Comparative impact assessment of COVID-19 policy interventions in five South Asian countries using reported and estimated unreported death counts during 2020-2021.

There has been raging discussion and debate around the quality of COVID death data in South Asia. According to WHO, of the 5.5 million reported COVID-19 deaths from 2020-2021, 0.57 million (10%) were contributed by five low and middle income countries (LMIC) countries in the Global South: India, Pakistan, Bangladesh, Sri Lanka and Nepal. However, a number of excess death estimates show that the actual death toll from COVID-19 is significantly higher than the reported number of deaths. For example, the IHME and WHO both project around 14.9 million total deaths, of which 4.5-5.5 million were attributed to these five countries in 2020-2021. We focus our gaze on the COVID-19 performance of these five countries where 23.5% of the world population lives in 2020 and 2021, via a counterfactual lens and ask, to what extent the mortality of one LMIC would have been affected if it adopted the pandemic policies of another, similar country? We use a Bayesian semi-mechanistic model developed by Mishra et al. (2021) to compare both the reported and estimated total death tolls by permuting the time-varying reproduction number (Rt) across these countries over a similar time period. Our analysis shows that, in the first half of 2021, mortality in India in terms of reported deaths could have been reduced to 96 and 102 deaths per million compared to actual 170 reported deaths per million had it adopted the policies of Nepal and Pakistan respectively. In terms of total deaths, India could have averted 481 and 466 deaths per million had it adopted the policies of Bangladesh and Pakistan. On the other hand, India had a lower number of reported COVID-19 deaths per million (48 deaths per million) and a lower estimated total deaths per million (80 deaths per million) in the second half of 2021, and LMICs other than Pakistan would have lower reported mortality had they followed India's strategy. The gap between the reported and estimated total deaths highlights the varying level and extent of under-reporting of deaths across the subcontinent, and that model estimates are contingent on accuracy of the death data. Our analysis shows the importance of timely public health intervention and vaccines for lowering mortality and the need for better coverage infrastructure for the death registration system in LMICs

A leverage points perspective on Arctic Indigenous food systems research: A systematic review

Arctic food systems are increasingly challenged by rapid climate change, loss of food security and subsequent weakening of food sovereignty, and destabilization of Indigenous practices. Despite growing scientific knowledge on Arctic food systems, Indigenous communities continue to struggle with a plethora of sustainability challenges. To develop a systemic understanding of these challenges, we performed a systematic review of 526 articles published between 1998 and 2021 on Arctic Indigenous food systems. We used the leverage points framework to structure our analysis to understand to what extent the existing Western scientific body of literature provides the necessary knowledge to understand the food system characteristics that give rise to the current sustainability challenges. We combined deductive qualitative and inductive quantitative approaches to identify gaps in the systemic understanding of Arctic Indigenous food systems. We characterized existing research across the four levels of systemic depth—parameters, feedbacks, design, intent—and identified promising directions for future research. Our analyses show that research on food systems is clustered within six main domains, we term environmental contaminants, diet and health, food security, food culture and economy, changing socio-ecological systems and marine and coast. Based on our analysis, we identify three directions for future research that we believe to be of particular importance to enable sustainability transformations of Arctic Indigenous food systems: (i) the decolonization of research practices, (ii) acknowledging the significance of systemic interdependencies across shallow and deep leverage points, and (iii) transdisciplinary action-oriented research collaborations directing transformative system interventions

Molecular Classification and Biomarkers of Outcome With Immunotherapy in Extensive-Stage Small-Cell Lung Cancer: Analyses of the CASPIAN Phase 3 Study

BACKGROUND: We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial. METHODS: 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry. RESULTS: In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry. CONCLUSIONS: These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03043872

Consequences Matter : Compassion in Conservation Means Caring for Individuals, Populations and Species

Funding This research received no external funding. Acknowledgments The manuscript benefitted from significant input from Dan Brockington, J.B. Callicott, Peter Coals, Tim Hodgetts, David Macdonald and Jeremy Wilson. Conflicts of Interest The authors declare no conflict of interest.Peer reviewedPublisher PD

Remodeling Lipid Metabolism and Improving Insulin Responsiveness in Human Primary Myotubes

OBJECTIVE: Disturbances in lipid metabolism are strongly associated with insulin resistance and type 2 diabetes (T2D). We hypothesized that activation of cAMP/PKA and calcium signaling pathways in cultured human myotubes would provide further insight into regulation of lipid storage, lipolysis, lipid oxidation and insulin responsiveness. METHODS: Human myoblasts were isolated from vastus lateralis, purified, cultured and differentiated into myotubes. All cells were incubated with palmitate during differentiation. Treatment cells were pulsed 1 hour each day with forskolin and ionomycin (PFI) during the final 3 days of differentiation to activate the cAMP/PKA and calcium signaling pathways. Control cells were not pulsed (control). Mitochondrial content, (14)C lipid oxidation and storage were measured, as well as lipolysis and insulin-stimulated glycogen storage. Myotubes were stained for lipids and gene expression measured. RESULTS: PFI increased oxidation of oleate and palmitate to CO(2) (p<0.001), isoproterenol-stimulated lipolysis (p = 0.01), triacylglycerol (TAG) storage (p<0.05) and mitochondrial DNA copy number (p = 0.01) and related enzyme activities. Candidate gene and microarray analysis revealed increased expression of genes involved in lipolysis, TAG synthesis and mitochondrial biogenesis. PFI increased the organization of lipid droplets along the myofibrillar apparatus. These changes in lipid metabolism were associated with an increase in insulin-mediated glycogen storage (p<0.001). CONCLUSIONS: Activation of cAMP/PKA and calcium signaling pathways in myotubes induces a remodeling of lipid droplets and functional changes in lipid metabolism. These results provide a novel pharmacological approach to promote lipid metabolism and improve insulin responsiveness in myotubes, which may be of therapeutic importance for obesity and type 2 diabetes

A family of dual-activity glycosyltransferasesphosphorylases mediates mannogen turnover and virulence in Leishmania parasites

Parasitic protists belonging to the genus Leishmania synthesize the non-canonical carbohydrate reserve, mannogen, which is composed of β-1,2-mannan oligosaccharides. Here, we identify a class of dual-activity mannosyltransferase/phosphorylases (MTPs) that catalyze both the sugar nucleotide-dependent biosynthesis and phosphorolytic turnover of mannogen. Structural and phylogenic analysis shows that while the MTPs are structurally related to bacterial mannan phosphorylases, they constitute a distinct family of glycosyltransferases (GT108) that have likely been acquired by horizontal gene transfer from gram-positive bacteria. The seven MTPs catalyze the constitutive synthesis and turnover of mannogen. This metabolic rheostat protects obligate intracellular parasite stages from nutrient excess, and is essential for thermotolerance and parasite infectivity in the mammalian host. Our results suggest that the acquisition and expansion of the MTP family in Leishmania increased the metabolic flexibility of these protists and contributed to their capacity to colonize new host niches

Classification schemes for knowledge translation interventions: a practical resource for researchers

Abstract Background As implementation science advances, the number of interventions to promote the translation of evidence into healthcare, health systems, or health policy is growing. Accordingly, classification schemes for these knowledge translation (KT) interventions have emerged. A recent scoping review identified 51 classification schemes of KT interventions to integrate evidence into healthcare practice; however, the review did not evaluate the quality of the classification schemes or provide detailed information to assist researchers in selecting a scheme for their context and purpose. This study aimed to further examine and assess the quality of these classification schemes of KT interventions, and provide information to aid researchers when selecting a classification scheme. Methods We abstracted the following information from each of the original 51 classification scheme articles: authors’ objectives; purpose of the scheme and field of application; socioecologic level (individual, organizational, community, system); adaptability (broad versus specific); target group (patients, providers, policy-makers), intent (policy, education, practice), and purpose (dissemination versus implementation). Two reviewers independently evaluated the methodological quality of the development of each classification scheme using an adapted version of the AGREE II tool. Based on these assessments, two independent reviewers reached consensus about whether to recommend each scheme for researcher use, or not. Results Of the 51 original classification schemes, we excluded seven that were not specific classification schemes, not accessible or duplicates. Of the remaining 44 classification schemes, nine were not recommended. Of the 35 recommended classification schemes, ten focused on behaviour change and six focused on population health. Many schemes (n = 29) addressed practice considerations. Fewer schemes addressed educational or policy objectives. Twenty-five classification schemes had broad applicability, six were specific, and four had elements of both. Twenty-three schemes targeted health providers, nine targeted both patients and providers and one targeted policy-makers. Most classification schemes were intended for implementation rather than dissemination. Conclusions Thirty-five classification schemes of KT interventions were developed and reported with sufficient rigour to be recommended for use by researchers interested in KT in healthcare. Our additional categorization and quality analysis will aid in selecting suitable classification schemes for research initiatives in the field of implementation science

Reducing chronic visuo-spatial neglect following right hemisphere stroke through instrument playing

Unilateral visuo-spatial neglect is a neuropsychological syndrome commonly resulting from right hemisphere stroke at the temporo-parietal junction of the infero-posterior parietal cortex. Neglect is characterized by reduced awareness of stimuli presented on patients' contralesional side of space. Inspired by evidence of increased spatial exploration of patients' left side achieved during keyboard scale-playing, the current study employed a music intervention that involved making sequential goal-directed actions in the neglected part of space, in order to determine whether this would bring about clinically significant improvement in chronic neglect. Two left neglect patients completed an intervention comprising four weekly 30-min music intervention sessions involving playing scales and familiar melodies on chime bars from right to left. Two cancellation tests Mesulam shape, Behavioral Inattention Test (BIT) star, the neglect subtest from the computerized TAP (Test of Attentional Performance) battery, and the line bisection test were administered three times during a preliminary baseline phase, before and after the four intervention sessions during the intervention phase to investigate short-term effects, and 1�week after the last intervention session to investigate whether any changes in performance would persist. Both patients demonstrated significant short-term and longer-lasting improvements on the Mesulam shape cancellation test. One patient also showed longer-lasting effects on the BIT star cancellation test and scored in the normal range 1�week after the intervention. These findings provide preliminary evidence that active music-making with a horizontally aligned instrument may help neglect patients attend more to their affected side

Pathogenic SPTBN1 variants cause an autosomal dominant neurodevelopmental syndrome

SPTBN1 mutations cause a neurodevelopmental syndrome characterized by intellectual disability, language and motor delays, autism, seizures and other features. The variants disrupt beta II-spectrin function and disturb cytoskeletal organization and dynamics. SPTBN1 encodes beta II-spectrin, the ubiquitously expressed beta-spectrin that forms micrometer-scale networks associated with plasma membranes. Mice deficient in neuronal beta II-spectrin have defects in cortical organization, developmental delay and behavioral deficiencies. These phenotypes, while less severe, are observed in haploinsufficient animals, suggesting that individuals carrying heterozygous SPTBN1 variants may also show measurable compromise of neural development and function. Here we identify heterozygous SPTBN1 variants in 29 individuals with developmental, language and motor delays;mild to severe intellectual disability;autistic features;seizures;behavioral and movement abnormalities;hypotonia;and variable dysmorphic facial features. We show that these SPTBN1 variants lead to effects that affect beta II-spectrin stability, disrupt binding to key molecular partners, and disturb cytoskeleton organization and dynamics. Our studies define SPTBN1 variants as the genetic basis of a neurodevelopmental syndrome, expand the set of spectrinopathies affecting the brain and underscore the critical role of beta II-spectrin in the central nervous system