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Abstract The demographical history of France remains largely understudied despite its central role toward understanding modern population structure across Western Europe. Here, by exploring publicly available Europe-wide genotype datasets together with the genomes of 3234 present-day and six newly sequenced medieval individuals from Northern France, we found extensive fine-scale population structure across Brittany and the downstream Loire basin and increased population differentiation between the northern and southern sides of the river Loire, associated with higher proportions of steppe vs. Neolithic-related ancestry. We also found increased allele sharing between individuals from Western Brittany and those associated with the Bell Beaker complex. Our results emphasise the need for investigating local populations to better understand the distribution of rare (putatively deleterious) variants across space and the importance of common genetic legacy in understanding the sharing of disease-related alleles between Brittany and people from western Britain and Ireland.

Background Task-sharing of spinal anaesthesia care by non-specialist graduate physicians, termed medical officers (MOs), is commonly practised in rural Indian healthcare facilities to mitigate workforce constraints. We sought to assess whether spinal anaesthesia failure rates of MOs were non-inferior to those of consultant anaesthesiologists (CA) following a standardised educational curriculum.Methods We performed a randomised, non-inferiority trial in three rural hospitals in Tamil Nadu and Chhattisgarh, India. Patients aged over 18 years with low perioperative risk (ASA I & II) were randomised to receive MO or CA care. Prior to the trial, MOs underwent task-based anaesthesia training, inclusive of remotely accessed lectures, simulation-based training and directly observed anaesthetic procedures and intraoperative care. The primary outcome measure was spinal anaesthesia failure with a non-inferiority margin of 5%. Secondary outcome measures consisted of incidence of perioperative and postoperative complications.Findings Between 12 July 2019 and 8 June 2020, a total of 422 patients undergoing surgical procedures amenable to spinal anaesthesia care were randomised to receive either MO (231, 54.7%) or CA care (191, 45.2%). Spinal anaesthesia failure rate for MOs (7, 3.0%) was non-inferior to those of CA (5, 2.6%); difference in success rate of 0.4% (95% CI=0.36–0.43%; p=0.80). Additionally, there were no statistically significant differences observed between the two groups for intraoperative or postoperative complications, or patients’ experience of pain during the procedure.Interpretation This study demonstrates that failure rates of spinal anaesthesia care provided by trained MOs are non-inferior to care provided by CAs in low-risk surgical patients. This may support policy measures that use task-sharing as a means of expanding anaesthesia care capacity in rural Indian hospitals.Trial registration number NCT04438811.

Background While recommendations for the optimal distribution of surgical services in high-income countries (HICs) exist, it is unclear how these translate to resource-limited settings. Given the significant shortage and maldistribution of surgical workforce and infrastructure in many low- and middle-income countries (LMICs), the optimal role of decentralization versus regionalization (centralization) of surgical care is unknown. The aim of this study is to review evidence around interventions aimed at redistributing surgical services in LMICs, to guide recommendations for the ideal organization of surgical services. Methods A narrative-based literature review was conducted to answer this question. Studies published in English between 1997 and 2017 in PubMed, describing interventions to decentralize or regionalize a surgical procedure in a LMIC, were included. Procedures were selected using the Disease Control Priorities’ (DCP3) Essential Surgery Package list. Intervention themes and outcomes were analyzed using a narrative, thematic synthesis approach. Primary outcomes included mortality, complications, and patient satisfaction. Secondary outcomes included input measures: workforce and infrastructure, and process measures: facility-based care, surgical volume, and referral rates. Results Thirty-five studies were included. Nine (33%) of the 27 studies describing decentralization showed an improvement in primary outcomes. The procedures associated with improved outcomes after decentralization included most obstetric, gynecological, and family planning services as well as some minor general surgery procedures. Out of 8 studies on regionalization (centralization), improved outcomes were shown for trauma care in one study and cataract extraction in one study. Conclusion Interventions aimed at decentralizing obstetric care to the district hospital and health center levels have resulted in mortality benefits in several countries. However, more evidence is needed to link service distribution to patient outcomes in order to provide recommendations for the optimal organization of other surgical procedures in LMICs. Considerations for the optimal distribution of surgical procedures should include the acuity of the condition for which the procedure is indicated, anticipated case volume, and required level of technical skills, resources, and infrastructure. These attributes should be considered within the context of each country.

INTRODUCTION:Half of all Ugandans (49%) turn to the private or private-not-for-profit (PNFP) sectors when faced with illness, yet little is known about the capacity of these sectors to deliver surgical services. We partnered with the Ministry of Health to conduct a nationwide mixed-methods evaluation of private and PNFP surgical capacity in Uganda. METHODS:A standardized validated facility assessment tool was utilized to assess facility infrastructure, service delivery, workforce, information management, and financing at a randomized nationally representative sample of 16 private and PNFP hospitals. Semi-structured interviews were conducted to qualitatively explore facilitating factors and barriers to surgical, obstetric and anaesthesia (SOA) care. Hospitals walk-throughs and retrospective reviews of operative logbooks were completed. RESULTS:Hospitals had a median of 177 beds and two operating rooms. Ten hospitals (62.5%) were able to perform all Bellwether procedures (cesarean section, laparotomy and open fracture treatment). Thirty-day surgical volume averaged 102 cases per facility. While most hospitals had electricity, oxygen, running water, and necessary equipment, many reported pervasive shortages of blood, surgical consumables, and anesthetic drugs. Several themes emerged from the qualitative analysis: (1) geographic distance and limited transportation options delay reaching care; (2) workforce shortages impede the delivery of surgical care; (3) emergency and obstetric volume overwhelm the surgical system; (4) medical and non-medical costs delay seeking, reaching, and receiving care; and (5) there is poor coordination of care with insufficient support systems. CONCLUSION:As in Uganda's public sector, barriers to surgery in private and PNFP hospitals in Uganda are cross-cutting and closely tied to resource availability. Critical policy and programmatic developments are essential to build and strengthen Ugandan surgical capacity across all sectors.

CD19-targeting CAR T cells have shown potency in clinical trials targeting B cell leukemia. Although mainly second generation (2G) CARs carrying CD28 or 4-1BB have been investigated in patients, preclinical studies suggest that third generation (3G) CARs with both CD28 and 4-1BB have enhanced capacity. However, little is known about the intracellular signaling pathways downstream of CARs. In the present work, we have analyzed the signaling capacity post antigen stimulation in both 2G and 3G CARs. 3G CAR T cells expanded better than 2G CAR T cells upon repeated stimulation with IL-2 and autologous B cells. An antigen-driven accumulation of CAR+ cells was evident post antigen stimulation. The cytotoxicity of both 2G and 3G CAR T cells was maintained by repeated stimulation. The phosphorylation status of intracellular signaling proteins post antigen stimulation showed that 3G CAR T cells had a higher activation status than 2G. Several proteins involved in signaling downstream the TCR were activated, as were proteins involved in the cell cycle, cell adhesion and exocytosis. In conclusion, 3G CAR T cells had a higher degree of intracellular signaling activity than 2G CARs which may explain the increased proliferative capacity seen in 3G CAR T cells. The study also indicates that there may be other signaling pathways to consider when designing or evaluating new generations of CARs.

Immunotherapy (eg interferon α) in combination with tyrosine kinase inhibitors is currently in clinical trials for treatment of chronic myeloid leukemia (CML). Cancer patients commonly have problems with so called immune escape mechanisms that may hamper immunotherapy. Hence, to study the function of the immune system in CML is of interest. In the present paper we have identified immune escape mechanisms in CML with focus on those that directly hamper T cells since these cells are important to control tumor progression. CML patient samples were investigated for the presence of myeloid-derived suppressor cells (MDSCs), expression of programmed death receptor ligand 1/programmed death receptor 1 (PD-L1/PD-1), arginase 1 and soluble CD25. MDSC levels were increased in samples from Sokal high risk patients (p

Human management of livestock and the presence of different breeds have been discussed in archaeozoology and animal breeding. Traditionally osteometrics has been the main tool in addressing these questions. We combine osteometrics with molecular sex identifications of 104 of 340 morphometrically analysed bones in order to investigate the use of cattle at the Eketorp ringfort on the Öland island in Sweden. The fort is dated to 300-1220/50 A.D., revealing three different building phases. In order to investigate specific patterns and shifts through time in the use of cattle the genetic data is evaluated in relation to osteometric patterns and occurrence of pathologies on cattle metapodia. Males were genotyped for a Y-chromosomal SNP in UTY19 that separates the two major haplogroups, Y1 and Y2, in taurine cattle. A subset of the samples were also genotyped for one SNP involved in coat coloration (MC1R), one SNP putatively involved in resistance to cattle plague (TLR4), and one SNP in intron 5 of the IGF-1 gene that has been associated to size and reproduction.The results of the molecular analyses confirm that the skeletal assemblage from Eketorp is dominated by skeletal elements from females, which implies that dairying was important. Pathological lesions on the metapodia were classified into two groups; those associated with the use as draught animals and those lesions without a similar aetiology. The results show that while bulls both exhibit draught related lesions and other types of lesions, cows exhibit other types of lesions. Interestingly, a few elements from females exhibit draught related lesions. We conclude that this reflects the different use of adult female and male cattle.Although we note some variation in the use of cattle at Eketorp between Iron Age and Medieval time we have found little evidence for the use of different types of animals for specific purposes. The use of specific (genetic) breeds seems to be a phenomenon that developed later than the Eketorp settlement.

Adiponectin is an adipokine with insulin-sensitising actions in vertebrates. Its receptors, AdipoR1 and AdipoR2, are PAQR-type proteins with 7-transmembrane domains and topologies reversed that of GPCR's, i.e. their C-termini are extracellular. We identified three adiponectin receptor homologs in the nematode C. elegans, named paqr-1, paqr-2 and paqr-3. These are differently expressed in the intestine (the main fat-storing tissue), hypodermis, muscles, neurons and secretory tissues, from which they could exert systemic effects. Analysis of mutants revealed that paqr-1 and -2 are novel metabolic regulators in C. elegans and that they act redundantly but independently from paqr-3. paqr-2 is the most important of the three paqr genes: mutants grow poorly, fail to adapt to growth at low temperature, and have a very high fat content with an abnormal enrichment in long (C20) poly-unsaturated fatty acids when combined with the paqr-1 mutation. paqr-2 mutants are also synthetic lethal with mutations in nhr-49, sbp-1 and fat-6, which are C. elegans homologs of nuclear hormone receptors, SREBP and FAT-6 (a Δ9 desaturase), respectively. Like paqr-2, paqr-1 is also synthetic lethal with sbp-1. Mutations in aak-2, the C. elegans homolog of AMPK, or nhr-80, another nuclear hormone receptor gene, suppress the growth phenotype of paqr-2 mutants, probably because they restore the balance between energy expenditure and storage. We conclude that paqr-1 and paqr-2 are receptors that regulate fatty acid metabolism and cold adaptation in C. elegans, that their main function is to promote energy utilization rather than storage, and that PAQR class proteins have regulated metabolism in metazoans for at least 700 million years.