22, 0.81), but there was no evidence of association with MMSE. Higher education level was also associated with higher scores on the MMSE (OR 1.22; 95% CI 1.07, 1.38) and DRS-2 total (OR 1.31; 95% CI 1.15, 1.50). Disease duration was not associated with cognitive performance on any measure when adjusting for age. Conclusion Male sex and APOE e4, along with age and lower education level, were associated with poorer cognitive performance among a population of predominantly non-demented PD patients.

A muskox neonate ( Ovibos moschatus) that died of starvation was diagnosed with congenital lenticular anomalies that included spherophakia and hypermature cataract associated with probable lens-induced lymphocytic uveitis and neutrophilic keratitis. Impaired sight as a result of cataract and associated inflammation likely contributed to abandonment and starvation, although maternal death cannot be excluded definitively. Ocular lesions, such as congenital cataracts and spherophakia in neonates, may be important factors affecting survival in free-ranging animals.

African Americans experience a significantly greater burden of Alzheimer’s disease (AD) compared to non-Hispanic White Americans. Raising awareness and increasing knowledge of AD within African American communities is an important step towards addressing these disparities. The purpose of this study was to assess the effectiveness of two approaches to sharing AD knowledge with community residents. Using a quasi-experimental design, African American participants were recruited through community partners and local resources in two comparable neighborhoods in Duval County, Florida, which formed the intervention and the comparison groups for this study. The identical 40-min educational lecture was provided to both groups. In the intervention community, the lecture was followed by focus group sessions modeled after the Dementia Friendly America toolkit. In the comparison community, the lecture was followed by a social event where participants could interact informally with the speaker and dementia outreach staff. A brief quantitative survey assessing AD knowledge was administered to participants in both groups before the education session, immediately after the lecture, and 2 months later. Results indicate that both groups improved their knowledge scores at immediate post-test. Scores for both groups declined at 2-month follow-up, but the comparison group’s scores declined more precipitously than the intervention group’s scores (p = 0.0.21). These results suggest that conducting focus groups and interviews following a lecture on AD may help better retain AD knowledge over time.

Scientists collect fleas (Siphonaptera) to survey for Yersinia pestis, the bacterial agent of plague. When studying fleas parasitizing prairie dogs (Cynomys spp.), two primary methods are used: (1)...

Introduction Controlling insulin-treated diabetes is challenging in low-resource settings where only Neutral Protamine Hagedorn (NPH), regular (R) and premixed insulin formulations are available, self-monitoring of blood glucose (SMBG) supplies are scarce and food insecurity is common. We examined the impact of a treatment protocol that includes sliding scale-based 70/30 insulin adjustments in Haiti. Methods Thirty young patients aged 11–28 years with diabetes treated with premixed 70/30 insulin twice daily were included in the study. The participants performed one or two daily self-monitoring of blood glucose (SMBG) tests and attended our diabetes clinic monthly. They were randomized to two treatment groups, with one group remaining on the 70/30 insulin formulation (group 70 [G70]) and the other group switching to self-mixed NPH + R (group NR [GNR]). Sliding scales for insulin correction doses and meal insulin doses were designed based on the total daily insulin dose (TDD), carbohydrate ratio and insulin sensitivity factor. SMBG tests and insulin were administered before the morning and evening meals. The frequency of visits to the diabetes clinic was increased to biweekly during a 14-week follow-up. Results Fifteen patients of each group were included in the analysis. Baseline characteristics, increase in total daily dose and number of missed SMBG tests and skipped meals at 14 weeks did not differ between the two groups. Hemoglobin A1c (HbA1c) decreased from 9.5% (interquartile range [IQR] 8.8, 10.5) (80.3 mmol/mol) to 8.0% (IQR 7.1%, 9.0%) (63.9 mmol/mol) in G70 (p = 0.01), and from 10.6% (IQR 8.1,% 13.1)% (92.4 mmol/mol) to 9.0% (IQR 7.6%, 9.6%) (74.9 mmol/mol) in GNR (p = 0.10), with no significant between-group difference in reductions (p = 0.12). No serious acute complications were reported. Stopping the use of sliding scales and resuming monthly visits increased HbA1c to values not significantly different from baseline in both groups after 15 weeks. Conclusion The use of sliding scales adjusted for missed SMBG tests and skipped meals, and frequent clinic visits that focus on patient self-management education significantly improved glycemic control in the patients with youth-onset diabetes in our study treated with premixed 70/30 human insulin in a low-resource setting.

Traumatic brain injury (TBI) alters stress responses, which may influence neuroinflammation and behavioral outcome. Sleep disruption (SD) is an understudied post-injury environmental stressor that directly engages stress-immune pathways. Thus, we predicted that maladaptive changes in the hypothalamic-pituitary-adrenal (HPA) axis after TBI compromise the neuroendocrine response to SD and exacerbate neuroinflammation. To test this, we induced lateral fluid percussion TBI or sham injury in female and male C57BL/6 mice aged 8–10 weeks that were then left undisturbed or exposed to 3 days of transient SD. At 3 days post-injury (DPI) plasma corticosterone (CORT) was reduced in TBI compared with sham mice, indicating altered HPA-mediated stress response to SD. This response was associated with approach-avoid conflict behavior and exaggerated cortical neuroinflammation. Post-injury SD specifically enhanced neutrophil trafficking to the injured brain in conjunction with dysregulated aquaporin-4 (AQP4) polarization. Delayed and persistent effects of post-injury SD were determined 4 days after SD concluded at 7 DPI. SD prolonged anxiety-like behavior regardless of injury and was associated with increased cortical Iba1 labeling in both sham and TBI mice. Strikingly, TBI SD mice displayed an increased number of CD45(+) cells near the site of injury, enhanced cortical glial fibrillary acidic protein (GFAP) immunolabeling, and persistent expression of Trem2 and Tlr4 7 DPI compared with TBI mice. These results support the hypothesis that post-injury SD alters stress-immune pathways and inflammatory outcomes after TBI. These data provide new insight to the dynamic interplay between TBI, stress, and inflammation.

Infants born very preterm (VPT) are at high risk of motor impairments such as cerebral palsy (CP), and diagnosis can take 2 years. Identifying in vivo determinants of CP could facilitate presymptomatic detection and targeted intervention. Our objectives were to derive micro‐ and macrostructural measures of sensorimotor white matter tract integrity from diffusion MRI at term‐equivalent age, and determine their association with early diagnosis of CP. We enrolled 263 VPT infants (≤32 weeks gestational age) as part of a large prospective cohort study. Diffusion and structural MRI were acquired at term. Following consensus guidelines, we defined early diagnosis of CP based on abnormal structural MRI at term and abnormal neuromotor exam at 3–4 months corrected age. Using Constrained Spherical Deconvolution, we derived a white matter fiber orientation distribution (fOD) for subjects, performed probabilistic whole‐brain tractography, and segmented nine sensorimotor tracts of interest. We used the recently developed fixel‐based (FB) analysis to compute fiber density (FD), fiber‐bundle cross‐section (FC), and combined fiber density and cross‐section (FDC) for each tract. Of 223 VPT infants with high‐quality diffusion MRI data, 14 (6.3%) received an early diagnosis of CP. The cohort's mean (SD) gestational age was 29.4 (2.4) weeks and postmenstrual age at MRI scan was 42.8 (1.3) weeks. FD, FC, and FDC for each sensorimotor tract were significantly associated with early CP diagnosis, with and without adjustment for confounders. Measures of sensorimotor tract integrity enhance our understanding of white matter changes that antecede and potentially contribute to the development of CP in VPT infants., Infants born very preterm are at high risk of motor impairments such as cerebral palsy. We report biomarkers of sensorimotor white matter tract integrity, derived from diffusion MRI at term‐equivalent age, that are associated with early diagnosis of cerebral palsy.

The patient presented to our clinic from out of state in October 2018. Previously, in 2014, he underwent an elective left total hip arthroplasty with a ceramic-on-polyethylene prosthesis for osteoarthritis. The surgery and recovery were uneventful. In November 2014, hives developed on his upper arms. Within weeks, the hives spread to his trunk and thighs but spared his face, palms, and soles. The symmetric, nonpruritic, nonpainful rash was without angioedema. The hives initially persisted for 5 days, followed by resolution for several days.

The Male Athlete Triad is a syndrome of 3 interrelated conditions most common in adolescent and young adult male endurance and weight-class athletes and includes the clinically relevant outcomes of (1) energy deficiency/low energy availability (EA) with or without disordered eating/eating disorders, (2) functional hypothalamic hypogonadism, and (3) osteoporosis or low bone mineral density with or without bone stress injury (BSI). The causal role of low EA in the modulation of reproductive function and skeletal health in the male athlete reinforces the notion that skeletal health and reproductive outcomes are the primary clinical concerns. At present, the specific intermediate subclinical outcomes are less clearly defined in male athletes than those in female athletes and are represented as subtle alterations in the hypothalamic-pituitary-gonadal axis and increased risk for BSI. The degree of energy deficiency/low EA associated with such alterations remains unclear. However, available data suggest a more severe energy deficiency/low EA state is needed to affect reproductive and skeletal health in the Male Athlete Triad than in the Female Athlete Triad. Additional research is needed to further clarify and quantify this association. The Female and Male Athlete Triad Coalition Consensus Statements include evidence statements developed after a roundtable of experts held in conjunction with the American College of Sports Medicine 64th Annual Meeting in Denver, Colorado, in 2017 and are in 2 parts-Part I: Definition and Scientific Basis and Part 2: The Male Athlete Triad: Diagnosis, Treatment, and Return-to-Play. In this first article, we discuss the scientific evidence to support the Male Athlete Triad model.

Diffuse optical tomography breast imaging system (DOTBIS) non-invasively measures tissue concentration of hemoglobin, which is a potential biomarker of short-term response to neoadjuvant chemotherapy. We evaluated whether DOTBIS-derived measurements are modifiable with targeted therapies, including AKT inhibition and endocrine therapy. We conducted a proof of principle study in seven postmenopausal women with stage I-III breast cancer who were enrolled in pre-surgical studies of the AKT inhibitor MK-2206 (n = 4) or the aromatase inhibitors exemestane (n = 2) and letrozole (n = 1). We performed DOTBIS at baseline (before initiation of therapy) and post-therapy in the affected breast (tumor volume) and contralateral, unaffected breast, and measured tissue concentrations (in μM) of total hemoglobin (ctTHb), oxyhemoglobin (ctO2Hb), and deoxyhemoglobin (ctHHb), as well as water fraction (%). We found consistent decreases in DOTBIS-measured hemoglobin concentrations in tumor volume, with median percent changes for ctTHb, ctHHb, ctO2Hb, and water fraction for the entire cohort of − 27.1% (interquartile range [IQR] 37.5%), − 49.8% (IQR 29.3%), − 33.5% (IQR 47.4%), and − 3.6% (IQR 10.6%), respectively. In the contralateral breast, median percent changes for ctTHb, ctHHb, ctO2Hb, and water fraction were + 1.8% (IQR 26.7%), − 8.6% (IQR 29.3%), + 6.2% (IQR 29.5%), and + 1.9% (IQR 30.7%), respectively. We demonstrated that DOTBIS-derived measurements are modifiable with pre-surgical AKT inhibition and endocrine therapy, supporting further investigation of DOTBIS as a potential imaging assessment of response to neoadjuvant targeted therapies in early stage breast cancer.

While checkpoint inhibitors have been approved in patients with newly metastatic PDL1-positive triple negative breast cancer, similar clinical benefit with immunotherapy alone or in combination with chemotherapy has not been observed in patients with hormone receptor-positive, HER2− negative breast cancer in the metastatic setting. However, in the ISPY2 trial, an increase in pathologic response has been observed with the addition of immunotherapy (± PARP inhibition) to chemotherapy compared to chemotherapy alone in patients with high-risk hormone receptor-positive, HER2− breast cancer. We review strategies to enhance the immunotherapeutic activity in this subtype of breast cancer, including combinations of checkpoint inhibition with chemotherapy, endocrine therapy, PARP inhibitors, HDAC inhibitors, CDK4/6 inhibitors, and radiotherapy. Combinations with agents targeting novel immunotherapeutic targets are also discussed. Though there remains an unmet need for immunotherapy approaches in patients with hormone-receptor positive breast cancer, there are a number of approaches that may lead to increased anti-tumor activity with immunotherapy in this tumor subtype.

Purpose The aim of this study was to examine whether use of regular aspirin and/or other non-steroidal anti-inflammatory drugs (NSAIDs) is associated with the development of age-related macular degeneration (AMD). Methods In the California Teachers Study cohort (N = 88,481) we identified diagnoses of AMD up to December 31, 2012 by linkage to statewide hospital discharge records. Aspirin, ibuprofen, other NSAIDs, and acetaminophen use and comprehensive risk factor information were collected via self-administered questionnaires at baseline in 1995–1996 and a follow-up questionnaire in 2005–2006. We employed Cox proportional hazard regression to model AMD risk. Results We did not find any associations between AMD and frequency and duration of aspirin or ibuprofen use reported at baseline. In the subsample with more specific information on medication use, we observed a 20% decrease in risk of AMD among low-dose aspirin users (HR 0.81, 95% CI 0.70–0.95) and a 55% decrease among cyclooxygenase-2 (COX-2) inhibitor users (HR 0.45, 95% CI 0.26–0.78) during 6.3 years of average follow-up. Conclusion The decrease in risk of intermediate- or late-stage AMD among women who reported regular use of low-dose aspirin or specific COX-2 inhibitors suggests a possible protective role for medications with COX-2 inhibitory properties or aspirin at doses used for cardiovascular disease prevention.

Purpose. Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect of taxane and platinum chemotherapy for breast cancer. Clinicians cannot accurately predict CIPN severity partly because its pathophysiology is poorly understood. Although inflammation may play a role in CIPN, there are limited human studies. Here, we identified the strongest predictors of CIPN using variables measured before taxane- or platinum-based chemotherapy, including serum inflammatory markers.Methods. 116 sedentary women with breast cancer (mean age 55 years) rated (1) numbness and tingling and (2) hot/coldness in hands/feet on 0-10 scales before and after six weeks of taxane- or platinum-based chemotherapy. A sub-study was added to collect cytokine data in the final 55 patients. We examined all linear models to predict CIPN severity at 6 weeks using pre-chemotherapy assessments of inflammatory, behavioral, clinical, and psychosocial factors. The final model was selected via goodness of fit.Results. The strongest pre-chemotherapy predictors of numbness and tingling were worse fatigue/anxiety/depression (explaining 27% of variance), older age (9%), and baseline neuropathy (5%). The strongest predictors of hot/coldness in hands/feet were worse baseline neuropathy (11%) and fatigue/anxiety/depression (6%). Inflammation was a risk for CIPN, per more pro-inflammatory IL-1β (6%) predicting numbness/tingling and less anti-inflammatory IL-10 predicting numbness and tingling (6%) and hot/coldness in hands/feet (9%).Conclusions. The strongest pre-chemotherapy predictors of CIPN included worse fatigue/anxiety/depression and baseline neuropathy. A pro-inflammatory state also predicted CIPN. Because this is an exploratory study, these results suggest specific outcomes (e.g., IL-1β) and effect size estimates for designing replication and extension studies.Trial Registration. NCT00924651

AIM To assess whether a FiASP-and-pramlintide closed-loop system has the potential to replace carbohydrate counting with a simple meal announcement (SMA) strategy (meal priming bolus without carbohydrate counting) without degrading glycaemic control compared with a FiASP closed-loop system. MATERIALS AND METHODS We conducted a 24-hour feasibility study comparing a FiASP system with full carbohydrate counting (FCC) with a FiASP-and-pramlintide system with SMA. We conducted a subsequent 12-day outpatient pilot study comparing a FiASP-and-placebo system with FCC, a FiASP-and-pramlintide system with SMA, and a FiASP-and-placebo system with SMA. Basal-bolus FiASP-and-pramlintide were delivered at a fixed ratio (1 U:10 μg). Glycaemic outcomes were measured, surveys evaluated gastrointestinal symptoms and diabetes distress, and participant interviews helped establish a preliminary coding framework to assess user experience. RESULTS Seven participants were included in the feasibility analysis. Time spent in 3.9-10 mmol/L was similar between both interventions (81%-84%). Four participants were included in the pilot analysis. Time spent in 3.9-10 mmol/L was similar between the FiASP-and-placebo with FCC and FiASP-and-pramlintide with SMA interventions (70%), but was lower in the FiASP-and-placebo with SMA intervention (60%). Time less than 3.9 mmol/L and gastrointestinal symptoms were similar across all interventions. Emotional distress was moderate at baseline, after the FiASP-and-placebo with FCC and SMA interventions, and fell after the FiASP-and-pramlintide with SMA intervention. SMA reportedly afforded participants flexibility and reduced mealtime concerns. CONCLUSIONS The FiASP-and-pramlintide system has the potential to substitute carbohydrate counting with SMA without degrading glucose control.

Background Preterm neonates frequently experience hypernatremia (plasma sodium concentrations >145 mmol/l), which is associated with clinical complications, such as intraventricular hemorrhage. Study design In this single center retrospective observational study, the following 7 risk factors for hypernatremia were analyzed in very low gestational age (VLGA, below 32 weeks) neonates: gestational age (GA), delivery mode (DM; vaginal or caesarian section), sex, birth weight, small for GA, multiple birth, and antenatal corticosteroids. Machine learning (ML) approaches were applied to obtain probabilities for hypernatremia. Results 824 VLGA neonates were included (median GA 29.4 weeks, median birth weight 1170 g, caesarean section 83%). 38% of neonates experienced hypernatremia. Maximal sodium concentration of 144 mmol/l (interquartile range 142–147) was observed 52 hours (41–65) after birth. ML identified vaginal delivery and GA as key risk factors for hypernatremia. The risk of hypernatremia increased with lower GA from 22% for GA ≥ 31–32 weeks to 46% for GA Conclusion VLGA neonates with vaginal delivery and low GA have the highest risk for hypernatremia. Early identification of neonates at risk and early intervention may prevent extreme sodium excursions and associated clinical complications. Hintergrund Bei Fruhgeborenen tritt haufig eine Hypernatriamie (Natrium im Plasma > 145 mmol/l) auf, welche mit klinischen Komplikationen wie Hirnblutungen assoziiert ist. Patienten und MethodenDiese retrospektive Beobachtungsstudie untersuchte folgenden 7 Risikofaktoren fur Hypernatriamie bei Neugeborenen mit sehr niedrigem Gestationsalter (VLGA, unter 32 Wochen): Gestationsalter (GA), Entbindungsmodus (DM) (vaginal oder Kaiserschnitt), Geschlecht, Geburtsgewicht, klein fur GA, Mehrlingsgeburt und pranatale Lungenreife. Durch maschinelles Lernen (ML) wurden Risikofaktoren fur Hypernatriamie analysiert. Ergebnisse 824 VLGA-Neugeborene wurden eingeschlossen (GA Median 29,4 Wochen, Geburtsgewicht Median 1170 g, Kaiserschnitt 83%). 38% der Neugeborenen zeigten eine Hypernatriamie. Die maximale Natriumkonzentration von 144 mmol/l (Interquartilbereich 142–147) wurde 52 Stunden (41–65) nach der Geburt beobachtet. ML identifizierte vaginale Geburt und GA als Hauptrisikofaktoren fur Hypernatriamie. Die Haufigkeit stieg mit niedrigerem GA von 22% fur GA ≥31–32 Wochen auf 46% fur GA Schlussfolgerung VLGA-Neugeborene mit vaginaler Entbindung und niedrigem GA haben das hochste Risiko fur Hypernatriamie. Fruhes Identifizieren von Risikopatienten und fruhe Intervention konnten extreme Natriumexkursionen und damit verbundene klinische Komplikationen verhindern.

Premature birth, race, and sex are contributing risk factors for retinopathy of prematurity (ROP) and have long-term impact on children’s retinal structure. Few studies investigate impact of race and sex on macular structure in children born preterm. This study compared foveal structure in preterm and full-term children. Children aged 4–18 years were enrolled into three groups: (1) ROP-risk group (n = 81), born at

RAS is the most frequently mutated oncogene in human cancer with nearly ~20% of cancer patients possessing mutations in one of three RAS genes (K, N or HRAS). However, KRAS is mutated in nearly 90% of pancreatic ductal carcinomas (PDAC). Although pharmacological inhibition of RAS has been challenging, KRAS(G12C)-specific inhibitors have recently entered the clinic. While KRAS(G12C) is frequently expressed in lung cancers, it is rare in PDAC. Thus, more broadly efficacious RAS inhibitors are needed for treating KRAS mutant-driven cancers such as PDAC. A RAS-specific tool biologic, NS1 Monobody, inhibits HRAS- and KRAS-mediated signalling and oncogenic transformation both in vitro and in vivo by targeting the α4–α5 allosteric site of RAS and blocking RAS self-association. Here, we evaluated the efficacy of targeting the α4-α5 interface of KRAS as an approach to inhibit PDAC development using an immunocompetent orthotopic mouse model. Chemically regulated NS1 expression inhibited ERK and AKT activation in KRAS(G12D) mutant KPC PDAC cells and reduced the formation and progression of pancreatic tumours. NS1-expressing tumours were characterized by increased infiltration of CD4 + T helper cells. These results suggest that targeting the #x3B1;4-#x3B1;5 allosteric site of KRAS may represent a viable therapeutic approach for inhibiting KRAS-mutant pancreatic tumours.

Psoriasis is associated with metabolic syndrome; however, the relationship of psoriasis severity with individual cardiometabolic risk factors is not clear. There is a reporting gap between the cardiometabolic risks among patients with psoriasis and what has been reported in the literature using US samples. The objective of this study was to examine the disease burden of psoriasis and assess the associations of psoriasis severity and cardiometabolic risk factors in a nationally representative sample. We conducted a cross-sectional study using the weighted pooled data from the National Ambulatory Medical Care Survey (NAMCS) 2007 through 2016. The NAMCS data were collected from US office-based physicians. Each physician was randomly assigned a specific week to report a sample of their cases. Patients were categorized as severe psoriasis if they were prescribed at least one systemic therapy. We used logistic regression models adjusting for potential confounders to estimate the associations of psoriasis severity with individual cardiometabolic factors. There were about 3.3 million office-based psoriasis visits per year with a mean age of 50 years, a female-to-male ratio of 1:1, and severe disease in 23%. We observed greater values of blood pressure, lipid profiles, and higher body mass index among patients with psoriasis, compared with patients without psoriasis. A higher proportion of the psoriasis patient group were overweight and obese (73.6% vs 62.9% in the non-psoriasis patient group). Compared to mild case groups, severe case groups tended to have a higher proportion of overweight/obese with a body mass index ≥ 25 kg/m2 (77% vs 73%). Obesity was weakly associated with psoriasis severity (adjusted odds ratio = 1.37, 95% confidence interval 0.98–1.91 for mild disease and adjusted odds ratio = 1.42, 95% confidence interval 0.80–2.52 for severe cases). Cardiometabolic factors are related health issues in psoriasis, and obesity is associated with greater psoriasis severity.

Objectives Up-to-date information on the occurrence of drug overdose is critical to guide public health response. The objective of our study was to evaluate a near–real-time fatal drug overdose surveillance system to improve timeliness of drug overdose monitoring. Methods We analyzed data on deaths in the King County (Washington) Medical Examiner’s Office (KCMEO) jurisdiction that occurred during March 1, 2017–February 28, 2018, and that had routine toxicology test results. Medical examiners (MEs) classified probable drug overdoses on the basis of information obtained through the death investigation and autopsy. We calculated sensitivity, positive predictive value, specificity, and negative predictive value of MEs’ classification by using the final death certificate as the gold standard. Results KCMEO investigated 2480 deaths; 1389 underwent routine toxicology testing, and 361 were toxicologically confirmed drug overdoses from opioid, stimulant, or euphoric drugs. Sensitivity of the probable overdose classification was 83%, positive predictive value was 89%, specificity was 96%, and negative predictive value was 94%. Probable overdoses were classified a median of 1 day after the event, whereas the final death certificate confirming an overdose was received by KCMEO an average of 63 days after the event. Conclusions King County MEs’ probable overdose classification provides a near–real-time indicator of fatal drug overdoses, which can guide rapid local public health responses to the drug overdose epidemic.

Purpose To examine associations between parental occupation and childhood germ cell tumors (GCTs) in offspring while distinguishing by common histologic subtype (i.e., yolk sac tumor and teratoma). Methods This population-based case–control study included childhood GCT cases in Denmark diagnosed 1968–2015 ( Results Overall, 178 childhood GCT cases (50 yolk sac tumors; 65 teratomas) and 4,355 controls were included for analysis. Maternal employment in education during pregnancy was associated with offspring GCTs (OR 2.45, 95% CI 1.23–4.90), especially yolk sac tumors (OR 5.27, 95% CI 1.94–14.28). High levels of both maternal and paternal occupational social contact were also associated with offspring yolk sac tumors across all exposure periods (ORs 2.30–4.63). No signals were observed for paternal occupational solvent exposure, while imprecise associations were estimated for maternal exposure (e.g., dichloromethane exposure during pregnancy, OR 1.51, 95% CI 0.77–2.95). Conclusion Our findings suggest that parental occupation is associated with offspring GCTs, with most consistent evidence supporting an association between maternal employment in education or other high social contact jobs and offspring yolk sac tumors.

Background Parkinson's disease (PD) patients exhibit deficits in saccade performance, pupil function, and blink rate. Isolated REM (rapid eye movement) Sleep Behavior Disorder (RBD) is a harbinger to PD making them candidates to investigate for early oculomotor abnormalities as PD biomarkers. Objectives We tested whether saccade, pupillary, and blink responses in RBD were similar to PD. Methods RBD (n = 22), PD (n = 22) patients, and healthy controls (CTRL) (n = 74) were studied with video-based eye-tracking. Results RBD patients did not have significantly different saccadic behavior compared to CTRL, but PD patients differed from CTRL and RBD. Both patient groups had significantly lower blink rates, dampened pupil constriction, and dilation responses compared to CTRL. Conclusion RBD and PD patients had altered pupil and blink behavior compared to CTRL. Because RBD saccade parameters were comparable to CTRL, pupil and blink brain areas may be impacted before saccadic control areas, making them potential prodromal PD biomarkers. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background: The standard of care for early-stage hormone receptor (HR)-positive breast cancer is 5-10 years of adjuvant endocrine therapy (ET), which is associated with a 50-60% relative risk reduction in breast cancer recurrence. However, patients remain at risk of recurrence up to 20 years after diagnosis, and there is a need for biomarkers of response to ET. While decrease in mammographic density (MD) is associated with improved disease-free survival (DFS), measurement is subject to variability in radiologists’ interpretations. We developed a novel, fully-automated convolutional neural network (CNN)-based mammographic evaluation that is a more accurate, independent predictor of breast cancer risk than MD. We evaluated the role of the CNN model as a pharmacodynamic biomarker of response to adjuvant ET among women with early-stage HR-positive breast cancer. Methods: We conducted a retrospective cohort study among women with HR-positive, stage I-III unilateral breast cancer diagnosed at Columbia University Irving Medical Center (CUIMC) in New York, NY, from 2007-2017, who received adjuvant ET and had at least two contralateral mammograms (baseline and on ET) in our electronic health record (EHR). Demographics, clinical characteristics, breast cancer treatment (surgery, radiation, systemic therapy), type of ET (aromatase inhibitor [AI], tamoxifen, or both), and breast cancer relapse (distant, local, new breast primary) were extracted from the EHR and New York Presbyterian Hospital (NYPH) Tumor Registry. We performed CNN analysis of contralateral mammograms at baseline (within 1 year of diagnosis and prior to ET) and at 1- and 2-year (y) follow-up on ET. The primary endpoint was change in CNN risk score, expressed as a continuous variable (range, 0-1.00). Paired t-tests were used to assess for differences in CNN scores between baseline and 1y and 2y follow-up. Logistic regression was used to evaluate if CNN scores at baseline and change from baseline were associated with relapse, with adjustment for known prognostic factors. Results: Of 2,559 women diagnosed with stage I-III HR-positive breast cancer at CUIMC from 2007-2017, 465 had serial mammograms available for CNN analysis. Mean age at diagnosis was 61.2y (SD, 12.2y), and 38.1% of women were non-Hispanic white, 12.5% non-Hispanic black, 39.8% Hispanic, and 9.7% other/unknown. At initial diagnosis, 62.2% had stage I tumors, 74.4% received lumpectomy, and 41.7% received chemotherapy. There were 28 (6.0%) breast cancer relapses (15 distant, 10 local, 3 new primary). Women who had relapsed were more likely to be obese (p=0.009), have higher tumor stage (p Conclusions: We demonstrated a significant change in CNN risk scores from baseline to short-term follow-up among women with early-stage breast cancer who received adjuvant ET. Women who relapsed had higher baseline CNN risk scores, but this was not significant. Due to the small number of relapses, change in CNN risk scores was not associated with breast cancer recurrence. The CNN risk model will be evaluated prospectively in adjuvant clinical trials, to further evaluate its role as a predictor of breast cancer relapse and response to adjuvant ET. Citation Format: Julia E McGuinness, Jana Lee, Aishwarya Anuraj, Simukayi Mutasa, Richard S Ha, MD, Katherine D Crew, MDMS. Use of a novel convolutional neural network (CNN)-based mammographic evaluation to assess response to adjuvant endocrine therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-21.

Background: A number of works provide information on the effectiveness of dienogest in uterine adenomyosis. However, information on the use of the drug at various degrees of the adenomatous nodes, is not presented in the available literature. Aim: The aim of the study was to evaluate the clinical efficacy of dienogest in the treatment of patients with adenomyosis 2nd and 3rd stage and chronic pelvic pain. Materials and methods: A comprehensive clinical survey and treatment of 46 patients with signs of adenomyosis were carried out. Patients were divided into two groups: 28 patients with stage 2 adenomyosis, 18 patients with type 3 adenomyosis were included in the 2nd group. On the first phase of the menstrual cycle all patients underwent hysteroscopy for endoscopic verification of the diagnosis using the traditional Karl Storz hysteroscopic stand with separate treatment and diagnostic curettage of the uterine cavity and cervical canal, followed by histological examination. After surgical treatment all patients received dienogest at a dose 2 mg/day for 6 months. The treatment was performed during 6 months. After 3, 6, and 12 months of the study, the patients included in the survey underwent a comprehensive examination with a clinical assessment of the manifestations of the disease. The level of pain manifestations was evaluated on a visual analog scale (VAS) with a range of 0–10 points. During pain assessment, its manifestations were differentiated—pain due to dyspareunia, dysmenorrhea, dyschezia, and chronic pelvic pain were evaluated. Results: In the group of patients with 2nd adenomyosis stage, the intake of dienogest for 6 months led to the absence of manifestations of uterine bleeding and dyschezia, a decrease in the frequency of dyspareunia—by 7.7 times. In patients with the 3rd stage of the disease, the decrease in the symptoms of adenomyosis was less pronounced, however, after taking the drug, a decrease in the frequency of uterine bleeding was found to be 6 times, dyspareunia 4 times, and dyschezia 5 times. Twelve months after the start of observation (6 months after the end of treatment), none of the patients with 2nd stage of disease showed severe pelvic pain, in the group with 3rd stage of adenomyosis there were only two of these patients (11.1%). At the same time, the vast majority of patients included in the study did not have manifestations of chronic pelvic pain—78.6% of patients with 2nd stage of adenomyosis and 55.6% of patients with 3rd stage of disease, the remaining 21.4% and 33.3% of patients of the first and second groups reported a significant decrease in the severity of pain. Conclusions: The inclusion of dienogest in the combined treatment of adenomyosis is clinically effective, contributing to the rapid and reliable relief of the main manifestations of the disease in patients with adenomyosis with grade 2 and 3 nodes. Treatment of adenomyosis with the use of dienogest is clinically effective, contributing to the rapid and reliable relief of the main manifestation of the disease.

AimThe Australian 'There is no place like home' project is implementing a paediatric low-risk febrile neutropenia (FN) programme across eight paediatric hospitals. We sought to identify the impact of the coronavirus disease 2019 (COVID-19) pandemic on programme implementation.MethodsPaediatric oncology, infectious diseases and emergency medicine health-care workers and parent/carers were surveyed to explore the impact of the COVID-19 pandemic on home-based FN care. Online surveys were distributed nationally to health-care workers involved in care of children with FN and to parents or carers of children with cancer.ResultsSurveys were completed by 78 health-care workers and 32 parents/carers. Overall, 95% of health-care workers had confidence in the safety of home-based FN care, with 35% reporting changes at their own hospitals in response to the pandemic that made them more comfortable with this model. Compared to pre-pandemic, >50% of parent/carers were now more worried about attending the hospital with their child and >80% were interested in receiving home-based FN care. Among both groups, increased telehealth access and acceptance of home-based care, improved patient quality of life and reduced risk of nosocomial infection were identified as programme enablers, while re-direction of resources due to COVID-19 and challenges in implementing change during a crisis were potential barriers.ConclusionThere is strong clinician and parent/carer support for home-based management of low-risk FN across Australia. Changes made to the delivery of cancer care in response to the pandemic have generally increased acceptance for home-based treatments and opportunities exist to leverage these to refine the low-risk FN programme.

The anterior pituitary gland secretes several endocrine hormones, essential for growth, reproduction and other basic physiological functions. Abnormal development or function of the pituitary gland leads to isolated or combined pituitary hormone deficiency (CPHD). At least 30 genes have been associated with human CPHD, including many transcription factors, such as POU1F1. CPHD occurs spontaneously also in mice and dogs. Two affected breeds have been reported in dogs: German Shepherds with a splice defect in the LHX3 gene and Karelian Bear Dogs (KBD) with an unknown genetic cause. We obtained samples from five KBDs presenting dwarfism and abnormal coats. A combined analysis of genome-wide association and next-generation sequencing mapped the disease to a region in chromosome 31 and identified a homozygous intronic variant in the fourth exon of the POU1F1 gene in the affected dogs. The identified variant, c.605-3C>A, resided in the splice region and was predicted to affect splicing. The variant's screening in three new prospective cases, related breeds, and ~ 8000 dogs from 207 breeds indicated complete segregation in KBDs with a carrier frequency of 8%, and high breed-specificity as carriers were found at a low frequency only in Lapponian Herders, a related breed. Our study establishes a novel canine model for CPHD with a candidate POU1F1 defect.

CONTEXT: Pain can be a debilitating side effect of radiation therapy (RT). Data from the general population has shown that sleep disturbance can influence pain incidence and severity; however, less is known about this relationship in breast cancer patients receiving RT. OBJECTIVES: This secondary analysis examined the association of pre-treatment moderate/severe levels of sleep disturbance with subsequent RT-induced pain after adjusting for pre-RT pain. METHODS: We report on 573 female breast cancer patients undergoing RT from a previously completed phase II clinical trial for radiation dermatitis. Sleep disturbance, total pain, and pain subdomains – sensory pain, affective pain, and perceived pain intensity were assessed at pre- and post-RT. At pre-RT, patients were dichotomized into 2 groups: those with moderate/severe sleep disturbance (N=85) vs. those with no/mild sleep disturbance (control; N=488). RESULTS: At pre-RT, women with moderate/severe sleep disturbance were younger, less likely to be married, more likely to have had mastectomy and chemotherapy, and more likely to have depression/anxiety disorder and fatigue than the control group (all p’s

Progressive supranuclear palsy (PSP) is the second most common neurodegenerative Parkinsonian disorder after Parkinson’s disease, and is characterized as a primary tauopathy. Leveraging the considerable clinical and neuropathologic heterogeneity associated with PSP, we measured tau neuropathology as quantitative traits to perform a genome-wide association study (GWAS) within PSP to identify genes and biological pathways that underlie the PSP disease process. In 882 PSP cases, semi-quantitative scores for phosphorylated tau-immunoreactive coiled bodies (CBs), neurofibrillary tangles (NFTs), tufted astrocytes (TAs), and tau threads were documented from 18 brain regions, and converted to latent trait (LT) variables using the R ltm package. LT analysis utilizes a multivariate regression model that links categorical responses to unobserved covariates allowing for a reduction of dimensionality, generating a single, continuous variable to account for the multiple lesions and brain regions assessed. We first tested for association with PSP LTs and the top PSP GWAS susceptibility loci. Significant SNP/LT associations were identified at rs242557 (MAPT H1c sub-haplotype) with hindbrain CBs and rs1768208 (MOBP) with forebrain tau threads. Digital microscopy was employed to quantify phosphorylated tau burden in midbrain tectum and red nucleus in 795 PSP cases and tau burdens were used as quantitative phenotypes in GWAS. Top associations were identified at rs1768208 with midbrain tectum and red nucleus tau burden. Additionally, we performed a PSP LT GWAS on an initial cohort, a follow-up SNP panel (37 SNPs, P –5) in an extended cohort, and a combined analysis. Top SNP/LT associations were identified at SNPs in or near SPTBN5/EHD4, SEC13/ATP2B2, EPHB1/PPP2R3A, TBC1D8, IFNGR1/OLIG3, ST6GAL1, HK1, CALB1, and SGCZ. Finally, testing for SNP/transcript associations using whole transcriptome and whole genome data identified significant expression quantitative trait loci at rs3088159/SPTBN5/EHD4 and rs154239/GHRL. Modeling tau neuropathology heterogeneity using LTs as quantitative phenotypes in a GWAS may provide substantial insight into biological pathways involved in PSP by affecting regional tau burden.

Pulmonary arterial hypertension is a chronic, progressive, and life-threatening disease in children with diverse causes of pulmonary arterial hypertension. The most severe cases of pulmonary arterial hypertension require aggressive treatments with systemic administration of continuous prostacyclin therapy, including treprostinil and epoprostenol. The successful use of continuous subcutaneous treprostinil therapy eliminates the need for an indwelling central venous catheter and its associated risks. However, pain at the subcutaneous infusion site, an expected side effect of this therapy, is often a deterrent to its widespread use. Effective subcutaneous treprostinil site maintenance and pain management is essential to achieve success with this therapy, but strategies surrounding site maintenance and pain control vary significantly between pediatric pulmonary hypertension treatment centers. In an attempt to standardize practice, a survey on the use of subcutaneous treprostinil and site maintenance and pain management strategies, as well as its perceived effectiveness, was disseminated to 13 pediatric pulmonary hypertension centers of the Pediatric Pulmonary Hypertension Network. Responses to the survey were collected and analyzed and were developed into a set of formalized strategies to facilitate knowledge sharing and standardization of practice.

Background Chronic myeloid leukemia (CML) and chronic neutrophilic leukemia (CNL) are two myeloproliferative neoplasms with mutually exclusive diagnostic criteria. A hallmark of CML is the Philadelphia chromosome (Ph), which results in a BCR-ABL1 fusion gene and constitutive tyrosine kinase activity. CNL is a Ph-negative neoplasm and is defined in part by the presence of CSF3R mutations, which drive constative JAK/STAT signaling. Case presentation Here, we report the exceedingly rare co-occurrence of two granulocytic myeloproliferative neoplasms in a 69-year old male patient. After an initial diagnosis of chronic myeloid leukemia, the patient’s clinical course was shaped by hematologic toxicity, the emergence of treatment-resistant BCR-ABL1 clones, and the expansion of a CSF3R-mutant clone without ABL1 mutations under selective pressure from tyrosine kinase inhibitors. The emergence of the CSF3R-mutant, neutrophilic clone led to the diagnosis of CNL as a second myeloproliferative neoplasm in the same patient. Conclusions This is the first reported case of CNL arising subsequent to CML, which occurred under selective pressure from targeted therapy in a patient with complex clonal architecture. Patients with such molecularly complex disease may ultimately benefit from combination therapy that targets multiple oncogenic pathways.

OBJECTIVE: Retinoblastoma is the most common primary intraocular tumor affecting children. We examine the role of parental occupational exposures and risk of retinoblastoma among offspring. METHODS: Our population-based case-control study linked data from four nationwide Danish registries and included all cases of retinoblastoma diagnosed in Danish children (

Normal vaginal microflora consists of a wide range of microorganisms that maintain optimal vaginal milieu, preventing the development of infectious and inflammatory diseases of the vulva and vagina. However, the use of drugs, changes in hormonal status, urinary incontinence and pelvic floor dysfunction can disrupt the optimal balance of the vaginal microbiota, which leads to the development of dysbiotic pathological processes. The first-line treatment for stress urinary incontinence is the installation of suburethral slings. If incontinence is combined with a cystocele, it is advisable to perform reconstructive surgery for anterior vaginal wall, which has high both anatomical and functional efficacy. Surgical correction of genital prolapse and stress urinary incontinence requires bladder catheterization, which further increases the risk for dysbiotic and inflammatory diseases of the urogenital tract. The widespread use of antibiotic therapy leads to the formation of resistant strains of microorganisms and is not always fully realized, especially in the presence of post void residual urine in the postoperative period. Vaginal Zalain suppositories are highly sensitive to Candida species, and the use of Zalagel Intim gel is associated not only with antifungal, but also anti-inflammatory effect. Complex therapy with Zalain suppositories and Zalagel Intim gel is highly effective in the treatment of cytolytic, bacterial vaginosis, vulvovaginal candidiasis, and can also be used as the prevention of infectious complications after corrective interventions for pelvic organ prolapse and stress urinary incontinence.

The ability of point-of-care ultrasound (POCUS) to provide rapid and accurate bedside assessment of both the heart and lungs allows it to be a powerful tool in the management of patients presenting with dyspnea. However, while ultrasound equipment is readily available even in remote healthcare settings in Canada, physicians lack effective training opportunities to develop expertise in this potentially life-saving skill. To answer this critical call to action, we have developed the Accelerated Remote Consultation Tele-POCUS in Cardiopulmonary Assessment (ARCTICA) program to innovate POCUS training for today’s physician leaders. This article outlines the background, research methods, and progress-to-date of ARCTICA.

Background: National neonatal surveillance for herpes simplex virus (HSV) disease suggests that the incidence of HSV disease may be higher in Queensland (QLD) than in other Australian States. We sought to investigate the incidence via a retrospective 13-year evaluation of statewide laboratory data, autopsy data and linked clinical records of infants with laboratory confirmed infection. Methods: All positive polymerase chain reaction HSV 1 and 2 results were obtained for infants 0-3 months of age from January 1, 2005 to December 31, 2017. Clinical data were obtained from patient records and parent questionnaires were used to evaluate long-term sequelae. Results: One hundred seventy-two infants with HSV positive polymerase chain reaction results: 121 (70.3%) with HSV 1. Of 104 (60.5%) infants with signs of HSV disease, 76 (73.1%) were neonates (≤28 days of age) [incidence 9.6 (95% confidence interval, 7.0-11.5) per 100,000 live births] and 28 (26.9%) were young infants (29-90 days of age) [3.6 (95% confidence interval, 2.4-5.4) per 100,000 live births]. The annual incidence of neonatal HSV disease increased significantly in Queensland over the study period (P < 0.01). Of the 76 neonates with HSV disease, 58 (76.3%) presented with the skin, eye, mouth (SEM) disease, 17 (22.4%) with HSV encephalitis and 11 (14.5%) had disseminated disease. Young infants presented with HSV skin, eye, mouth disease (21, 75.0%) or HSV encephalitis (6, 21.4%). Death occurred in 12/104 (11.5%) infants (all neonates) with 10 attributable to HSV disease. Conclusion: The incidence of neonatal HSV disease in QLD is almost 3 times the national reported incidence. Further research is being undertaken to explore reasons for this change and implications for practice.

Background: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs.Study Design: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier.Results: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random.Conclusions: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics.

OBJECTIVE: Four decades ago the “controlled drinking” controversy roiled the alcohol field. Data have subsequently accumulated indicating that non-abstinent alcohol use disorder (AUD) recovery is achievable, but questions remain whether it is sustainable long-term. This study examined whether non-abstinent recovery at three years following AUD treatment is associated with better functioning at 10 years following treatment. METHODS: Data were from the 10-year follow-up of Project MATCH (New Mexico site only, n=146; 30.1% female, 58.6% non-White). Recovery was defined by latent profile analyses based on psychosocial functioning and alcohol consumption three years following treatment. Drinking practices and consequences, depression, purpose in life, and anger were assessed 10 years following treatment. Distal outcome analyses examined differences in drinking and functional outcomes at 10 years as a function of the 3-year latent profiles. Analyses were pre-registered at https://osf.io/3hbxr. RESULTS: Four latent profiles identified at three years following treatment (i.e., low functioning frequent heavy drinkers, low functioning infrequent heavy drinkers, high functioning heavy drinkers, and high functioning infrequent non-heavy drinkers) were significantly associated with outcomes ten years following treatment. The two high functioning profiles at three years had the highest level of psychological functioning at ten years post-treatment, regardless of alcohol consumption level. Abstinence at three years did not predict better psychological functioning at ten years. CONCLUSIONS: Non-abstinent AUD recovery is possible and is sustainable for up to 10 years following treatment. The current findings align with recent proposals to move beyond relying on alcohol consumption as a central defining feature of AUD recovery.

Missense variants ABI3_rs616338-T and PLCG2_rs72824905-G were previously associated with elevated or reduced risk of Alzheimer’s disease (AD), respectively. Despite reports of associations with other neurodegenerative diseases, there are few studies of these variants in purely neuropathologically diagnosed cohorts. Further, the effect of these mutations on neurodegenerative disease pathologies is unknown. In this study, we tested the effects of ABI3_rs616338-T and PLCG2_rs72824905-G on disease risk in autopsy cohorts comprised of 973 patients diagnosed neuropathologically with Lewy body disease (LBD-NP) and 1040 with progressive supranuclear palsy (PSP), compared to 3351 controls. LBD-NP patients were further categorized as high, intermediate and low likelihood of clinical dementia with Lewy bodies (DLB-CL) based on DLB Consortium criteria. We also tested for association with both Braak neurofibrillary tau tangle (nTotal = 2008, nPSP = 1037, nLBD-NP = 971) and Thal phase amyloid plaque scores (nTotal = 1786, nPSP = 1018, nLBD-NP = 768). Additionally, 841 PSP patients had quantitative tau neuropathology measures that were assessed for genetic associations. There was no statistically significant association with disease risk for either LBD-NP or PSP in our study. LBD intermediate category disease risk was significantly associated with ABI3_rs616338-T (OR = 2.65, 95% CI 1.46–4.83, p = 0.001). PLCG2_rs72824905-G was associated with lower Braak stage (ß = − 0.822, 95% CI − 1.439 to − 0.204, p = 0.009). This effect was more pronounced in the PSP (ß = − 0.995, 95% CI − 1.773 to − 0.218, p = 0.012) than LBD-NP patients (ß = − 0.292, 95% CI − 1.283 to 0.698, p = 0.563). PLCG2_rs72824905-G also showed association with reduced quantitative tau pathology for each lesion type and overall tau burden in PSP (ß = − 0.638, 95% CI − 1.139 to − 0.136, p = 0.013). These findings support a role for PLCG2_rs72824905-G in suppressing tau neuropathology. ABI3_rs616338-T may influence disease risk specifically in the LBD-NP intermediate category comprised of patients with diffuse neocortical or limbic LB, concurrently with moderate or high AD neuropathology, respectively. Our study provides a potential mechanism of action for the missense PLCG2 variant and suggests a differential disease risk effect for ABI3 in a distinct LBD-NP neuropathologic category.

Osteosarcoma is the most prevalent bone malignant tumor with a high mortality rate among children and adolescents (10–19 years of age). The Aryl Hydrocarbon Receptor (AHR) is a ligand-dependent transcription factor associated with xenobiotic detoxification and carcinogenesis. It is known that some AHR ligands are included in the composition of drugs used in cancer therapy. However, there are few works devoted to the study of their effect on osteosarcoma cells. In this work, three primary cell cultures were obtained from biopsy material of malignant bone tumors of human osteosarcoma. AHR protein levels were high in all primary osteosarcoma cell cultures. The functional activity of AHR in osteosarcoma cells was estimated by induction of its target genes by known exogenous ligands: indirubin and indole-3-carbinol. The genes of cytochrome P450 1 family CYP1 were analyzed as AHR target genes: CYP1A1, CYP1A2, and CYP1B1. It was shown that the aryl hydrocarbon receptor is functionally active in all cultures, but the target genes were induced differently by ligand treatment within the same cell culture.

Malaria remains one of the most deadly infectious diseases, causing hundreds of thousands of deaths each year, primarily in young children and pregnant mothers. Here, we report the discovery and derivatization of a series of pyrazolo[3,4-b]pyridines targeting Plasmodium falciparum, the deadliest species of the malaria parasite. Hit compounds in this series display sub-micromolar in vitro activity against the intraerythrocytic stage of the parasite as well as little to no toxicity against the human fibroblast BJ and liver HepG2 cell lines. In addition, our hit compounds show good activity against the liver stage of the parasite but little activity against the gametocyte stage. Parasitological profiles, including rate of killing, docking, and molecular dynamics studies, suggest that our compounds may target the Qo binding site of cytochrome bc1.

Despite substantial improvements in the outcomes of patients with cancer over the past two decades, older adults (aged ≥65 years) with cancer are a rapidly increasing population and continue to have worse outcomes than their younger counterparts. Managing cancer in this population can be challenging because of competing health-related and ageing-related conditions that can influence treatment decision-making and affect outcomes. Geriatric screening tools and comprehensive geriatric assessment can help to identify patients who are most at risk of poor outcomes from cancer treatment and to better allocate treatment for these patients. The use of evidence-based management strategies to optimize geriatric conditions can improve communication and satisfaction between physicians, patients and caregivers as well as clinical outcomes in this population. Clinical trials are currently underway to further determine the effect of geriatric assessment combined with management interventions on cancer outcomes, as well as the predictive value of geriatric assessment in context of treatment with contemporary systemic therapies, such as immunotherapies and targeted therapies. In this Review, we summarize the unique challenges of treating older adults with cancer and describe current guidelines as well as investigational studies underway to improve the outcomes of these patients.

Medullary thyroid carcinoma (MTC) often presents with advanced disease and takes an aggressive course as compared with more well-differentiated thyroid cancers. The role of adjuvant therapy, specifically external beam radiotherapy (EBRT), remains disputed. This study investigated the impact of EBRT on survival in MTC.Cross-sectional analysis of a national database.Patients with MTC were identified from the SEER program (Surveillance, Epidemiology, and End Results).Collected variables included age, sex, race, T and N stages, lymph node yield, and use of EBRT. Propensity score matching was performed to determine the association of EBRT with overall and disease-specific survival.A total of 2046 patients with locoregional MTC were identified. Of these, 152 received EBRT. Patients receiving EBRT were older and had more advanced disease. EBRT was not associated with differences in overall survival (hazard ratio, 1.12; 95% CI, 0.76-1.65) or disease-specific survival (1.66; 0.93-2.95), as well as in subset analysis of age and disease extent. Long-term overall survival was similar, with 77.3% (95% CI, 70.1%-85.3%) and 58.3% (48.2%-70.5%) of patients without EBRT alive at 5 and 10 years, respectively (vs 70.7% [63.2%-79.1%] and 52.3% [43.3%-63.2%] of patients with EBRT). There were no differences in 5- and 10-year disease-specific survival.EBRT was not associated with improved overall or disease-specific survival in patients with MTC. Decisions regarding EBRT must be made with consideration of morbidity relative to benefit for individual patients.

Background Social support may be a protective factor for the mental health of public safety personnel (PSP), who are frequently exposed to potentially psychologically traumatic events and report substantial post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) symptoms. Research examining perceived social support and its association with PTSD and MDD in different PSP categories (e.g. firefighters, paramedics) is limited. Aims To examine differences in perceived social support across PSP and determine whether perceived social support is associated with differences in rates of MDD and PTSD. Methods We asked Canadian PSP, including correctional workers and officers, public safety communications officials, firefighters, paramedics, municipal and provincial police officers, and Royal Canadian Mounted Police (RCMP) officers, to complete an online anonymous survey that assessed socio-demographic information (e.g. occupation, sex, marital status, service years), social supports and symptoms of mental disorders, including PTSD and MDD. Analyses included ANOVA and logistic regression models. Results Perceived social support differed by PSP occupation. RCMP officers reported lower social support than all other PSP except paramedics. For most PSP categories, PSP who reported greater social support were less likely to screen positive for PTSD (adjusted odds ratios [AORs]: 0.90–0.93). Across all PSP categories, greater perceived social support was associated with a decreased likelihood of screening positive for MDD (AORs: 0.85–0.91). Conclusions Perceived social support differs across some PSP categories and predicts PTSD and MDD diagnostic status. Studies involving diagnostic clinical interviews, longitudinal designs and social support interventions are needed to replicate and extend our results.

Divergent protein context helps explain why polyglutamine expansion diseases differ clinically and pathologically. This heterogeneity may also extend to how polyglutamine disease proteins are handled by cellular pathways of proteostasis. Studies suggest, for example, that the ubiquitin-proteasome shuttle protein Ubiquilin-2 (UBQLN2) selectively interacts with specific polyglutamine disease proteins. Here we employ cellular models, primary neurons and mouse models to investigate the potential differential regulation by UBQLN2 of two polyglutamine disease proteins, huntingtin (HTT) and ataxin-3 (ATXN3). In cells, overexpressed UBQLN2 selectively lowered levels of full-length pathogenic HTT but not of HTT exon 1 fragment or full-length ATXN3. Consistent with these results, UBQLN2 specifically reduced accumulation of aggregated mutant HTT but not mutant ATXN3 in mouse models of Huntington’s disease (HD) and spinocerebellar ataxia type 3 (SCA3), respectively. Normally a cytoplasmic protein, UBQLN2 translocated to the nuclei of neurons in HD mice but not in SCA3 mice. Remarkably, instead of reducing the accumulation of nuclear mutant ATXN3, UBQLN2 induced an accumulation of cytoplasmic ATXN3 aggregates in neurons of SCA3 mice. Together these results reveal a selective action of UBQLN2 toward polyglutamine disease proteins, indicating that polyglutamine expansion alone is insufficient to promote UBQLN2-mediated clearance of this class of disease proteins. Additional factors, including nuclear translocation of UBQLN2, may facilitate its action to clear intranuclear, aggregated disease proteins like HTT.

Large-scale brain bulk-RNAseq studies identified molecular pathways implicated in Alzheimer’s disease (AD), however these findings can be confounded by cellular composition changes in bulk-tissue. To identify cell intrinsic gene expression alterations of individual cell types, we designed a bioinformatics pipeline and analyzed three AD and control bulk-RNAseq datasets of temporal and dorsolateral prefrontal cortex from 685 brain samples. We detected cell-proportion changes in AD brains that are robustly replicable across the three independently assessed cohorts. We applied three different algorithms including our in-house algorithm to identify cell intrinsic differentially expressed genes in individual cell types (CI-DEGs). We assessed the performance of all algorithms by comparison to single nucleus RNAseq data. We identified consensus CI-DEGs that are common to multiple brain regions. Despite significant overlap between consensus CI-DEGs and bulk-DEGs, many CI-DEGs were absent from bulk-DEGs. Consensus CI-DEGs and their enriched GO terms include genes and pathways previously implicated in AD or neurodegeneration, as well as novel ones. We demonstrated that the detection of CI-DEGs through computational deconvolution methods is promising and highlight remaining challenges. These findings provide novel insights into cell-intrinsic transcriptional changes of individual cell types in AD and may refine discovery and modeling of molecular targets that drive this complex disease.

Rationale: MicroRNAs are potent regulators of biologic systems that are critical to tissue homeostasis. Individual microRNAs have been identified in airway samples. However, a systems analysis of the microRNA–mRNA networks present in the sputum that contribute to airway inflammation in asthma has not been published. Objectives: Identify microRNA and mRNA networks in the sputum of patients with asthma. Methods: We conducted a genome-wide analysis of microRNA and mRNA in the sputum from patients with asthma and correlated expression with clinical phenotypes. Weighted gene correlation network analysis was implemented to identify microRNA networks (modules) that significantly correlate with clinical features of asthma and mRNA expression networks. MicroRNA expression in peripheral blood neutrophils and lymphocytes and in situ hybridization of the sputum were used to identify the cellular sources of microRNAs. MicroRNA expression obtained before and after ozone exposure was also used to identify changes associated with neutrophil counts in the airway. Measurements and Main Results: Six microRNA modules were associated with clinical features of asthma. A single module (nely) was associated with a history of hospitalizations, lung function impairment, and numbers of neutrophils and lymphocytes in the sputum. Of the 12 microRNAs in the nely module, hsa-miR-223-3p was the highest expressed microRNA in neutrophils and was associated with increased neutrophil counts in the sputum in response to ozone exposure. Multiple microRNAs in the nely module correlated with two mRNA modules enriched for TLR (Toll-like receptor) and T-helper cell type 17 (Th17) signaling and endoplasmic reticulum stress. hsa-miR-223-3p was a key regulator of the TLR and Th17 pathways in the sputum of subjects with asthma. Conclusions: This study of sputum microRNA and mRNA expression from patients with asthma demonstrates the existence of microRNA networks and genes that are associated with features of asthma severity. Among these, hsa-miR-223-3p, a neutrophil-derived microRNA, regulates TLR/Th17 signaling and endoplasmic reticulum stress.