The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding to host receptors including ACE2. An alternate entry receptor for the virus was recently ...proposed to be basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses speculating on the role of this host receptor in viral infection and pathogenesis. Here, we report that we are unable to find evidence supporting the role of basigin as a putative spike binding receptor. Recombinant forms of the SARS-CoV-2 spike do not interact with basigin expressed on the surface of human cells, and by using specialized assays tailored to detect receptor interactions as weak or weaker than the proposed basigin-spike binding, we report no evidence for a direct interaction between the viral spike protein to either of the two common isoforms of basigin. Finally, removing basigin from the surface of human lung epithelial cells by CRISPR/Cas9 results in no change in their susceptibility to SARS-CoV-2 infection. Given the pressing need for clarity on which viral targets may lead to promising therapeutics, we present these findings to allow more informed decisions about the translational relevance of this putative mechanism in the race to understand and treat COVID-19.
Magnetic resonance imaging (MRI) has detected changes in pancreas volume and other characteristics in type 1 and type 2 diabetes. However, differences in MRI technology and approaches across ...locations currently limit the incorporation of pancreas imaging into multisite trials. The purpose of this study was to develop a standardized MRI protocol for pancreas imaging and to define the reproducibility of these measurements. Calibrated phantoms with known MRI properties were imaged at five sites with differing MRI hardware and software to develop a harmonized MRI imaging protocol. Subsequently, five healthy volunteers underwent MRI at four sites using the harmonized protocol to assess pancreas size, shape, apparent diffusion coefficient (ADC), longitudinal relaxation time (T1), magnetization transfer ratio (MTR), and pancreas and hepatic fat fraction. Following harmonization, pancreas size, surface area to volume ratio, diffusion, and longitudinal relaxation time were reproducible, with coefficients of variation less than 10%. In contrast, non-standardized image processing led to greater variation in MRI measurements. By using a standardized MRI image acquisition and processing protocol, quantitative MRI of the pancreas performed at multiple locations can be incorporated into clinical trials comparing pancreas imaging measures and metabolic state in individuals with type 1 or type 2 diabetes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Anti-Müllerian hormone (AMH) is a product of growing ovarian follicles. The concentration of AMH in blood may also reflect the non-growing follicle (NGF) population, i.e. the ovarian reserve, and be ...of value in predicting reproductive lifespan. A full description of AMH production up to the menopause has not been previously reported.
By searching the published literature for AMH concentrations in healthy pre-menopausal females, and using our own data (combined n = 3,260) we have generated and robustly validated the first model of AMH concentration from conception to menopause. This model shows that 34% of the variation in AMH is due to age alone. We have shown that AMH peaks at age 24.5 years, followed by a decline to the menopause. We have also shown that there is a neonatal peak and a potential pre-pubertal peak. Our model allows us to generate normative data at all ages.
These data highlight key inflection points in ovarian follicle dynamics. This first validated model of circulating AMH in healthy females describes a transition period in early adulthood, after which AMH reflects the progressive loss of the NGF pool. The existence of a neonatal increase in gonadal activity is confirmed for females. An improved understanding of the relationship between circulating AMH and age will lead to more accurate assessment of ovarian reserve for the individual woman.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hospital-associated disability (HAD), defined as loss of independence in activities of daily living (ADL) following acute hospitalization, is observed among older adults. The study objective is to ...determine overall prevalence of HAD among older adults hospitalized in acute care, and to assess the impact of study initiation year in moderation of prevalence.
Meta-analysis of data collected from randomized trials, quasi-experimental, and prospective cohort studies. English-language searches to identify included studies were completed February 2018 and updated May 2018 of electronic databases and reference lists of studies and reviews. Included studies were human subjects investigations that measured ADL ≥2 time points before or during and after hospitalization and reported prevalence of ADL decline among older adults.
Acute care hospital units.
Adults aged ≥65 years hospitalized in medical-surgical acute care; total sample size across all included studies was 7375.
Independence in ADL was assessed using the Katz Index of Independence in Activities of Daily Living and Barthel Index of Independence in Activities of Daily Living.
Random effects meta-analysis across included studies identified combined prevalence of HAD as 30% (95% CI 24%, 33%; P < .001). The effect of study initiation year on the prevalence rate was minimal. A large amount of heterogeneity was observed between studies, which may be due in part to nonstandardized measurement of ADL impairment or other methodological differences.
Hospitalization in acute care poses a significant risk to functional independence of older adults, and this risk is unchanged despite shorter lengths of stay. The evidence supports the continued need for hospital-based programs that provide assessment of functional ability and identification of at-risk older adults in order to better treat and prevent HAD.
Metabarcoding can rapidly determine the species composition of bulk samples and thus aids biodiversity and ecosystem assessment. However, it is essential to use primer sets that minimize ...amplification bias among taxa to maximize species recovery. Despite this fact, the performance of primer sets employed for metabarcoding terrestrial arthropods has not been sufficiently evaluated. This study tests the performance of 36 primer sets on a mock community containing 374 insect species. Amplification success was assessed with gradient PCRs and the 21 most promising primer sets selected for metabarcoding. These 21 primer sets were also tested by metabarcoding a Malaise trap sample. We identified eight primer sets, mainly those including inosine and/or high degeneracy, that recovered more than 95% of the species in the mock community. Results from the Malaise trap sample were congruent with the mock community, but primer sets generating short amplicons produced potential false positives. Taxon recovery from both mock community and Malaise trap sample metabarcoding were used to select four primer sets for additional evaluation at different annealing temperatures (40–60 °C) using the mock community. The effect of temperature varied by primer pair but overall it only had a minor effect on taxon recovery. This study reveals the weak performance of some primer sets employed in past studies. It also demonstrates that certain primer sets can recover most taxa in a diverse species assemblage. Thus, based our experimental set up, there is no need to employ several primer sets targeting the same gene region. We identify several suitable primer sets for arthropod metabarcoding, and specifically recommend BF3 + BR2, as it is not affected by primer slippage and provides maximal taxonomic resolution. The fwhF2 + fwhR2n primer set amplifies a shorter fragment and is therefore ideal when targeting degraded DNA (e.g., from gut contents).
Background Repair of the subscapularis with reverse total shoulder arthroplasty (rTSA) is controversial. The purpose of this study is to quantify rTSA outcomes in patients with and without ...subscapularis repair to determine if there is any impact on clinical outcomes. Methods Three hundred forty patients received rTSA and had the subscapularis repaired, whereas 251 patients received rTSA and did not have the subscapularis repaired. The patients were scored preoperatively and at latest follow-up using the Simple Shoulder Test; University of California, Los Angeles; American Shoulder and Elbow Surgeons; Constant; and Shoulder Pain and Disability Index metrics. Motion was also measured. Mean follow-up was 37 months. Results All patients showed significant improvements in pain and function after treatment with rTSA. For both cohorts, American Shoulder and Elbow Surgeons and Constant scores significantly improved, as did range of motion. The repaired cohort had significantly higher postoperative scores as measured by 4 of the 5 metrics and significantly more internal rotation, whereas the non-repaired cohort had significantly more active abduction and passive external rotation. The complication rate was 7.4% (0% dislocations) for the subscapularis-repaired cohort and 6.8% (1.2% dislocations) for the non–subscapularis-repaired cohort. Conclusions Significant clinical improvements were observed for both the subscapularis-repaired and non-repaired cohorts, with some statistical differences observed using a variety of outcome measures. Repair of the subscapularis did not lead to inferior clinical outcomes as predicted by biomechanical models. No difference was noted in the complication or scapular notching rates between cohorts. These clinical results show that rTSA using a lateralized humeral prosthesis delivers reliable clinical improvements with a low risk of instability, regardless of subscapularis repair.
More than 100,000 genetic variants are classified as disease causing in public databases. However, the true penetrance of many of these rare alleles is uncertain and might be over-estimated by ...clinical ascertainment. Here, we use data from 379,768 UK Biobank (UKB) participants of European ancestry to assess the pathogenicity and penetrance of putatively clinically important rare variants. Although rare variants are harder to genotype accurately than common variants, we were able to classify as high quality 1,244 of 4,585 (27%) putatively clinically relevant rare (MAF < 1%) variants genotyped on the UKB microarray. We defined as “clinically relevant” variants that were classified as either pathogenic or likely pathogenic in ClinVar or are in genes known to cause two specific monogenic diseases: maturity-onset diabetes of the young (MODY) and severe developmental disorders (DDs). We assessed the penetrance and pathogenicity of these high-quality variants by testing their association with 401 clinically relevant traits. 27 of the variants were associated with a UKB trait, and we were able to refine the penetrance estimate for some of the variants. For example, the HNF4A c.340C>T (p.Arg114Trp) (GenBank: NM_175914.4) variant associated with diabetes is <10% penetrant by the time an individual is 40 years old. We also observed associations with relevant traits for heterozygous carriers of some rare recessive conditions, e.g., heterozygous carriers of the ERCC4 c.2395C>T (p.Arg799Trp) variant that causes Xeroderma pigmentosum were more susceptible to sunburn. Finally, we refute the previous disease association of RNF135 in developmental disorders. In conclusion, this study shows that very large population-based studies will help refine our understanding of the pathogenicity of rare genetic variants.
Wright et al. discuss the increased reporting of immune checkpoint inhibitor (CPI)-associated diabetes. They analyzed VigiBase, the World Health Organization's database of individual case safety ...reports, and detected 283 cases of new-onset DM from 2014 to April 2018 following treatment with CPI using the following preferred terms according to MedDRA (Medical Dictionary for Regulatory Activities): diabetic ketoacidosis (DKA), diabetic ketosis, type 1 diabetes mellitus, or fulminant type 1 diabetes mellitus; any one of these was sufficient to define CPI-DM. They noted a marked increase in reporting of CPI-DM over this time period, with over 50% of cases reported in 2017. Overall, half of the patients with DM presented in DKA (50.2%); 5.6% of all cases were also on steroids at diagnosis of DM, and 6.4% were on noninsulin diabetes medications in addition to insulin. Prior and/or subsequent cancer therapies are unknown, but no other immunomodulatory medications were reported.
Background Reverse total shoulder arthroplasty (RTSA) has been shown to be an effective treatment for proximal humerus fracture (PHF). This study evaluates outcomes of all patients with PHF treated ...with RTSA as a primary procedure for acute PHF, a delayed primary procedure for symptomatic PHF malunion or nonunion, a revision procedure for failed PHF hemiarthroplasty (HA), or a revision procedure for failed open reduction and internal fixation (ORIF). Methods Patients who underwent RTSA for PHF were evaluated for active range of motion and Shoulder Pain and Disability Index (SPADI), Simple Shoulder Test-12, American Shoulder and Elbow Surgeons (ASES), University of California–Los Angeles (UCLA) shoulder rating scale, Constant, and 12-Item Short Form Health Survey scores. Scaption and external rotation (ER) strength were also assessed. Results RTSA was performed in 49 patients with PHF; 13 patients underwent RTSA for acute PHF, 13 for malunion or nonunion, 12 for failed PHF HA, and 11 for failed PHF ORIF. ER range of motion, SPADI, ASES, UCLA, and Constant scores achieved significance. The acute fracture group significantly outperformed the failed HA group in SPADI, ASES, and UCLA scores. The malunion/nonunion group significantly outperformed the failed HA group in ASES and UCLA scores. The acute fracture and malunion/nonunion groups each had significantly greater ER than the failed HA group. Conclusion RTSA is an effective treatment option for PHF as both a primary and a revision procedure. Primary RTSA outperformed RTSA done as a revision procedure. RTSA for acute PHF is comparable to RTSA for malunions and nonunions. Our outcomes of revision RTSA for failed HA and ORIF are more promising than previously published.
The interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and human host factors enable the virus to propagate infections that lead to Coronavirus Disease 2019 (COVID-19). ...The spike protein is the largest structural component of the virus and mediates interactions essential for infection, including with the primary angiotensin-converting enzyme 2 (ACE2) receptor. We performed two independent cell-based systematic screens to determine whether there are additional proteins by which the spike protein of SARS-CoV-2 can interact with human cells. We discovered that in addition to ACE2, expression of LRRC15 also causes spike protein binding. This interaction is distinct from other known spike attachment mechanisms such as heparan sulfates or lectin receptors. Measurements of orthologous coronavirus spike proteins implied the interaction was functionally restricted to SARS-CoV-2 by accessibility. We localized the interaction to the C-terminus of the S1 domain and showed that LRRC15 shares recognition of the ACE2 receptor binding domain. From analyzing proteomics and single-cell transcriptomics, we identify LRRC15 expression as being common in human lung vasculature cells and fibroblasts. Levels of LRRC15 were greatly elevated by inflammatory signals in the lungs of COVID-19 patients. Although infection assays demonstrated that LRRC15 alone is not sufficient to permit viral entry, we present evidence that it can modulate infection of human cells. This unexpected interaction merits further investigation to determine how SARS-CoV-2 exploits host LRRC15 and whether it could account for any of the distinctive features of COVID-19.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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