Numb positively regulates Hedgehog signaling at the ciliary pocket.

Hedgehog (Hh) signaling relies on the primary cilium, a cell surface organelle that serves as a signaling hub for the cell. Using proximity labeling and quantitative proteomics, we identify Numb as a ciliary protein that positively regulates Hh signaling. Numb localizes to the ciliary pocket and acts as an endocytic adaptor to incorporate Ptch1 into clathrin-coated vesicles, thereby promoting Ptch1 exit from the cilium, a key step in Hh signaling activation. Numb loss impedes Sonic hedgehog (Shh)-induced Ptch1 exit from the cilium, resulting in reduced Hh signaling. Numb loss in spinal neural progenitors reduces Shh-induced differentiation into cell fates reliant on high Hh activity. Genetic ablation of Numb in the developing cerebellum impairs the proliferation of granule cell precursors, a Hh-dependent process, resulting in reduced cerebellar size. This study highlights Numb as a regulator of ciliary Ptch1 levels during Hh signal activation and demonstrates the key role of ciliary pocket-mediated endocytosis in cell signaling.

Foxp1 suppresses cortical angiogenesis and attenuates HIF-1alpha signaling to promote neural progenitor cell maintenance.

Neural progenitor cells within the cerebral cortex undergo a characteristic switch between symmetric self-renewing cell divisions early in development and asymmetric neurogenic divisions later. Yet, the mechanisms controlling this transition remain unclear. Previous work has shown that early but not late neural progenitor cells (NPCs) endogenously express the autism-linked transcription factor Foxp1, and both loss and gain of Foxp1 function can alter NPC activity and fate choices. Here, we show that premature loss of Foxp1 upregulates transcriptional programs regulating angiogenesis, glycolysis, and cellular responses to hypoxia. These changes coincide with a premature destabilization of HIF-1α, an elevation in HIF-1α target genes, including Vegfa in NPCs, and precocious vascular network development. In vitro experiments demonstrate that stabilization of HIF-1α in Foxp1-deficient NPCs rescues the premature differentiation phenotype and restores NPC maintenance. Our data indicate that the endogenous decline in Foxp1 expression activates the HIF-1α transcriptional program leading to changes in the tissue environment adjacent to NPCs, which, in turn, might alter their self-renewal and neurogenic capacities.

Malignant ureteral obstruction: comparison of metallic, 8 French and 6 French ureteric stents after failure of initial ureteric stent.

PURPOSE: Malignant ureteric obstruction is a significant management challenge. The failure of ureteric stents often leads to long-term nephrostomy tubes. This is delayed for as long as possible due to its' associated morbidity. Several types of ureteric stents are available, however there is little evidence demonstrating which stents are better for preventing progression to nephrostomy tubes. This study looked to determine whether a new 6 French (Fr) polymer stent, 8Fr polymer stent or metallic stent achieved a longer functional duration once the initial polymer ureteric stent failed. METHODS: A retrospective, longitudinal study was performed at a single tertiary institution. All patients who underwent ureteric stenting with a 6Fr polymer stent for malignancy between 2010 and 2020 were included. Patients were followed up until death with ureteric stent in situ or permanent nephrostomy tube insertion. RESULTS: A total of 46 patients (66 ureters) had ureteric stents inserted for malignancy. From initial ureteric stent failure, 10 stents were changed to a new 6Fr polymer stent, 42 were changed to an 8Fr polymer stent and 14 were changed to a Resonance® 6Fr metallic stent. The Resonance 6Fr metallic stent had the longest median functional duration of 14 months (p = 0.012). CONCLUSION: Resonance® 6Fr metallic stents appear to have a significantly longer functional duration than a new 6Fr polymer stent or 8Fr polymer stent, which may allow patients to enjoy a better quality of life and delay permanent nephrostomy tube insertion.

Cognitive processes that underlie mathematically gifted emergent bilinguals.

The purpose of this study was to determine those cognitive measures that increase the likelihood of identifying mathematically gifted students who are emerging bilinguals. Elementary school children (Grades 1, 2, and 3) were administered a battery of math, vocabulary, reading, and cognitive measures (short-term memory, inhibition, and working memory in their first language (L1: Spanish) and second language (L2: English). Multilevel polytomous logistic modeling compared mathematically gifted children with children who were average math achievers or low math achievers. The results indicated that cognitive parameters that included estimation and working memory in the L2 and problem-solving in the L1 were unique predictors that significantly influenced whether a child was categorized as gifted relative to average achievers. Relative to average achievers, L2 parameters (magnitude judgment) and English reading were significantly related to the identification of children with low math computation. The results are discussed in terms of a multidimensional model that taps domain-specific skills and general cognitive processes that increase the ability to correctly identify children who score in the gifted range in both their L1 and L2.

Gut and oral microbiome modulate molecular and clinical markers of schizophrenia-related symptoms: A transdiagnostic, multilevel pilot study.

Although increasing evidence links microbial dysbiosis with the risk for psychiatric symptoms through the microbiome-gut-brain axis (MGBA), the specific mechanisms remain poorly characterized. In a diagnostically heterogeneous group of treated psychiatric cases and nonpsychiatric controls, we characterized the gut and oral microbiome, plasma cytokines, and hippocampal inflammatory processes via proton magnetic resonance spectroscopic imaging (1H-MRSI). Using a transdiagnostic approach, these data were examined in association with schizophrenia-related symptoms measured by the Positive and Negative Syndrome Scale (PANSS). Psychiatric cases had significantly greater heterogeneity of gut alpha diversity and an enrichment of pathogenic taxa, like Veillonella and Prevotella, in the oral microbiome, which was an accurate classifier of phenotype. Cases exhibited significantly greater positive, negative, and general PANSS scores that uniquely correlated with bacterial taxa. Strong, positive correlations of bacterial taxa were also found with cytokines and hippocampal gliosis, dysmyelination, and excitatory neurotransmission. This pilot study supports the hypothesis that the MGBA influences psychiatric symptomatology in a transdiagnostic manner. The relative importance of the oral microbiome in peripheral and hippocampal inflammatory pathways was highlighted, suggesting opportunities for probiotics and oral health to diagnose and treat psychiatric conditions.

Kidney outcomes after methanol and ethylene glycol poisoning: a systematic review and meta-analysis.

INTRODUCTION: Ingestions with methanol, ethylene glycol, diethylene glycol, propylene glycol, and isopropanol are rare yet exceedingly dangerous conditions that may require emergent management with kidney replacement therapy. Little is known regarding short- and long-term kidney outcomes post-ingestion. OBJECTIVES: To comprehensively synthesize existing evidence regarding short- and long-term kidney and other outcomes of adult patients following these poisonings. METHODS: We developed a search strategy in MEDLINE via OVID and then translated it into other databases including EMBASE (via OVID), PubMed, CENTRAL (via OVID). The databases were searched from their dates of inception to 29 July 2021. A grey literature search was conducted in the International Traditional Medicine Clinical Trial Registry and ClinicalTrials.gov. All interventional and observational studies and case series with ≥ five participants that reported on the outcomes of toxic alcohol (methanol, ethylene glycol, diethylene glycol, propylene glycol and isopropanol) poisonings in adult patients ≥18 years old were included. Studies that reported mortality, kidney outcomes and/or complications attributed to toxic alcohol poisoning were eligible. RESULTS: The search strategy identified 1,221 citations. Sixty-seven studies (13 retrospective observational studies, one prospective observational study, 53 case series) met inclusion criteria (total N = 2,327 participants). No randomized controlled trials were identified per our prespecified criteria. Generally, included studies had small sample sizes (median of 27 participants) and were of low quality. Methanol and/or ethylene glycol poisoning made up 94.1% of included studies, whereas one study reported on isopropanol and none reported on propylene glycol. Results of the 13 observational studies of methanol and/or ethylene glycol poisoning were pooled for meta-analyses. The pooled in-hospital mortality estimates amongst patients with methanol and ethylene glycol poisoning were 24 and 11%, respectively. A more recent year of publication, female sex and mean age were associated with lower in-hospital mortality amongst individuals with ethylene glycol poisoning. Although hemodialysis was the most frequently employed kidney replacement therapy, the indications for initiation of this therapy were not reported in the majority of studies. At hospital discharge, kidney recovery occurred in 64.7-96.3% of patients with ethylene glycol poisoning. In studies of methanol and/or ethylene glycol poisoning, 2-3.7% of individuals required ongoing dialysis. Only one study reported post-discharge mortality. Furthermore, long-term toxic alcohol-mediated sequelae, such as visual and neurologic outcomes, were scarcely reported. DISCUSSION: Ingestions of methanol and ethylene glycol were associated with a significant short-term risk of mortality. Although a wealth of literature in the form of case reports and case series exists, high-quality evidence regarding kidney outcomes after these poisonings is lacking. We identified a paucity of standardized reporting in clinical presentations, therapeutics and outcomes amongst adults with toxic alcohol poisoning. Amongst the included studies, there was substantial heterogeneity encompassing study type, outcomes, duration of follow-up and treatment modalities. These sources of heterogeneity restricted our ability to perform comprehensive meta-analyses of all outcomes of interest. An additional limitation is the lack of studies pertaining to propylene glycol and the paucity of data on isopropanol. CONCLUSIONS: The indications for hemodialysis, long-term kidney recovery and long-term mortality risk vary widely in these poisonings and are inconsistently reported in the literature. This highlights the need for further research with standardized reporting of baseline kidney function, indications for initiation of kidney replacement therapy and short-term and long-term kidney outcomes. REGISTRATION: This systematic review protocol is registered at PROSPERO, CRD42018101955.

Renal mucormycosis in post-COVID patients in Australia.

Renal mucormycosis is a rare entity that has been described with significant associated morbidity and mortality. It is an opportunistic infection affecting immunocompromised patients. With the pandemic of COVID-19, we report the first case of renal mucormycosis in Australia secondary to COVID-19 and its management.

Creating accessibility in academic negotiations.

The process of evaluating and negotiating a tenure-track job offer is unstructured and highly variable, making it susceptible to bias and inequitable outcomes. We outline common aspects of and recommendations for negotiating an academic job offer in the life sciences to support equitable recruitment of diverse faculty.

Meta-analytic Techniques to Assess the Association Between N-acetylcysteine and Acute Kidney Injury After Contrast Administration: A Systematic Review and Meta-analysis.

Importance: The most suitable analytic method to systematically analyze numerous trials with contradictory results is unclear. Multiple trials assessing the use of N-acetylcysteine (NAC) for prevention of contrast-induced acute kidney injury (CI-AKI) have had contradictory results with recent trials confirming a lack of benefit. Objective: To systematically review the literature on NAC for the prevention of CI-AKI, and to explore the heterogeneity, publication bias, and small-study effect to determine the most suitable analytic method in a setting where the literature is contradictory. Data Sources: Medline, Embase, and Cochrane Central Register of Controlled Trials databases were used to find randomized clinical trials (RCTs) comparing NAC with any other prophylactic agent or placebo in adults. Study Selection: The search included studies published in English from database inception to January 2020. Two independent reviewers screened the studies, extracted data, and performed the risk of bias assessment. Data Extraction and Synthesis: A meta-analysis was conducted about the effect of NAC on CI-AKI, the need for dialysis, and mortality. Fixed and random effects analyses were also performed. Funnel plots and the trim and fill method were used for assessment of publication bias. Metaregression was performed to explore the heterogeneity and subgroup analysis to examine the association between NAC and CI-AKI when studies were categorized according to sample size and number of events. Results: A total of 101 trials were included in this meta-analysis. The median sample size was 112 (range, 20 to 4993). Twenty-nine trials had a sample size of 200 or more, and only 3 trials had a sample size of 500 or more. Forty-five trials reported the need for kidney replacement therapy, and 41 trials reported mortality as an outcome. NAC seemed to show a benefit, with a pooled OR of 0.72 (95% CI, 0.63-0.82) using random effects model and a pooled OR of 0.82 (95% CI 0.76-0.90) using a fixed effects model. However, there was significant heterogeneity (I2 = 37.6; P < .001) and significant publication bias, which was reduced only when restricting to large RCTs (N ≥ 500). The clinical outcomes (ie, the need for kidney replacement therapy and mortality) revealed little heterogeneity and no publication bias, and each provided a robust neutral summary result. Conclusions and Relevance: In this meta-analysis, NAC was associated with a benefit in the prevention of CI-AKI. However, because of substantial publication bias and other biases, standard meta-analytic techniques resulted in significant heterogeneity and a spurious, or factitious, association, even when using a random effects model. When the analysis was restricted to RCTs with a large sample size to account for publication bias or restricted to trials with clinical outcomes, this issue was reduced and resulted in more robust and neutral effect sizes.

Cognitive and academic growth among emergent bilingual children at risk and not at risk for math difficulties.

One purpose of this study was to identify cognitive processes within the English (second language [L2]) and Spanish (first language [L1]) language systems that underlie growth in math problem solving among emergent bilingual (EB) children with and without math difficulties (MD). A second purpose was to determine those L1 cognitive processes that play an essential role in predicting math word-problem-solving difficulties. To this end, children (N = 275; children with MD = 90) in Grades 1, 2, and 3 at Wave 1 were administered a battery of math, reading, vocabulary, and cognitive (short-term memory [STM], working memory [WM], rapid naming, and inhibition) measures. The battery of tests was administered again 1 year and 2 years later to the same participants. Three findings were important. First, multilevel logistic modeling suggested that the log-odds of identifying children with MD were best captured by the level of performance on measures of fluid intelligence, Spanish STM, and English WM. Second, the log-odds of identifying children with MD were uniquely related to growth on WM, computation, and number magnitude judgment measures. Finally, the level of performance on L1 measures of reading, calculation, and naming speed and inhibition facilitated the identification of children with MD. In contrast, growth on all Spanish measures, except vocabulary and estimation, increased the log-odds of identifying children with MD. In general, the results suggest that there are constraints or inefficiencies in cognitive processes within and across both language systems that underlie the development of EB children's MD. The results highlight the importance of the phonological and executive systems of WM as important predictors of EB children's math problem-solving difficulties.

Diet or additional supplement to increase potassium intake: protocol for an adaptive clinical trial.

BACKGROUND: High blood pressure is the leading cause of cardiovascular disease worldwide. The prevalence of high blood pressure is steadily rising as the population grows amongst older adults with the ageing population. Therapeutical treatments are widely available to decrease blood pressures, in addition to many lifestyle options, such as dietary changes and exercise. There is a marked preference amongst patients, as reiterated by Hypertension Canada, for more research into non-therapeutic methods for controlling blood pressure or to reduce the burden of taking many pills to control high blood pressure. Indeed, effective options do exist, especially with diet, specifically decreasing sodium and increasing potassium intake. Current public health outreach primarily focusses on sodium intake, even though potassium intake remains low in the Western world. Excellent data exist in published research that increasing potassium intake, either via dietary modification or supplements, reduces blood pressure and reduces risk of cardiovascular outcomes such as stroke. However, the advice most often provided by medical professionals is to 'eat more fruits and vegetables' which has little impact on patient outcomes. METHODS: We propose to do a clinical trial in two stages with an adaptive trial design. In the first stage, participants with high blood pressure and proven low potassium intake (measured on the basis of a 24-h urine collection) will get individually tailored dietary advice, reinforced by weekly supportive phone/email support. At 4 weeks, if there has not been a measured increase in potassium intake, participants will be prescribed an additional potassium supplement. Testing will be conducted again at 8 weeks, to confirm the efficacy of the potassium supplement. Final measurements will be planned at 52 weeks to observe and measure the persistence of the effect of diet or additional supplement. Concurrent measurements of sodium intake, blood pressure, participant satisfaction, and safety measures will also be done. DISCUSSION: The results of the study will help determine the most effective method of increasing potassium intake, thus reducing blood pressure and need for blood pressure-lowering medicines, and at the same time potentially increasing participant satisfaction. The current guidelines recommend changes in diet, not a potassium supplement, to increase potassium intake; hence, the two-stage design will only add supplements if the most rigorous dietary advice does not work. TRIAL REGISTRATION: This study has been registered on ClinicalTrials.gov NCT03809884 . Registered on January 18, 2019.

GLI3 Is Required for OLIG2+ Progeny Production in Adult Dorsal Neural Stem Cells.

The ventricular-subventricular zone (V-SVZ) is a postnatal germinal niche. It holds a large population of neural stem cells (NSCs) that generate neurons and oligodendrocytes for the olfactory bulb and (primarily) the corpus callosum, respectively. These NSCs are heterogeneous and generate different types of neurons depending on their location. Positional identity among NSCs is thought to be controlled in part by intrinsic pathways. However, extrinsic cell signaling through the secreted ligand Sonic hedgehog (Shh) is essential for neurogenesis in both the dorsal and ventral V-SVZ. Here we used a genetic approach to investigate the role of the transcription factors GLI2 and GLI3 in the proliferation and cell fate of dorsal and ventral V-SVZ NSCs. We find that while GLI3 is expressed in stem cell cultures from both dorsal and ventral V-SVZ, the repressor form of GLI3 is more abundant in dorsal V-SVZ. Despite this high dorsal expression and the requirement for other Shh pathway members, GLI3 loss affects the generation of ventrally-, but not dorsally-derived olfactory interneurons in vivo and does not affect trilineage differentiation in vitro. However, loss of GLI3 in the adult dorsal V-SVZ in vivo results in decreased numbers of OLIG2-expressing progeny, indicating a role in gliogenesis.

Intravenous albumin for the prevention of hemodynamic instability during sustained low-efficiency dialysis: a randomized controlled feasibility trial (The SAFER-SLED Study).

BACKGROUND: Hemodynamic instability is a frequent complication of sustained low-efficiency dialysis (SLED) treatments in the ICU. Intravenous hyperoncotic albumin may prevent hypotension and facilitate ultrafiltration. In this feasibility trial, we sought to determine if a future trial, powered to evaluate clinically relevant outcomes, is feasible. METHODS: This single-center, blinded, placebo-controlled, randomized feasibility trial included patients with acute kidney injury who started SLED in the ICU. Patients were randomized to receive 25% albumin versus 0.9% saline (control) as 100 mL boluses at the start and midway through SLED, for up to 10 sessions. The recruitment rate and other feasibility outcomes were determined. Secondary exploratory outcomes included ultrafiltration volumes and metrics of hemodynamic instability. RESULTS: Sixty patients (271 SLED sessions) were recruited over 10 months. Age and severity of illness were similar between study groups. Most had septic shock and required vasopressor support at baseline. Protocol adherence occurred for 244 sessions (90%); no patients were lost to follow-up; no study-related adverse events were observed; open label albumin use was 9% and 15% in the albumin and saline arms, respectively. Ultrafiltration volumes were not significantly different. Compared to the saline group, the albumin group experienced less hemodynamic instability across all definitions assessed including a smaller absolute decrease in systolic blood pressure (mean difference 10.0 mmHg, 95% confidence interval 5.2-14.8); however, there were significant baseline differences in the groups with respect to vasopressor use prior to SLED sessions (80% vs 61% for albumin and saline groups, respectively). CONCLUSIONS: The efficacy of using hyperoncotic albumin to prevent hemodynamic instability in critically ill patients receiving SLED remains unclear. A larger trial to evaluate its impact in this setting, including evaluating clinically relevant outcomes, is feasible. Trial registration ClinicalTrials.gov (NCT03665311); First Posted: Sept 11th, 2018. https://clinicaltrials.gov/ct2/show/NCT03665311?term=NCT03665311&draw=2&rank=1.

Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength.

Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.

A Systematic Review of the Effect of N-Acetylcysteine on Serum Creatinine and Cystatin C Measurements.

INTRODUCTION: N-acetylcysteine (NAC) is an antioxidant that can regenerate glutathione and is primarily used for acetaminophen overdose. NAC has been tested and used for preventing iatrogenic acute kidney injury or slowing the progression of chronic kidney disease, with mixed results. There are conflicting reports that NAC may artificially lower measured serum creatinine without improving kidney function, potentially by assay interference. Given these mixed results, we conducted a systematic review of the literature to determine whether there is an effect of NAC on kidney function as measured with serum creatinine and cystatin C. METHODS: A literature search was conducted to identify all study types reporting a change in serum creatinine after NAC administration. The primary outcome was change in serum creatinine after NAC administration. The secondary outcome was a change in cystatin C after NAC administration. Subgroup analyses were conducted to assess effect of creatinine assay (Jaffe vs. non-Jaffe and intravenous vs. oral). RESULTS: Six studies with a total of 199 participants were eligible for the systematic review and meta-analysis. There was a small but significant decrease in serum creatinine after NAC administration overall (weighted mean difference [WMD], -2.80 µmol/L [95% confidence interval {CI} -5.6 to 0.0]; P = 0.05). This was greater with non-Jaffe methods (WMD, -3.24 µmol/L [95% CI -6.29 to -0.28]; P = 0.04) than Jaffe (WMD, -0.51 µmol/L [95% CI -7.56 to 6.53]; P = 0.89) and in particular with intravenous (WMD, -31.10 µmol/L [95% CI -58.37 to -3.83]; P = 0.03) compared with oral NAC (WMD, -2.5 µmol/L [95% CI -5.32 to 0.32]; P = 0.08). There was no change in cystatin C after NAC administration. DISCUSSION: NAC causes a decrease in serum creatinine but not in cystatin C, suggesting analytic interference rather than an effect on kidney function. Supporting this, the effect was greater with non-Jaffe methods of creatinine estimation. Future studies of NAC should use the Jaffe method of creatinine estimation when kidney outcomes are being reported. Even in clinical settings, the use of an enzymatic assay when high doses of intravenous NAC are being used may result in underdiagnosis or delayed diagnosis of acute kidney injury.

Posttraumatic Stress Disorder-Associated Cognitive Deficits on the Repeatable Battery for the Assessment of Neuropsychological Status in a Veteran Population.

BACKGROUND: Posttraumatic stress disorder (PTSD) is a frequent problem of veterans receiving care and is often associated with cognitive deficits. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a well-validated cognitive screening measure often used in the US Department of Veterans Affairs (VA), particularly in neurorehabilitation settings. However, the influence of PTSD on RBANS performance is unclear, particularly within a heterogeneous VA outpatient population in which PTSD and traumatic brain injury (TBI) may not be the primary focus of care. METHODS: Participants included 153 veterans with complex deployment-related health problems, including a diagnosis of PTSD (n = 98) and a history of TBI (n = 92). All veterans completed a targeted cognitive battery that included the Wechsler Test of Adult Reading, the Wechsler Adults Intelligence Scale, measure assessing processing speed, attention, and cognitive flexibility, and RBANS. RESULTS: A diagnosis of PTSD was associated with worse performance on the Story Recall subtest of the RBANS, but not on any other cognitive measures. A diagnosis of mild TBI, or co-occurring PTSD and TBI did not predict cognitive performance on any measures. CONCLUSIONS: The RBANS best captured cognitive deficits associated with PTSD compared with a history of mild TBI or co-occurring mild TBI and PTSD. These findings may provide insight into the interpretation and attribution of cognitive deficits in the veteran population.