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Background: Primary graft dysfunction (PGD) is the leading cause of short- and long-term mortality associated with lung transplantation. The impact of pretransplantation blood transfusions for recipients is not fully elucidated. Methods: This is a retrospective review of 206 consecutive lung transplantations performed at a single academic center (Northwestern University Feinberg School of Medicine, Chicago, IL) from January 2018 to July 2022. Data on patient characteristics, pretransplantation laboratory values, transfusion requirements, and intraoperative and postoperative outcomes were collected. Results: PGD grade 3 (PGD 3) occurred in 13.2% of the cohort (n = 28). A total of 33 patients received a blood transfusion within 4 weeks, whereas 21 patients received a blood transfusion a week before their lung transplant. Pretransplantation transfusions were strongly associated with a higher incidence of PGD 3 (48.5% vs 6.9%; P < .001). There was no significant difference in 1-year survival between the pretransplantation transfused group and the nontransfused group (77.7% vs 88.0%; P = .478). The 1year survival was reduced in recipients with PGD 3 compared with recipients without PGD 3 (63.5% vs 89.9%; P = .0012). In univariate analysis, pretransplant and intratransplant predictors of PGD 3 included younger age (P < .01), pretransplant extracorporeal membrane oxygenation (ECMO) use (P < .001), higher lung allocation score (P < .001), coronavirus disease 2019 (COVID-19)–related acute respiratory distress syndrome (P < .01), blood transfusion within 4 weeks (P < .001), longer operative time (P < .001), intratransplant blood transfusion (P < .001), and intratransplant venoarterial ECMO use (P < .001). Conclusions: Pretransplantation blood transfusions could be associated with a higher rate of PGD. The findings indicated the potential risks of pretransplantation blood transfusions in lung transplant recipients.

Nitrosamine impurities identified in several pharmaceuticals during recent times has raised concerns leading to product recalls worldwide and necessitating sensitive liquid and gas chromatographic methods for trace level detection of nitrosamine impurities. This study developed and validated a ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method for the quantification of NDMA in Levosulpuride drug substance and tablet formulation. Current method utilizes a triple quadrupole analyzer, atmospheric pressure chemical ionization (APCI) ionization source and multiple reaction monitoring (MRM) scan mode for the analysis. Chromatographic separation was achieved on a Gemini NX-C18 column (150 × 4.6 mm, 3 µm) maintained at 40 °C. The mobile phase consisted of a binary gradient of solvent A (0.1 % formic acid in water) and solvent B (methanol), with a total run time of 18 minutes. Current method achieved excellent linearity, recovery, precision, and sensitivity. Greenness of the developed method was evaluated using the GAPI, AGREE, and AES metrics. Current method is sensitive and selective for NDMA in levosulpuride drug substance and tablet formulations and can be employed for routine quality control analysis in pharmaceutical industry.

Background: Social and psychosocial determinants are associated with cardiovascular health (CVH). Objectives: To quantify the contributions of social and psychosocial factors to racial/ethnic differences in CVH. Methods: In the Multi-Ethnic Study of Atherosclerosis and Mediators of Atherosclerosis in South Asians Living in America cohorts, Kitagawa-Blinder-Oaxaca decomposition quantified the contributions of social and psychosocial factors to differences in mean CVH score (range 0–14) in Black, Chinese, Hispanic, or South Asian compared with White participants. Results: Among 7,978 adults (mean age 61 [SD 10] years, 52 % female), there were 1,892 Black (mean CVH score for decomposition analysis 7.96 [SD 2.1]), 804 Chinese (CVH 9.69 [1.8]), 1,496 Hispanic (CVH 8.00 [2.1]), 1,164 South Asian (CVH 9.16 [2.0]), and 2,622 White (CVH 8.91 [2.1]) participants. The factors that were associated with the largest magnitude of explained differences in mean CVH score were income for Black participants (if mean income in Black participants were equal to White participants, Black participants’ mean CVH score would be 0.14 [SE 0.05] points higher); place of birth for Chinese participants (if proportion of US-born and foreign-born individuals among Chinese adults were equivalent to White participants, Chinese participants’ mean CVH score would be 0.22 [0.10] points lower); and education for Hispanic and South Asian participants (if educational attainment were equivalent to White participants, Hispanic and South Asian participants’ mean CVH score would be 0.55 [0.11] points higher and 0.37 [0.11] points lower, respectively). Conclusions: In these multiethnic US cohorts, social and psychosocial factors were associated with racial/ethnic differences in CVH.

To improve the packaging properties of pea protein isolate (PPI) films, 2 wt% of essential oil (EO) from garlic, ginger, or cinnamon was individually incorporated into the films. The film properties were evaluated after the addition of EOs. The resulting PPI active films were applied to salmon to explore their efficacy in a real food system. The results indicated that the moisture content (MC), total soluble matter (TSM), water vapor permeability (WVP), water contact angle (WCA), tensile strength (TS), and elongation at break (EAB) of PPI film decreased after adding EOs, with the extent of the decrease varying based on the type of oil. SEM images revealed that the distribution of EOs within the film matrix differed: garlic EO was mainly distributed within the internal structure, while ginger and cinnamon EOs were primarily on the surface. FTIR analysis confirmed the interactions between PPI and EOs. When applied to salmon, garlic EO and ginger EO promoted lipid oxidation, whereas cinnamon EO significantly delayed it. Although PPI-based active films containing garlic or cinnamon EOs showed remarkable antibacterial activity in vitro, they did not inhibit bacterial growth in salmon. Additionally, EOs in active films may notably alter the color and sensory properties of salmon, potentially influencing consumer acceptance. Our findings demonstrated that the EO type is a key factor in influencing the properties of edible films. More importantly, the effectiveness of active films is closely related to the specific food system in which they are applied.

Strains of Salmonella are a frequent cause of foodborne illness and are known to contaminate poultry products. Most Salmonella testing methods can qualitatively detect Salmonella and cannot quantify or estimate the Salmonella load in samples. Therefore, the aim of this study was to standardize and validate a partitioned-based digital PCR (dPCR) assay for the detection and estimation of Salmonella contamination levels in poultry rinses. Pure culture Salmonella strains were cultured, enumerated, cold-stressed for 48 h, and used to inoculate whole carcass chicken rinse (WCCR) at 1–4 log CFU/30 mL and enriched at 37 °C for 5 h. Undiluted DNA samples with primer and probes targeting the Salmonella-specific invA gene were used for the dPCR assay. The dPCR assay was highly specific, with a limit of detection of 0.001 ng/μL and a limit of quantification of 0.01 ng/μL. The dPCR assay further showed no PCR reaction inhibition up to 5 μg of crude DNA extract. The assays accurately detected all cold-stressed Salmonella in inoculated WCCR samples following a 5-h enrichment. Most importantly, when converted to log, the dPCR copies/μL values accurately estimated the inoculated Salmonella levels. The dPCR assay standardized in this study is a robust method for the detection and estimation of Salmonella concentration in contaminated food samples. This approach can allow same-day decision-making for poultry processors attempting to maintain limits and controls on Salmonella contamination.

Objective: Assess trusted sources of information, perceived message effectiveness, and preferred dissemination strategies regarding adolescent HPV vaccination among U.S. Vietnamese parents. Methods: Data came from an observational, explanatory sequential mixed-methods study with U.S. Vietnamese parents of adolescents (408 survey participants; 32 interview participants). Surveys and interviews were conducted in both Vietnamese and English. Mixed-methods data were integrated and analyzed for confirmation, expansion, or discordance. Results: Both quantitative and qualitative findings confirm high trust in HPV vaccination information from providers, government agencies, and cancer organizations. Messages perceived as effective emphasize vaccine safety, experts' endorsement, importance of vaccination prior to HPV exposure, and preventable cancers. Qualitative findings expanded quantitative results, demonstrating a desire for evidence-based information in the Vietnamese language and addressing cultural concerns (e.g., effectiveness or potential side effects specific to Vietnamese adolescents, whether parents should delay HPV vaccination for Vietnamese adolescents). Quantitative and qualitative findings were incongruent about whether parents would trust information about HPV vaccination that is disseminated via social media. Conclusion: We identified credible messengers, feasible strategies, and elements of impactful messages for interventions to increase adolescent HPV vaccination for U.S. Vietnamese. Innovation: We focus on a high-risk, underserved population and integrate mixed-methods design and analysis.

The association of self-reported BMI at age 20, at age 40, the highest BMI within the past 3 years, and current BMI with current mid-life cardiovascular risk factors and coronary artery calcium (CAC) was evaluated among 1148 South Asian American participants (mean age 57 years) in the MASALA study. A 1 kg/m2 higher BMI at age 20 was associated with higher odds of hypertension (aOR 1.07, 95% CI 1.03–1.12), pre-diabetes/diabetes (aOR 1.05 [1.01–1.09]), and prevalent CAC (aOR 1.06 [1.02–1.11]) in mid-life. Associations were similar for all BMI measures. Weight across young adulthood is associated with mid-life cardiovascular health in South Asian American adults.

Home blood pressure management, including self-monitoring and medication self-titration, is an efficient and cost-effective tool. Although its use is increasing globally, little is known about the feasibility of such interventions in low and middle-income countries. Further, the perspectives and experiences of healthcare providers who play a big role in ensuring the success of home blood pressure management interventions have not been documented. This qualitative study was conducted with a total of 35 healthcare providers (60% female, mean [SD] age = 37.3 [6.9 years] years), through 4 in-depth interviews from Peru, and 8 in-depth interviews and 4 focus groups from Cameroon. Study participants (healthcare providers) include physicians (primary care physicians), specialists (cardiologists and geriatricians), and nurses that were purposively recruited from two hospitals in two of the largest cities in both countries. Results were thematically analyzed by two researchers. Themes derived were related to feasibility and acceptability, and largely reflected providers in both countries endorsing home blood pressure management. Providers’ concerns were in three main areas; 1) safety of patients when they self-titrate medications, 2) resources such as healthcare financing, local hospital policies that support communications with patients for home blood pressure management, and 3) sustainability through patient adherence, incorporating home blood pressure management within clinical guidelines and hospital policies, and complementing with continued health education and lifestyle modifications. According to providers, home blood pressure management may be feasible and acceptable if tailored multi-faceted protocols were introduced bearing in mind local contexts.

Summary: Background: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. Methods: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1–17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). Findings: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p

Objectives: The 2018 and 2019 U.S. guidelines for the management of cholesterol and primary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend consideration of cardiovascular risk-enhancing factors (REFs), including South Asian ancestry, to refine ASCVD risk estimation. However, the associations of REFs with atherosclerosis are unclear in South Asian American adults, who have a disproportionately elevated premature coronary heart disease risk. In the Mediators of Atherosclerosis in South Asians Living in America (MASALA) cohort, we investigated associations of individual REFs, or the number of REFs, with coronary artery calcium (CAC). Methods: Using baseline and follow-up data from MASALA, we evaluated the association of REFs (family history of ASCVD, low-density lipoprotein cholesterol ≥160 mg/dL, triglycerides ≥175 mg/dL, lipoprotein(a) >50 mg/dL, high-sensitivity C-reactive protein [hsCRP] ≥2.0 mg/dL, ankle-brachial index

Purpose: Social support may have benefits on cardiovascular health (CVH). CVH is evaluated using seven important metrics (Life's Simple 7; LS7) established by the American Heart Association (e.g., smoking, diet). However, evidence from longitudinal studies is limited and inconsistent. The objective of this study is to examine the longitudinal relationship between social support and CVH, and assess whether psychosocial risks (e.g., anger and stress) modify the relationship in a racially/ethnically diverse population. Methods: Participants from three harmonized cohort studies – Jackson Heart Study, Mediators of Atherosclerosis in South Asians Living in America, and Multi-Ethnic Study of Atherosclerosis – were included. Repeated-measures modified Poisson regression models were used to examine the overall relationship between social support (in tertiles) and CVH (LS7 metric), and to assess for effect modification by psychosocial risk. Results: Among 7724 participants, those with high (versus low) social support had an adjusted prevalence ratio (aPR) and 95% confidence interval (CI) for ideal or intermediate (versus poor) CVH of 0.99 (0.96–1.03). For medium (versus low) social support, the aPR (95% CI) was 1.01 (0.98–1.05). There was evidence for modification by employment and anger. Those with medium (versus low) social support had an aPR (95% CI) of 1.04 (0.99–1.10) among unemployed or low anger participants. Corresponding results for employed or high anger participants were 0.99 (0.94–1.03) and 0.97 (0.91–1.03), respectively. Conclusion: Overall, we observed no strong evidence for an association between social support and CVH. However, some psychosocial risks may be modifiers. Prospective studies are needed to assess the social support-CVH relationship by psychosocial risks in racially/ethnically diverse populations.

We describe cardiovascular health (CVH) in second-generation (U.S.-born) South Asian Americans in the MASALA study, a population for whom CVH is not previously described. CVH factors in second-generation (N = 21) compared with first-generation (N = 495) South Asian Americans included: total cholesterol (199 ± 31 versus 191 ± 35 mg/dL, p = 0.25), low-density lipoprotein cholesterol (121 ± 27 versus 115 ± 30 mg/dL, p = 0.41), triglycerides (163 ± 197 versus 138 ± 72 mg/dL, p = 0.10), diet score (66 ± 8 versus 70 ± 6 points, p = 0.06), BMI (27.6 ± 4.9 versus 26.2 ± 4.1 kg/m2, p = 0.12), and CAC prevalence (26.3% versus 23.9%, p = 0.34). Age- and sex-adjusted differences were not statistically significant. Further investigation of CVH in this risk-enhanced population may help identify differences between second-generation and first-generation immigrant South Asians in the U.S.

Background: Nowadays, there is a lot more emphasis on promoting health, wellbeing, and self-care including stress management strategies. Health is regarded as a natural extension of a wellness-oriented lifestyle. The objectives are to measure knowledge, evaluate the efficacy of a video education program, and examine the relationship between before and after-existing knowledge measurement and specified socio factors on Urinary tract infections (UTI) and neurological stress in teenage girls.Materials and methods: This study employed an uncontrolled experimental study design. Initially, the mean and standard deviation of before and after-existing knowledge were determined. The ‘t’ test was applied to compare the variance between the before-existing and after-existing knowledge measurements of teenage girls on UTI and neurological stress, to find the efficacy of a video education program on eliminating urinary tract infection and neurological stress in teenage girls. Finally, the Chi-square model is used to measure the relationship between before-existing knowledge measurements and social characteristics.Results and interpretation: The analyzed data found that the teenage girls' mean after-existing knowledge measurement was 33.46% times greater than their mean before-existing knowledge measurement of 24.6%. According to the findings, there is no strong relationship between teenage girls before-existing knowledge measurement and selected socio-demographic factors.Conclusion: According to the study's findings, there is a critical need for healthcare providers to educate teenage girls about the interception of UTI prevalence and neurological stress management strategies inorder to avoid UTI among teenage girls.

Penetrating injuries of the thorax and abdomen, such as gunshot and stabbing, are rare in children. We present the case of a pediatric patient with a history of remote gunshot injury presenting with a late aneurysm in the left ventricle. (Level of Difficulty: Intermediate.)

Ag nanoparticles (AgNPs) catalyst material is bio-synthesized and fully examined using various spectroscopy and microscopy techniques. Further this synthesized material is used for hydroxylation reaction, for this purpose we developed a simple and versatile bio-based method from aryl boronic acids to phenol. The reaction was studied in the presence of low cost ligand in a hydrated reaction medium without any hazardous organic solvents, as a result a finite amount of yield was achieved in short time (

Seasonal influenza in the United States is estimated to cause 9–35 million illnesses annually, with resultant economic burden amounting to $47-$150 billion. Reliable real-time forecasts of influenza can help public health agencies better manage these outbreaks. Here, we investigate the feasibility of three autoregressive methods for near-term forecasts: an Autoregressive Integrated Moving Average (ARIMA) model with time-varying order; an ARIMA model fit to seasonally adjusted incidence rates (ARIMA-STL); and a feed-forward autoregressive artificial neural network with a single hidden layer (AR-NN). We generated retrospective forecasts for influenza incidence one to four weeks in the future at US National and 10 regions in the US during 5 influenza seasons. We compared the relative accuracy of the point and probabilistic forecasts of the three models with respect to each other and in relation to two large external validation sets that each comprise at least 20 other models.Both the probabilistic and point forecasts of AR-NN were found to be more accurate than those of the other two models overall. An additional sub-analysis found that the three models benefitted considerably from the use of search trends based 'nowcast' as a proxy for surveillance data, and these three models with use of nowcasts were found to be the highest ranked models in both validation datasets. When the nowcasts were withheld, the three models remained competitive relative to models in the validation sets. The difference in accuracy among the three models, and relative to models of the validation sets, was found to be largely statistically significant.Our results suggest that autoregressive models even when not equipped to capture transmission dynamics can provide reasonably accurate near-term forecasts for influenza. Existing support in open-source libraries make them suitable non-naïve baselines for model comparison studies and for operational forecasts in resource constrained settings where more sophisticated methods may not be feasible. Keywords: Influenza-like illness, Forecasts, Near-term incidence, Auto-regressive models, Neural networks

Respiratory syncytial virus (RSV) infections peak during the winter months in the United States, yet the timing, intensity, and onset of these outbreaks vary each year. An RSV vaccine is on the cusp of being released; precise models and accurate forecasts of RSV epidemics may prove vital for planning where and when the vaccine should be deployed. Accurate forecasts with sufficient spatial and temporal resolution could also be used to support the prevention or treatment of RSV infections. Previously, we developed and validated an RSV forecast system at the regional scale in the United States. This model-inference system had considerable forecast skill, relative to the historical expectance, for outbreak peak intensity, total outbreak size, and onset, but only marginal skill for predicting the timing of the outbreak peak. Here, we use a superensemble approach to combine three forecasting methods for RSV prediction in the US at three different spatial resolutions: national, regional, and state. At the regional and state levels, we find a substantial improvement of forecast skill, relative to historical expectance, for peak intensity, timing, and onset outbreak up to two months in advance of the predicted outbreak peak. Moreover, due to the greater variability of RSV outbreaks at finer spatial scales, we find that improvement of forecast skill at the state level exceeds that at the regional and national levels. Such finer scale superensemble forecasts may be more relevant for effecting local-scale interventions, particularly in communities with a high burden of RSV infection. Keywords: RSV, Superensemble, Forecast, Infectious disease, Bayesian modeling, Outbreaks, Epidemics, Computational biology

Untreated hypertension may contribute to increased atherosclerotic cardiovascular disease (ASCVD) risk in South Asians (SA). We assessed HTN prevalence among untreated adults free of baseline ASCVD from the MASALA & MESA studies. The proportion of participants who received discordant recommendations regarding antihypertensive pharmacotherapy use by the 2017-ACC/AHA and JNC7 Guidelines across CAC score categories in each race/ethnic group was calculated. Compared with untreated MESA participants (n = 3896), untreated SA (n = 445) were younger (55±8 versus 59±10 years), had higher DBP (73±10 versus 70±10 mmHg), total cholesterol (199±34 versus 196±34 mg/dL), statin use (16% versus 9%) and CAC=0 prevalence (69% versus 58%), with fewer current smokers (3% versus 15%) and lower 10-year-ASCVD-risk (6.4% versus 9.9%) (all p100 and thus may be better at informing hypertension management in American South Asians.

A critical factor that influences the success of an in-vitro fertilization (IVF) treatment cycle is the quality of the transferred embryo. Embryo morphology assessments, conventionally performed through manual microscopic analysis suffer from disparities in practice, selection criteria, and subjectivity due to the experience of the embryologist. Convolutional neural networks (CNNs) are powerful, promising algorithms with significant potential for accurate classifications across many object categories. Network architectures and hyper-parameters affect the efficiency of CNNs for any given task. Here, we evaluate multi-layered CNNs developed from scratch and popular deep-learning architectures such as Inception v3, ResNET-50, Inception-ResNET-v2, NASNetLarge, ResNeXt-101, ResNeXt-50, and Xception in differentiating between embryos based on their morphological quality at 113 h post insemination (hpi). Xception performed the best in differentiating between the embryos based on their morphological quality.

Mycobacterium avium-complex (MAC) is an infectious granulomatous disease which is associated with hypercalcemia especially in immunocompromised patients. We present an unusual case of MAC infection in an immunocompetent patient presenting as hypercalcemia.A 76-year-old immunocompetent male was admitted for hypercalcemia of 12.6 mg/dl found on outpatient evaluation for fatigue. PTH level was low 8 pmol/L, Vitamin D 25hydroxy was 29 ng/ml, 1,25 dihydroxy vitamin D (1,25(OH)2 vitamin D) levels was low at 11 pg/ml, PTH related peptide was 1.1 pmol/L. Hypercalcemia resolved with intravenous hydration and bisphosphonate administration. CT chest identified a nodule with central cavity in the right upper lobe. Pathology from percutaneous biopsy of thenodule demonstrated granulomatous inflammation. AFB culture came positive for MAC. Patient was treated with Azithromycin, Rifabutin and Ethambutol for twelve months.Granulomatous diseases like MAC cause hypercalcemia via activation of macrophages which express extrarenal 1- alpha -hydroxylase. It converts vitamin D to its active form 1,25(OH)2 vitamin D causing its excess, leading to hypercalcemia. Interestingly, in our patient calcium level was elevated with appropriately low PTH but 1,25(OH)2 vitamin D level was also low. There are few reported cases of hypercalcemia in granulomatous disease with normal levels of 1,25(OH)2 vitamin D levels, and our case is the first one to have MAC associated hypercalcemia with low 1,25(OH)2 vitamin D levels, suggesting an alternative mechanism for hypercalcemia in these patients

Background: Atraumatic rotary subluxation of the atlantoaxial joint (Grisel’s syndrome) is a rare cause of torticollis. Although rare, prompt recognition and treatment of this disorder is essential in preventing permanent deformity.Case presentationA 4-year-old female with no significant past medical history presented to the emergency department (ED) after an outpatient positive streptococcus test with intermittent subjective fevers for one week. In the ED, the patient had a temperature of 103.0 F and was found to have a leukocytosis of 26,700 K/UL with a leftward shift of neutrophils. Initial radiograph of the neck found asymmetric soft tissue fullness and increased opacity in the right upper and mid cervical neck. Subsequently, contrast-enhanced computed tomography (CT) of the soft tissues of the neck found a right-sided retropharyngeal abscess measuring 1.5 cm. It was located medial to the carotid space with surrounding edema, inflammation, and fluid tracking inferiorly along the prevertebral soft tissues. There was associated lateral displacement of the right cervical internal carotid artery and jugular veins with regional stenosis. Additionally, there was atlantoaxial subluxation of C1 on C2. The patient was medically managed with intravenous antibiotics. The patient received dexamethasone for the edema and was admitted as an inpatient. She subsequently improved and had an uneventful hospital course with discharge to home. Conclusions: Grisel’s syndrome is an infrequent diagnosis, which is seen with atlantoaxial rotary subluxation accompanying infection or recent otolaryngolic surgery. Diagnosis typically requires cross-sectional imaging, often with CT. Without treatment with reduction and immobilization, there can be permanent fixed deformity.

Accurate forecasts could enable more informed public health decisions. Since 2013, CDC has worked with external researchers to improve influenza forecasts by coordinating seasonal challenges for the United States and the 10 Health and Human Service Regions. Forecasted targets for the 2014–15 challenge were the onset week, peak week, and peak intensity of the season and the weekly percent of outpatient visits due to influenza-like illness (ILI) 1–4 weeks in advance. We used a logarithmic scoring rule to score the weekly forecasts, averaged the scores over an evaluation period, and then exponentiated the resulting logarithmic score. Poor forecasts had a score near 0, and perfect forecasts a score of 1.Five teams submitted forecasts from seven different models. At the national level, the team scores for onset week ranged from

Summary: Early infantile epileptic encephalopathies (EOEE) are a debilitating spectrum of disorders associated with cognitive impairments. We present a clinical report of a KCNT2 mutation in an EOEE patient. The de novo heterozygous variant Phe240Leu SLICK was identified by exome sequencing and confirmed by Sanger sequencing. Phe240Leu rSlick and hSLICK channels were electrophysiologically, heterologously characterized to reveal three significant alterations to channel function. First, [Cl−]i sensitivity was reversed in Phe240Leu channels. Second, predominantly K+-selective WT channels were made to favor Na+ over K+ by Phe240Leu. Third, and consequent to altered ion selectivity, Phe240Leu channels had larger inward conductance. Further, rSlick channels induced membrane hyperexcitability when expressed in primary neurons, resembling the cellular seizure phenotype. Taken together, our results confirm that Phe240Leu is a “change-of-function” KCNT2 mutation, demonstrating unusual altered selectivity in KNa channels. These findings establish pathogenicity of the Phe240Leu KCNT2 mutation in the reported EOEE patient. : Gururaj et al. report a KCNT2 mutation in a patient with epileptic encephalopathy and employ electrophysiological analyses to establish channel properties that could underlie epileptogenesis: namely, inhibition by high [Cl−]i and loss of exclusive selectivity to K+. Furthermore, primary neurons expressing Ph240Leu display a hyperexcitable phenotype. Keywords: seizures, epileptic encephalopathy, ion channels, potassium channels, Slick, KCNT2, selectivity, Xenopus oocytes, Slack, KCNT1

Summary The clinical importance of anterior foregut endoderm (AFE) derivatives, such as thyrocytes, has led to intense research efforts for their derivation through directed differentiation of pluripotent stem cells (PSCs). Here, we identify transient overexpression of the transcription factor (TF) NKX2-1 as a powerful inductive signal for the robust derivation of thyrocyte-like cells from mouse PSC-derived AFE. This effect is highly developmental stage specific and dependent on FOXA2 expression levels and precise modulation of BMP and FGF signaling. The majority of the resulting cells express thyroid TFs (Nkx2-1, Pax8, Foxe1, Hhex) and thyroid hormone synthesis-related genes (Tg, Tpo, Nis, Iyd) at levels similar to adult mouse thyroid and give rise to functional follicle-like epithelial structures in Matrigel culture. Our findings demonstrate that NKX2-1 overexpression converts AFE to thyroid epithelium in a developmental time-sensitive manner and suggest a general methodology for manipulation of cell-fate decisions of developmental intermediates.

Tyrosine kinases are important for the development of pathological angiogenesis, a critical factor for survival and proliferation of tumor cells. Inhibition of tyrosine kinases either through targeted binding of its ligands or inhibition of its receptor has led to significant hindrance in angiogenesis and has improved survival for several cancers. Several of these antibodies or small molecules have been approved for treatment of recurrent and resistant cancers over the last decade. Although generally well tolerated, tyrosine kinase inhibitors have been linked with development of hypertension and proteinuria. We review the literature for incidence and severity of hypertension and proteinuria among several tyrosine kinase inhibitors, their pathophysiologic mechanisms, and provide a guide for screening and management.

Background: Clinical trials with N-acetylcysteine (NAC) in perioperative cardiovascular settings have shown inconsistent effects for renal endpoints. We aimed to systematically review these trials to ascertain its role in prevention of post-cardiovascular surgery acute renal failure., Methods: We searched MEDLINE, EMBASE, Cochrane Renal Health Library, and Google Scholar for randomized controlled studies that evaluated NAC in adult patients undergoing cardiovascular surgery. Acute renal failure, acute renal failure requiring dialysis, and mortality were the primary outcomes. Additional outcomes studied were length of intensive care unit stay, postoperative serum creatinine, creatinine clearance, renal biomarkers, and adverse effects of NAC., Results: Twelve studies comprising 1,324 patients were found to be eligible. Meta-analytic estimates showed that NAC was not associated with reduction in acute renal failure (odds ratio [OR]: 0.89, 95% confidence interval [CI]: 0.68 to 1.15), acute renal failure requiring dialysis (OR: 1.09, 95% CI: 0.57 to 2.09) or mortality (OR: 0.95, 95% CI: 0.53 to 1.71). N-acetylcysteine was well tolerated but was not associated with any reduction in the length of intensive care unit stay. It had inconsistent effects on postoperative serum creatinine, creatinine clearance, and renal biomarkers. Subgroup analysis restricted to studies using intravenous NAC preparation showed a nonsignificant trend toward reduction in acute renal failure (OR: 0.81, 95% CI: 0.61 to 1.08) without any significant change in other outcomes., Conclusions: Overall analysis of the existent literature shows that NAC is not beneficial in the prevention of post-cardiovascular surgery renal dysfunction. Routine use of NAC for this indication should be avoided.