Human Diversity of Killer Cell Immunoglobulin-Like Receptors and Human Leukocyte Antigen Class I Alleles and Ebola Virus Disease Outcomes

We investigated the genetic profiles of killer cell immunoglobulin-like receptors (KIRs) in Ebola virus–infected patients. We studied the relationship between KIR–human leukocyte antigen (HLA) combinations and the clinical outcomes of patients with Ebola virus disease (EVD). We genotyped KIRs and HLA class I alleles using DNA from uninfected controls, EVD survivors, and persons who died of EVD. The activating 2DS4–003 and inhibitory 2DL5 genes were significantly more common among persons who died of EVD; 2DL2 was more common among survivors. We used logistic regression analysis and Bayesian modeling to identify 2DL2, 2DL5, 2DS4–003, HLA-B-Bw4-Thr, and HLA-B-Bw4-Ile as probably having a significant relationship with disease outcome. Our findings highlight the importance of innate immune response against Ebola virus and show the association between KIRs and the clinical outcome of EVD.     

Highly Pathogenic Avian Influenza A(H5N8) Virus Spread by Short- and Long-Range Transmission,France, 2016–17

We detected 3 genotypes of highly pathogenic avian influenza A(H5N8) virus in France during winter 2016–17. Genotype A viruses caused dramatic economic losses in the domestic duck farm industry in southwestern France. Our phylogenetic analysis suggests that genotype A viruses formed 5 distinct geographic clusters in southwestern France. In some clusters, local secondary transmission might have been started by a single introduction. The intensity of the viral spread seems to correspond to the density of duck holdings in each production area. To avoid the introduction of disease into an unaffected area, it is crucial that authorities limit the movements of potentially infected birds.     

Animal Reservoirs and Hosts for Emerging Alphacoronaviruses and Betacoronaviruses

The ongoing global pandemic caused by coronavirus disease has once again demonstrated the role of the family Coronaviridae in causing human disease outbreaks. Because severe acute respiratory syndrome coronavirus 2 was first detected in December 2019, information on its tropism, host range, and clinical manifestations in animals is limited. Given the limited information, data from other coronaviruses might be useful for informing scientific inquiry, risk assessment, and decision-making. We reviewed endemic and emerging infections of alphacoronaviruses and betacoronaviruses in wildlife, livestock, and companion animals and provide information on the receptor use, known hosts, and clinical signs associated with each host for 15 coronaviruses detected in humans and animals. This information can be used to guide implementation of a One Health approach that involves human health, animal health, environmental, and other relevant partners in developing strategies for preparedness, response, and control to current and future coronavirus disease threats.     

Components of the Gut Microbiome That Influence Bone Tissue-Level Strength

Modifications to the constituents of the gut microbiome influence bone density and tissue-level strength, but the specific microbial components that influence tissue-level strength in bone are not known. Here, we selectively modify constituents of the gut microbiota using narrow-spectrum antibiotics to identify components of the microbiome associated with changes in bone mechanical and material properties. Male C57BL/6J mice (4 weeks) were divided into seven groups (n = 7–10/group) and had taxa within the gut microbiome removed through dosing with: (i) ampicillin; (ii) neomycin; (iii) vancomycin; (iv) metronidazole; (v) a cocktail of all four antibiotics together (with zero-calorie sweetener to ensure intake); (vi) zero-calorie sweetener only; or (vii) no additive (untreated) for 12 weeks. Individual antibiotics remove only some taxa from the gut, while the cocktail of all four removes almost all microbes. After accounting for differences in geometry, whole bone strength was reduced in animals with gut microbiome modified by neomycin (−28%, p = 0.002) and was increased in the group in which the gut microbiome was altered by sweetener alone (+39%, p < 0.001). Analysis of the fecal microbiota detected seven lower-ranked taxa differentially abundant in animals with impaired tissue-level strength and 14 differentially abundant taxa associated with increased tissue-level strength. Histological and serum markers of bone turnover and trabecular bone volume per tissue volume (BV/TV) did not differ among groups. These findings demonstrate that modifications to the taxonomic components of the gut microbiome have the potential to decrease or increase tissue-level strength of bone independent of bone quantity and without noticeable changes in bone turnover. © 2021 American Society for Bone and Mineral Research (ASBMR).     

Successful 18-h acellular extracorporeal perfusion and replantation of porcine limbs - Histology versus nerve stimulation

The current standard for composite tissue preservation is static cold storage (SCS) and is limited to 6 h until irreversible muscle damage occurs. Extracorporeal perfusion (ECP) is a promising technique for prolonged preservation, however, functional results have been scarcely researched. This article assessed neuromuscular function and compared results to histological alterations to predict muscle damage after ECP. Forelimbs of twelve Dutch landrace pigs were amputated and preserved by 4 h SCS at 4–6 °C (n = 6) or 18 h mid-thermic ECP with University of Wisconsin solution (n = 6). Limbs were replanted and observed for 12 h. Sham surgery was performed on contralateral forelimbs (n = 12). Histology analysis scored four subgroups representing different alterations (higher score equals more damage). Muscle contraction after median nerve stimulation was comparable between ECP, SCS, and sham limbs (P = 0.193). Histology scores were higher in ECP limbs compared to SCS limbs (4.8 vs. 1.5, P = 0.013). This was mainly based on more oedema in these limbs. In-vivo muscle contraction was well preserved after 18 h ECP compared to short SCS, although histology seemed inferior in this group. Histology, therefore, did not correlate to muscle function at 12 h after replantation. This leads to the question whether histology or neuromuscular function is the best predictor for transplant success.     

Glutamine Metabolism in Osteoprogenitors Is Required for Bone Mass Accrual and PTH-Induced Bone Anabolism in Male Mice

Skeletal homeostasis critically depends on the proper anabolic functioning of osteolineage cells. Proliferation and matrix synthesis are highly demanding in terms of biosynthesis and bioenergetics, but the nutritional requirements that support these processes in bone-forming cells are not fully understood. Here, we show that glutamine metabolism is a major determinant of osteoprogenitor function during bone mass accrual. Genetic inactivation of the rate-limiting enzyme glutaminase 1 (GLS1) results in decreased postnatal bone mass, caused by impaired biosynthesis and cell survival. Mechanistically, we uncovered that GLS1-mediated glutamine catabolism supports nucleotide and amino acid synthesis, required for proliferation and matrix production. In addition, glutamine-derived glutathione prevents accumulation of reactive oxygen species and thereby safeguards cell viability. The pro-anabolic role of glutamine metabolism was further underscored in a model of parathyroid hormone (PTH)-induced bone formation. PTH administration increases glutamine uptake and catabolism, and GLS1 deletion fully blunts the PTH-induced osteoanabolic response. Taken together, our findings indicate that glutamine metabolism in osteoprogenitors is indispensable for bone formation. © 2020 American Society for Bone and Mineral Research (ASBMR).     

External beam radiation therapy improves survival in elderly metastatic prostate cancer patients with low PSA

BackgroundIt is unknown, whether metastatic prostate cancer (CaP) patients with intermediate life expectancy (5–10 years) should be considered for external beam radiation therapy (EBRT) to the prostate. We addressed this void.MethodsWithin the Surveillance, Epidemiology, and End Results database (2004–2016), we identified 835 M1a or M1b CaP substaged patients with prostate-specific antigen (PSA) < 20 ng/ml and with intermediate life expectancy (LE) 5 to 10 years, treated with EBRT or no EBRT. Inverse probability of treatment-weighting (IPTW), Kaplan-Meier plots and Cox-regression models (CRMs) were used.ResultsOverall, 179 (21.4%) patients received EBRT and 656 (78.6%) did not. EBRT rates increased from 13.9 to 23.8% (2004–2016; P= 0.04). After IPTW-adjustment, median OS was 45 vs. 35 months, in EBRT vs. no EBRT patients (P < 0.001). In IPTW-adjusted Cox-regression models, EBRT independently predicted lower overall mortality (hazard ratio [HR]: 0.7, CI 0.61–0.89; P= 0.001). After stratification according to M1 substages, EBRT was associated with lower overall mortality in M1a (HR: 0.2, CI 0.05–0.91; P= 0.03) and M1b (HR: 0.7, CI 0.55–0.88; P = 0.003) substages.ConclusionEBRT was associated with lower mortality in metastatic CaP patients with low PSA and intermediate LE (5–10 years). In consequence, greater consideration for EBRT should be given in those patients. However, it is important to consider study limitations until clinical trials confirm the proposed benefit.     

Regional anaesthesia for orthopaedic procedures

Regional anaesthetic techniques are fundamental in the anaesthetic care of orthopaedic patients. They may be used as the primary anaesthetic technique or to provide postoperative pain relief. Compared to general anaesthesia alone, regional techniques can provide superior perioperative analgesia, fewer systemic drug adverse effects such as nausea, vomiting and confusion, and earlier mobilization which can reduce nosocomial complications and facilitate expedited hospital discharge. Disadvantages include block failure, nerve injury, unrecognised injury to the anaesthetised limb, prolonged motor blockade and local anaesthetic toxicity. Preoperative assessment should identify contraindications, document pre-existing neurological deficits, and clarify surgical and perioperative aims. Informed consent should be obtained after a clear explanation of the procedure, its risks, and potential complications. Serious and long-term neurological complications are rare and may be reduced by an awake regional technique, sonographic guidance, regular aspiration and by ensuring low pressure injections. Postoperative follow-up is essential and suspicious neurological findings should be detected, investigated, and managed in an early and timely manner.