Genomics and phenomics of body mass index reveals a complex disease network.

Elevated body mass index (BMI) is heritable and associated with many health conditions that impact morbidity and mortality. The study of the genetic association of BMI across a broad range of common disease conditions offers the opportunity to extend current knowledge regarding the breadth and depth of adiposity-related diseases. We identify 906 (364 novel) and 41 (6 novel) genome-wide significant loci for BMI among participants of European (N~1.1 million) and African (N~100,000) ancestry, respectively. Using a BMI genetic risk score including 2446 variants, 316 diagnoses are associated in the Million Veteran Program, with 96.5% showing increased risk. A co-morbidity network analysis reveals seven disease communities containing multiple interconnected diseases associated with BMI as well as extensive connections across communities. Mendelian randomization analysis confirms numerous phenotypes across a breadth of organ systems, including conditions of the circulatory (heart failure, ischemic heart disease, atrial fibrillation), genitourinary (chronic renal failure), respiratory (respiratory failure, asthma), musculoskeletal and dermatologic systems that are deeply interconnected within and across the disease communities. This work shows that the complex genetic architecture of BMI associates with a broad range of major health conditions, supporting the need for comprehensive approaches to prevent and treat obesity.

A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality.

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P < 0.05) in the joint meta-analysis with the HGI (Ncases = 44,820; Ncontrols = 1,775,827; OR, 0.97 [0.95-1.00]; P = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.

Association of Kidney Comorbidities and Acute Kidney Failure With Unfavorable Outcomes After COVID-19 in Individuals With the Sickle Cell Trait.

Importance: Sickle cell trait (SCT), defined as the presence of 1 hemoglobin beta sickle allele (rs334-T) and 1 normal beta allele, is prevalent in millions of people in the US, particularly in individuals of African and Hispanic ancestry. However, the association of SCT with COVID-19 is unclear. Objective: To assess the association of SCT with the prepandemic health conditions in participants of the Million Veteran Program (MVP) and to assess the severity and sequelae of COVID-19. Design, Setting, and Participants: COVID-19 clinical data include 2729 persons with SCT, of whom 353 had COVID-19, and 129 848 SCT-negative individuals, of whom 13 488 had COVID-19. Associations between SCT and COVID-19 outcomes were examined using firth regression. Analyses were performed by ancestry and adjusted for sex, age, age squared, and ancestral principal components to account for population stratification. Data for the study were collected between March 2020 and February 2021. Exposures: The hemoglobin beta S (HbS) allele (rs334-T). Main Outcomes and Measures: This study evaluated 4 COVID-19 outcomes derived from the World Health Organization severity scale and phenotypes derived from International Classification of Diseases codes in the electronic health records. Results: Of the 132 577 MVP participants with COVID-19 data, mean (SD) age at the index date was 64.8 (13.1) years. Sickle cell trait was present in 7.8% of individuals of African ancestry and associated with a history of chronic kidney disease, diabetic kidney disease, hypertensive kidney disease, pulmonary embolism, and cerebrovascular disease. Among the 4 clinical outcomes of COVID-19, SCT was associated with an increased COVID-19 mortality in individuals of African ancestry (n = 3749; odds ratio, 1.77; 95% CI, 1.13 to 2.77; P = .01). In the 60 days following COVID-19, SCT was associated with an increased incidence of acute kidney failure. A counterfactual mediation framework estimated that on average, 20.7% (95% CI, -3.8% to 56.0%) of the total effect of SCT on COVID-19 fatalities was due to acute kidney failure. Conclusions and Relevance: In this genetic association study, SCT was associated with preexisting kidney comorbidities, increased COVID-19 mortality, and kidney morbidity.

Feasibility of establishing a veterinary marker to total residue in edible tissues with non-radiolabeled study using high-resolution mass spectrometry.

Traditionally, in vivo metabolism and total residue studies in veterinary drug research were conducted using radiolabeled drug where information on metabolite profiles and marker residue to total residue ratio is obtained. The Veterinary International Conference on Harmonisation (VICH) guideline GL46 indicates that the metabolism and residue kinetics in food-producing animals may be documented by an alternative approach, one other than the traditional radiolabeled study. High-resolution mass spectrometry (HRMS) has been widely used in human pharmaceutical R&D from metabolite profiling and identification in early drug discovery to first-in-human (FIH) studies in development. Recent advances in data mining tools have greatly improved the metabolite profiling capability with HRMS. It is now routine to study metabolism using non-radiolabeled samples without missing any major metabolites. In the current paper, we explored the feasibility of conducting non-radiolabeled marker residue studies to obtain metabolism information using HRMS. Metabolite profiles of gamithromycin in edible tissues of sheep treated with 6 mg/kg body weight subcutaneous injections were obtained with HRMS. The semi-quantitative relationship between the level of gamithromycin and the total treatment-related residues was established by determining the percentages of extracted ion chromatograms for metabolites and parent compound residues in each tissue. Major components (gamithromycin and its metabolite, declad) were measured quantitatively using a validated liquid chromatography/tandem mass spectrometry (LC-MS/MS) method. Metabolite profiles in excreta were also obtained and the major components measured quantitatively with a LC-MS/MS method to ensure no major metabolite was missing. Combining previous knowledge of marker residue studies in cattle and swine, as well as an in vitro comparative metabolism study with metabolite data across various species, gamithromycin was designated as the marker residue in sheep edible tissues. The marker to total residue ratios were established using a combination of the semi-quantitative HRMS results and quantitative results with the major components: the marker residue and declad. The pros and cons of the HRMS method as well as the appropriate use of the method for marker residue studies are discussed.

Genome-wide and phenome-wide analysis of ideal cardiovascular health in the VA Million Veteran Program.

BACKGROUND: Genetic studies may help identify causal pathways; therefore, we sought to identify genetic determinants of ideal CVH and their association with CVD outcomes in the multi-population Veteran Administration Million Veteran Program. METHODS: An ideal health score (IHS) was calculated from 3 clinical factors (blood pressure, total cholesterol, and blood glucose levels) and 3 behavioral factors (smoking status, physical activity, and BMI), ascertained at baseline. Multi-population genome-wide association study (GWAS) was performed on IHS and binary ideal health using linear and logistic regression, respectively. Using the genome-wide significant SNPs from the IHS GWAS, we created a weighted IHS polygenic risk score (PRSIHS) which was used (i) to conduct a phenome-wide association study (PheWAS) of associations between PRSIHS and ICD-9 phenotypes and (ii) to further test for associations with mortality and selected CVD outcomes using logistic and Cox regression and, as an instrumental variable, in Mendelian Randomization. RESULTS: The discovery and replication cohorts consisted of 142,404 (119,129 European American (EUR); 16,495 African American (AFR)), and 45,766 (37,646 EUR; 5,366 AFR) participants, respectively. The mean age was 65.8 years (SD = 11.2) and 92.7% were male. Overall, 4.2% exhibited ideal CVH based on the clinical and behavioral factors. In the multi-population meta-analysis, variants at 17 loci were associated with IHS and each had known GWAS associations with multiple components of the IHS. PheWAS analysis in 456,026 participants showed that increased PRSIHS was associated with a lower odds ratio for many CVD outcomes and risk factors. Both IHS and PRSIHS measures of ideal CVH were associated with significantly less CVD outcomes and CVD mortality. CONCLUSION: A set of high interest genetic variants contribute to the presence of ideal CVH in a multi-ethnic cohort of US Veterans. Genetically influenced ideal CVH is associated with lower odds of CVD outcomes and mortality.

Plasma pharmacokinetics, pulmonary disposition, and safety of subcutaneous gamithromycin in alpacas.

The study objective was to determine the disposition of gamithromycin in plasma, peripheral blood polymorphonuclear cells (PMNs), pulmonary epithelial lining fluid (PELF), and bronchoalveolar lavage (BAL) cells in alpacas. A single subcutaneous injection of gamithromycin (6.6 mg/kg) was administered to six healthy adult alpacas. At various time points after administration, gamithromycin concentrations were analyzed via LC-MS/MS in plasma, PMNs, PELF, and BAL cells until Day 14 post-injection. Plasma gamithromycin concentrations were measured in all six alpacas; the remaining three body compartments were analyzed in four alpacas. Gamithromycin rapidly concentrated in blood PMNs, BAL cells, and PELF. Shorter Tmax , and lower Cmax, and AUC were observed in plasma than in the other three compartments. Cmax was highest in BAL cells (26001.80 ± 12400.00 ng/ml) and PMNs (2573.00 ± 963.30 ng/ml) compared to PELF (660.80 ± 413.70 ng/ml) and plasma (452.30 ± 196.20 ng/ml). Mean terminal half-lives were 72.60 ± 14.10 h in plasma, 56.60 ± 10.60 h in PELF, 62.80 ± 85.30 h in PMNs, and 93.60 ± 124.80 h in BAL cells. No injection site reactions occurred. One alpaca developed colic but no other adverse reactions were noted. Overall, gamithromycin was highly concentrated in white blood cells and pulmonary fluids/cells. Clinical utilization of gamithromycin in alpacas should be done with caution until further investigation of potential for colic.

Gamithromycin in sheep: Pharmacokinetics and clinical evaluation against ovine footrot.

In the context of a development program to obtain the market authorization of injectable gamithromycin 15% w/v solution (Zactran®, Boehringer Ingelheim) for use in sheep against footrot, the pharmacokinetic profile of gamithromycin was established and the safety and efficacy of the treatment were confirmed in a multicenter field study in Europe. The basic pharmacokinetic parameters established in healthy young Merino sheep administered gamithromycin at 6 mg/kg body weight based on the analysis of plasma samples which were collected in intervals up to 12 days after subcutaneous injection were: area under the curve until last quantifiable concentration, 8.88 ± 2.33 µg*h/mL; maximum plasma concentration, 448 ± 180 ng/mL; terminal half-life, 42.5 ± 5.25 h. The safety and clinical efficacy against footrot of gamithromycin 15% w/v solution were evaluated in comparison to tilmicosin 30% w/v solution (Micotil®, Elanco) treatment in 364 sheep of various breeds, sex and age from commercial farms in the United Kingdom (2 sites), Germany (3 sites) and France (1 site). Animals were enrolled based on lesions characteristic of footrot and lameness associated with the presence of footrot-related bacterial pathogens and were randomly allocated and treated in a 1:1 ratio with a single subcutaneous dose of gamithromycin or tilmicosin at label dosage (6 or 10 mg/kg body weight, respectively). Lameness and footrot lesions were evaluated at five and 21 days after treatment; the injection site in all animals was examined the day after treatment and followed up daily in the animals with injection site reaction until complete injection site reaction resolution. Samples of 310 and 120 animals tested positive for Dichelobacter nodosus and Fusobacterium necrophorum, respectively, at inclusion, and data of 359 animals were included into the combined analyses (5 animals excluded for unintentional overdosing [1], lack of follow-up [1], concurrent antibiotic medication for non-footrot conditions [3]). Lameness scores at 21 days after treatment demonstrated a significantly (p = 0.0396) better success for the gamithromycin treatment compared to the tilmicosin treatment (97.8% vs. 93.3%). Post-dosing footrot lesion scores followed similar trends of rapid and marked decrease (improvement) for both treatments with similar (p = 0.127) treatment success for the gamithromycin and tilmicosin treatments (97.8% and 96.0%, respectively). Both treatments were safe; injection site reactions noted in 19 gamithromycin- and 25 tilmicosin-treated animals resolved within five days or six days of treatment, respectively. Gamithromycin 15% w/v solution administered once to sheep by subcutaneous injection at 6 mg/kg body weight demonstrated a pharmacokinetic profile similar to that reported previously in sheep and cattle and was confirmed to be a safe and efficacious treatment for naturally occurring ovine footrot in a multicenter clinical field study conducted in Europe.

Gamithromycin in swine: Pharmacokinetics and clinical evaluation against swine respiratory disease.

The pharmacokinetics of gamithromycin were evaluated in 26 male castrated and female crossbred swine administered gamithromycin 15% w/v (Zactran®, Boehringer Ingelheim) intravenously at 6 mg/kg bodyweight or intramuscularly at 3, 6 or 12 mg/kg bodyweight. Blood samples were collected up to Day 10 to establish the plasma profile of gamithromycin, bioavailability and dose proportionality. When administered by intramuscular injection at 6 mg/kg BWT, pharmacokinetic parameters were as follows: area under the curve until last quantifiable plasma concentration, 5.13 ± 0.957 µg*hours/ml; maximum plasma concentration, 960 ± 153 ng/ml at 5 to 15 min; terminal half-life of 94.1 ± 20.4 hr. Absolute bioavailability was 92.2%. Increase in systemic exposure was proportional to the gamithromycin dose level over the range 3-12 mg/kg BWT. No gender-related statistically significant difference in exposure was observed. For clinical evaluation of Zactran® against swine respiratory disease, 305 pigs from six commercial farms in three countries in Europe with signs associated with Actinobacillus pleuropneumoniae and/or Haemophilus parasuis and/or Pasteurella multocida and/or Bordetella bronchiseptica were used. At each site, animals were treated once in a 1:1 ratio with a single intramuscular dose of Zactran® (6 mg gamithromycin/kg bodyweight) or Zuprevo® (4% w/v tildipirosin at 4 mg/kg bodyweight; MSD Animal Health) at the recommended dose respectively. Animals were observed and scored daily for 10 consecutive days for signs of swine respiratory disease (depression, respiration and rectal temperature), and animals presenting signs of clinical swine respiratory disease (Depression Score 3 and/or Respiratory Score 3 associated with Rectal Temperature > 40.0°C) were removed from the study and considered as treatment failure. Animals which remained in the study were individually assessed for 'treatment success' or 'treatment failure' (Depression Score ≥ 1 and Rectal Temperature > 40.0°C or Respiratory Score ≥ 1 and Rectal Temperature > 40.0°C). Using a non-inferiority hypothesis test (non-inferiority margin = 0.10), the proportion of treatment successes in the Zactran® group (97%) was equivalent to or better than that in the Zuprevo® group (93%).

When is protection from impact needed for the face as well as the eyes in occupational environments?

BACKGROUND: The most commonly identified reason for requiring or using occupational eye and face protection is for protection against flying objects. Standards vary on what risk may require protection of the eyes alone and what requires protection for the whole face. Information on the minimum energy transfer for face damage to occur is not well-established. METHODS: The heads of pigs were used as the common model for human skin. A 6 mm steel ball projected at velocities between 45 and 135 m/s was directed at the face area. Examples of impacts were filmed with a high-speed camera and the resulting damage was rated visually on a scale from 1 (no visible damage) to 5 (penetrated the skin and embedded in the flesh). RESULTS: The results for the cheek area indicate that 85 m/s is the velocity above which damage is more likely to occur unless the skin near the lip is included. For damage to the lip area to be avoided, the velocity needs to be 60 m/s or less. CONCLUSION: The present data support a maximum impact velocity of 85 m/s, provided the thinner and more vulnerable skin of the lids and orbital adnexa is protected. If the coverage area does not extend to the orbital adnexa, then the absolute upper limit for the velocity is 60 m/s. At this stage, eye-only protection, as represented by the lowest level of impact test in the standards in the form of a drop ball test, is not in question.

Comparison between orogastric tube/bougie and a suction calibration system for effects on operative duration, staple-line corkscrewing, and esophageal perforation during laparoscopic sleeve gastrectomy.

INTRODUCTION: Placement of a bougie for sleeve sizing during laparoscopic sleeve gastrectomy (LSG) is recommended. We compared this standard with a suction calibration system (SCS) that performs all functions with one insertion, and measured each step's duration. METHODS: Primary LSG was performed using a bougie and SCS in alternating order. Number of tube movements to achieve optimal placement, durations of decompression, leak testing, and overall operative time, and remnant linear measurements were obtained. RESULTS: LSG was performed in 26 patients (15 women, 11 men; mean age 36.8 years; mean BMI 45.3 kg/m(2)). The mean number of tube movements was significantly greater for the bougie than for the SCS (8.13 vs. 3.58; p < 0.0001). Percent reductions achieved using the SCS were: time to full decompression of the stomach, 62% (21 vs. 8 s; p < 0.138); tube placement, 51% (101 vs. 49 s; p < 0.0001); leak testing, 78% (119 vs. 26 s; p < 0.0003); and mean operative duration (from tube insertion to end of stapling), 21% (875 vs. 697 s; p < 0.019). Variance of the staple-line distance, measured from the greater curvature to the staple line, was 1.64 and 0.92 for the bougie and SCS, respectively, indicating a reduction in corkscrewing, for a 43.9% straighter sleeve. CONCLUSION: SCS maintained the gastric wall in place, thereby preventing corkscrewing, and reducing total operating time. Reducing the number of tube insertions may prevent esophageal damage and accidental tube stapling.

A Thickness Calibration Device Is Needed to Determine Staple Height and Avoid Leaks in Laparoscopic Sleeve Gastrectomy.

BACKGROUND: Leaks after sleeve gastrectomy (SG) may be due to a mismatch between staple height and tissue thickness. The aim of this study was to determine the range of gastric thicknesses in three areas of stapling. METHODS: SG was performed using a 40-Fr suction calibration system 4 cm from the pylorus. Measurement of combined gastric walls was accomplished with an applied pressure of 8 g/mm(2) on the fundus, midbody, and antrum. RESULTS: We enrolled 26 SG patients (15 women, 11 men; mean age 36.8 years). Body mass index (BMI) averaged 45.3 kg/m(2) overall, 44.7 kg/m(2) for males and 45.7 kg/m(2) for females. Although male patients had a thicker stomach antrum than female patients (3.12 vs. 3.09 mm), the midbody (2.57 vs. 3.09 mm) and proximal areas (1.67 vs. 1.72 mm) were thicker in female patients. However, some maximum fundus thicknesses were up to 2.83 mm in females and 2.28 mm in males. Some antra were as thick as 4.07 mm in females and 5.39 mm in males. Also, men had a longer average staple line (22.95 vs. 19.90 cm). CONCLUSION: Because of the range of gastric thicknesses, a single staple height cannot be used to appose the full range of gastric wall thicknesses without potentially causing necrosis or poor apposition. To help avoid leaks, a thickness calibration device is needed to determine correct staple height.

Gamithromycin plasma and skin pharmacokinetics in sheep.

This study assessed the plasma kinetics and skin/plasma concentration ratio of the azalide antibiotic gamithromycin (ZACTRAN(®), Merial) in sheep after a single subcutaneous administration at 6 mg/kg bodyweight. Gamithromycin concentrations in plasma samples collected at various intervals up to 21 days following treatment and metacarpal skin obtained from animals at two, five and ten days after treatment were determined by liquid chromatography-tandem mass spectrometry methods. After administration, gamithromycin was rapidly absorbed, and individual maximum plasma concentrations were observed within 6 hours post-dose. Plasma peak concentration was 573 ± 168 ng/ml. The mean area under the plasma concentration versus time curve extrapolated to infinity was 8.00 ± 1.41 µg · hr/ml, and the mean terminal half-life was 34.5 ± 5.4 hours. Gamithromycin skin concentrations were much higher than the plasma concentrations resulting in skin/plasma concentration ratios of approximately 21, 58, and 138 at two, five and ten days post-dose, respectively, demonstrating extensive distribution to skin tissue.

The intravenous and oral pharmacokinetics of afoxolaner used as a monthly chewable antiparasitic for dogs.

The pharmacokinetics of afoxolaner in dogs was evaluated following either intravenous or after oral administration of NEXGARD(®), a soft chewable formulation. Afoxolaner is a member of one of the newest classes of antiparasitic agents, known as antiparasitic isoxazolines. The soft chewable formulation underwent rapid dissolution, and afoxolaner was absorbed quickly following oral administration of the minimum effective dose of 2.5mg/kg, with maximum plasma concentrations (Cmax) of 1,655 ± 332 ng/mL observed 2-6h (Tmax) after treatment. The terminal plasma half-life was 15.5 ± 7.8 days, and oral bioavailability was 73.9%. Plasma concentration-versus-time curves fit a 2-compartment model and increased proportionally with dose over the oral dose range of 1.0-4.0mg/kg, and over the oral dose range from 1.0 to 40 mg/kg. Following an intravenous dose of 1mg/kg, the volume of distribution (Vd) was 2.68 ± 0.55 L/kg, and the systemic clearance was 4.95 ± 1.20 mL/h/kg. Afoxolaner plasma protein binding was >99.9% in dogs. One major metabolite, formed following hydroxylation of afoxolaner, was identified in dog plasma, urine and bile. When afoxolaner is administered orally, there is a strong correlation between afoxolaner plasma concentration and efficacy with EC90 values of 23 ng/mL for Ctenocephalides felis and ≥ 100 ng/mL for Rhipicephalus sanguineus sensu lato and Dermacentor variabilis. The pharmacokinetic properties of afoxolaner are suited for a monthly administration product because the fast absorption and long terminal half-life support a rapid onset of action while ensuring month-long efficacy.

Disposition of gamithromycin in plasma, pulmonary epithelial lining fluid, bronchoalveolar cells, and lung tissue in cattle.

OBJECTIVE: To determine the disposition of gamithromycin in plasma, pulmonary epithelial lining fluid (PELF), bronchoalveolar lavage (BAL) cells, and lung tissue homogenate in cattle. ANIMALS: 33 healthy Angus calves approximately 7 to 8 months of age. PROCEDURES: Calves were randomly assigned to 1 of 11 groups consisting of 3 calves each, which differed with respect to sample collection times. In 10 groups, 1 dose of gamithromycin (6 mg/kg) was administered SC in the neck of each calf (0 hours). The remaining 3 calves were not treated. Gamithromycin concentrations in plasma, PELF, lung tissue homogenate, and BAL cells (matrix) were measured at various points by means of high-performance liquid chromatography with tandem mass spectrometry. RESULTS: Time to maximum gamithromycin concentration was achieved at 1 hour for plasma, 12 hours for lung tissue, and 24 hours for PELF and BAL cells. Maximum gamithromycin concentration was 27.8 µg/g, 17.8 µg/mL, 4.61 µg/mL, and 0.433 µg/mL in lung tissue, BAL cells, PELF, and plasma, respectively. Terminal half-life was longer in BAL cells (125.0 hours) than in lung tissue (93.0 hours), plasma (62.0 hours), and PELF (50.6 hours). The ratio of matrix to plasma concentrations ranged between 4.7 and 127 for PELF, 16 and 650 for lung tissue, and 3.2 and 2,135 for BAL cells. CONCLUSIONS AND CLINICAL RELEVANCE: Gamithromycin was rapidly absorbed after SC administration. Potentially therapeutic concentrations were achieved in PELF, BAL cells, and lung tissue within 30 minutes after administration and persisted for 7 (PELF) to > 15 (BAL cells and lung tissue) days after administration of a single dose.