Mind the buffering capacity of citric acid

Many microbial cultures are buffered with citric acid over a pH range of 2.5 to 7.0 since the pKa values for this triprotic acid are 3.13, 4.76 and 6.40, as shown in The Merck Index (pp 330-331, 10th Edition, Martha Windholz, ed.). However, the information about the buffering range of this weak acid is controvertial since the pKa3 value may be 5.40, as specified in Day and Underwood (Quantitative Analysis, 6th Edition, 1991, p. 662. New Jersey: Prentice Hall). With this in mind, we determined the pKa values of citric acid at concentrations ranging from 5 mM to 50 mM, concentrations which are the most employed in buffers for the culture of many microorganisms

Human cortical organoids expose a differential function of GSK3 on cortical neurogenesis

The regulation of the proliferation and polarity of neural progenitors is crucial for the development of the brain cortex. Animal studies have implicated glycogen synthase kinase 3 (GSK3) as a pivotal regulator of both proliferation and polarity, yet the functional relevance of its signaling for the unique features of human corticogenesis remains to be elucidated. We harnessed human cortical brain organoids to probe the longitudinal impact of GSK3 inhibition through multiple developmental stages. Chronic GSK3 inhibition increased the proliferation of neural progenitors and caused massive derangement of cortical tissue architecture. Single-cell transcriptome profiling revealed a direct impact on early neurogenesis and uncovered a selective role of GSK3 in the regulation of glutamatergic lineages and outer radial glia output. Our dissection of the GSK3-dependent transcriptional network in human corticogenesis underscores the robustness of the programs determining neuronal identity independent of tissue architecture

Cardiometabolic multimorbidity is associated with a worse Covid-19 prognosis than individual cardiometabolic risk factors. A multicentre retrospective study (CoViDiab II)

Background: Cardiometabolic disorders may worsen Covid-19 outcomes. We investigated features and Covid-19 outcomes for patients with or without diabetes, and with or without cardiometabolic multimorbidity. Methods: We collected and compared data retrospectively from patients hospitalized for Covid-19 with and without diabetes, and with and without cardiometabolic multimorbidity (defined as ≥ two of three risk factors of diabetes, hypertension or dyslipidaemia). Multivariate logistic regression was used to assess the risk of the primary composite outcome (any of mechanical ventilation, admission to an intensive care unit [ICU] or death) in patients with diabetes and in those with cardiometabolic multimorbidity, adjusting for confounders. Results: Of 354 patients enrolled, those with diabetes (n = 81), compared with those without diabetes (n = 273), had characteristics associated with the primary composite outcome that included older age, higher prevalence of hypertension and chronic obstructive pulmonary disease (COPD), higher levels of inflammatory markers and a lower PaO2/FIO2 ratio. The risk of the primary composite outcome in the 277 patients who completed the study as of May 15th, 2020, was higher in those with diabetes (Adjusted Odds Ratio (adjOR) 2.04, 95%CI 1.12-3.73, p = 0.020), hypertension (adjOR 2.31, 95%CI: 1.37-3.92, p = 0.002) and COPD (adjOR 2.67, 95%CI 1.23-5.80, p = 0.013). Patients with cardiometabolic multimorbidity were at higher risk compared to patients with no cardiometabolic conditions (adjOR 3.19 95%CI 1.61-6.34, p = 0.001). The risk for patients with a single cardiometabolic risk factor did not differ with that for patients with no cardiometabolic risk factors (adjOR 1.66, 0.90-3.06, adjp = 0.10). Conclusions: Patients with diabetes hospitalized for Covid-19 present with high-risk features. They are at increased risk of adverse outcomes, likely because diabetes clusters with other cardiometabolic conditions

Motivational determinants among physicians in Lahore, Pakistan

Introduction: Human resource crises in developing countries have been identified as a critical aspect of poor quality and low accessibility in health care. Worker motivation is an important facet of this issue. Specifically, motivation among physicians, who are an important bridge between health systems and patients, should be considered. This study aimed to identify the determinants of job motivation among physicians, a neglected perspective, especially in developing countries. Methods: A stratified random sample of 360 physicians was selected from public primary, public secondary and public and private tertiary health facilities in the Lahore district, Pakistan. Pretested, semi-structured, self-administered questionnaires were used. For the descriptive part of this study, physicians were asked to report their 5 most important work motivators and demotivators within the context of their current jobs and in general. Responses were coded according to emergent themes and frequencies calculated. Of the 30 factors identified, 10 were classified as intrinsic, 16 as organizational and 4 as socio-cultural. Results: Intrinsic and socio-cultural factors like serving people, respect and career growth were important motivators. Conversely, demotivators across setups were mostly organizational, especially in current jobs. Among these, less pay was reported the most frequently. Fewer opportunities for higher qualifications was a demotivator among primary and secondary physicians. Less personal safety and poor working conditions were important in the public sector, particularly among female physicians. Among private tertiary physicians financial incentives other than pay and good working conditions were motivators in current jobs. Socio-cultural and intrinsic factors like less personal and social time and the inability to financially support oneself and family were more important among male physicians. Conclusion: Motivational determinants differed across different levels of care, sectors and genders. Nonetheless, the important motivators across setups in this study were mostly intrinsic and socio-cultural, which are difficult to affect while the demotivators were largely organizational. Many can be addressed even at the facility level such as less personal safety and poor working conditions. Thus, in resource limited settings a good strategic starting point could be small scale changes that may markedly improve physicians' motivation and subsequently the quality of health care

Interaction of Crohn's Disease Susceptibility Genes in an Australian Paediatric Cohort

Genetic susceptibility is an important contributor to the pathogenesis of Crohn's disease (CD). We investigated multiple CD susceptibility genes in an Australian paediatric onset CD cohort. Newly diagnosed paediatric onset CD patients (n = 72) and controls (n = 98) were genotyped for 34 single nucleotide polymorphisms (SNPs) in 18 genetic loci. Gene-gene interaction analysis, gene-disease phenotype analysis and genetic risk profiling were performed for all SNPs and all genes. Of the 34 SNPs analysed, four polymorphisms on three genes (NOD2, IL23R, and region 3p21) were significantly associated with CD status (p<0.05). All three CD specific paediatric polymorphisms on PSMG1 and TNFRSF6B showed a trend of association with p<0.1. An additive gene-gene interaction involving TLR4, PSMG1, TNFRSF6B and IRGM was identified with CD. Genes involved in microbial processing (TLR4, PSMG1, NOD2) were significantly associated either at the individual level or in gene-gene interactive roles. Colonic disease was significantly associated with disease SNP rs7517847 (IL23R) (p<0.05) and colonic and ileal/colonic disease was significantly associated with disease SNP rs125221868 (IBD5) and SLC22A4 & SLC22A4/5 variants (p<0.05). We were able to demonstrate genetic association of several genes to CD in a paediatric onset cohort. Several of the observed associations have not been reported previously in association with paediatric CD patients. Our findings demonstrate that CD genetic susceptibility in paediatric patients presents as a complex interaction between numerous genes

MKS3/TMEM67 mutations are a major cause of COACH syndrome, a joubert syndrome related disorder with liver involvement

The acronym COACH defines an autosomal recessive condition of Cerebellar vermis hypo/ aplasia, Oligophrenia, congenital Ataxia, Coloboma and Hepatic fibrosis. Patients present the “molar tooth sign”, a midbrain-hindbrain malformation pathognomonic for Joubert Syndrome (JS) and Related Disorders (JSRDs). The main feature of COACH is congenital hepatic fibrosis (CHF), resulting from malformation of the embryonic ductal plate. CHF is invariably found also in Meckel syndrome (MS), a lethal ciliopathy already found to be allelic with JSRDs at the CEP290 and RPGRIP1L genes. Recently, mutations in the MKS3 gene (approved symbol TMEM67), causative of about 7% MS cases, have been detected in few Meckel-like and pure JS patients. Analysis of MKS3 in 14 COACH families identified mutations in 8 (57%). Features such as colobomas and nephronophthisis were found only in a subset of mutated cases. These data confirm COACH as a distinct JSRD subgroup with core features of JS plus CHF, which major gene is MKS3, and further strengthen gene-phenotype correlates in JSRDs