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Very-low calorie diets (VLCD) and the glucagon-like peptide-1 receptor agonist (GLP1RA) Semaglutide induce significant weight loss and improve glycaemic control in individuals with type 2 diabetes (T2D). This pilot study was conducted to explore the comparative short-term effects of these interventions individually, and in combination, on weight, body composition and metabolic outcomes. Thirty individuals with T2D (age 18–75 years, BMI 27–50 kg m−2) were randomly assigned to receive Semaglutide (SEM), 800 kilocalorie/day VLCD (VLCD), or both in combination (COMB) for 12 weeks. Measurement of weight and glycated haemoglobin (HbA1c), dual energy X-ray absorptiometry, and intravenous glucose tolerance tests (IVGTT) were performed at baseline and post-intervention. Diet diaries were utilised to assess compliance. Insulin first phase response during IVGTT provided a marker of pancreatic beta-cell function, and insulin sensitivity was estimated using HOMA-IR. Significantly greater reductions in body weight and fat mass were observed in VLCD and COMB, than SEM (p < 0.01 v both). VLCD and COMB resulted in a 5.4 and 7 percentage-point greater weight loss than SEM, respectively. HbA1c and fasting glucose reduced significantly in all groups, however fasting insulin and HOMA-IR improved in VLCD and COMB only. Insulin first phase response during IVGTT increased in SEM and COMB, and this increase was significantly greater in COMB than VLCD (p < 0.01). VLCD elicited greater short-term losses of weight and fat mass than Semaglutide. Adding VLCD to Semaglutide stimulated further weight loss than Semaglutide alone. The combination did not yield any additive effects on weight and body composition above VLCD alone, but did provoke greater improvements in pancreatic beta-cell function. Thus, combination of Semaglutide and VLCD warrants further exploration as a novel approach to T2D management. [ABSTRACT FROM AUTHOR]

[Display omitted] Inborn errors of immunity (IEI) often lack specific disease models and personalized management. Signal transducer and activator of transcription (STAT)-1 gain of function (GoF) is such example of an IEI with diverse clinical phenotype with unclear pathomechanisms and unpredictable response to therapy. Limitations in obtaining fresh samples for functional testing and research further highlights the need for patient-specific ex vivo platforms. Using STAT1-GoF as an example IEI, we investigated the potential of patient-derived expanded potential stem cells (EPSC) as an ex vivo platform for disease modeling and personalized treatment. We generated EPSC derived from individual STAT1-GoF patients. STAT1 mutations were confirmed with Sanger sequencing. Functional testing including STAT1 phosphorylation/dephosphorylation and gene expression with or without Janus activating kinase inhibitors were performed. Functional tests were repeated on EPSC lines with GoF mutations repaired by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) editing. EPSC were successfully reprogrammed from STAT1-GoF patients and expressed the same pluripotent makers as controls, with distinct morphologic differences. Patient-derived EPSC recapitulated the functional abnormalities of index STAT1-GoF patients with STAT1 hyperphosphorylation and increased expression of STAT1 and its downstream genes (IRF1, APOL6, and OAS1) after IFN-γ stimulation. Addition of ruxolitinib and baricitinib inhibited STAT1 hyperactivation in STAT1-GoF EPSC in a dose-dependent manner, which was not observed with tofacitinib. Corrected STAT1 phosphorylation and downstream gene expression were observed among repaired STAT1-GoF EPSC cell lines. This proof-of-concept study demonstrates the potential of our patient-derived EPSC platform to model STAT1-GoF. We propose this platform when researching, recapitulating, and repairing other IEI in the future. [ABSTRACT FROM AUTHOR]

Muscle protein synthesis (MPS) and muscle protein breakdown (MPB) are influenced through dietary protein intake and physical (in)activity, which it follows, regulate skeletal muscle (SKM) mass across the lifespan. Following consumption of dietary protein, the bio-availability of essential amino acids (EAA), and primarily leucine (LEU), drive a transient increase in MPS with an ensuing refractory period before the next MPS stimulation is possible (due to the "muscle full" state). At the same time, MPB is periodically constrained via reflex insulin actions. Layering exercise on top of protein intake increases the sensitivity of SKM to EAA, therefore extending the muscle full set-point (∼48 h), to permit long-term remodelling (e.g., hypertrophy). In contrast, ageing and physical inactivity are associated with a premature muscle full set-point in response to dietary protein/EAA and contractile activity. Of all the EAA, LEU is the most potent stimulator of the mechanistic target of rapamycin complex 1 (mTORC1)-signalling pathway, with the phosphorylation of mTORC1 substrates increasing ∼3-fold more than with all other EAA. Furthermore, maximal MPS stimulation is also achieved following low doses of LEU-enriched protein/EAA, negating the need for larger protein doses. As a result, LEU supplementation has been of long term interest to maximise muscle anabolism and subsequent net protein accretion, especially when in tandem with resistance exercise. This review highlights current knowledge vis-à-vis the anabolic effects of LEU supplementation in isolation, and in enriched protein/EAA sources (i.e., EAA and/or protein sources with added LEU), in the context of ageing, exercise and unloading states. [ABSTRACT FROM AUTHOR]

Data on the prognostic value of high-sensitivity C-reactive protein (hs-CRP) levels in patients with chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI) are limited. Patients undergoing PCI at a tertiary center from January 2012 to December 2019 were included. CKD was defined as a glomerular filtration rate (GFR) <60 mL/min/1.73m2 and elevated hs-CRP was defined as >3 mg/L. Acute myocardial infarction (MI), acute heart failure, neoplastic disease, patients undergoing hemodialysis, or hs-CRP >10 mg/L were exclusion criteria. The primary outcome was major adverse cardiac events (MACE), a composite of all-cause death, MI, and target vessel revascularization at 1-year after PCI. Out of 12,410 patients, 3029 (24.4 %) had CKD. Elevated hs-CRP levels were found in 31.8 % of CKD and 25.8 % of no-CKD patients. At 1 year, MACE occurred in 87 (11.0 %) CKD patients with elevated hs-CRP and 163 (9.5 %) with low hs-CRP (adj. HR 1.26, 95 % CI 0.94–1.68); among no-CKD patients, in 200 (10 %) and 470 (8.1 %), respectively (adj. HR 1.21, 95 % CI 1.00–1.45). Hs-CRP was associated with an increased risk of all-cause death in both CKD (Adj. HR 1.92, 95 % CI 1.07–3.44) and no-CKD patients (adj. HR 3.02, 95 % CI 1.74–5.22). There was no interaction between hs-CRP and CKD status. Among patients undergoing PCI without acute MI, elevated hs-CRP values were not associated with a higher risk of MACE at 1 year, but with increased mortality hazards consistently in patients with or without CKD. [Display omitted] • The role of high-sensitivity C-reactive protein (hs-CRP) in percutaneous coronary intervention (PCI) is still uncertain. • In a large PCI registry, 25% of patients had chronic kidney disease (CKD) and about 27% had elevated hs-CRP • Elevated hs-CRP was not associated with higher risk of major adverse cardiac events at 1 year • Elevated hs-CRP was an independent predictor of all-cause death at 1 year • These results were consistent in patients with or without CKD [ABSTRACT FROM AUTHOR]

Cystic fibrosis (CF) is one of the most common life-limiting autosomal-recessive disorders and is caused by genetic defects in the CF transmembrane conductance regulator (CFTR) gene. Some of the features of this multisystem disease can be present in primary immunodeficiency (PID). We hypothesized that a carrier CFTR status might be associated with worse outcome regarding structural lung disease in patients with PID. A within-cohort and population-level statistical genomic analysis of a large European cohort of PID patients was performed using genome sequence data. Genomic analysis of variant pathogenicity was performed. Compared to the general population, p.Phe508del carriage was enriched in lung-related PID. Additionally, carriage of several pathogenic CFTR gene variants were increased in PID associated with structural lung damage compared to PID patients without the structural lung damage. We identified 3 additional biallelic cases, including several variants not traditionally considered to cause CF. Genome sequencing identified cases of CFTR dysfunction in PID, driving an increased susceptibility to infection. Large national genomic services provide an opportunity for precision medicine by interpreting subtle features of genomic diversity when treating traditional Mendelian disorders. [ABSTRACT FROM AUTHOR]

Transcarotid arterial revascularization (TCAR) has gained popularity as an alternative to carotid endarterectomy (CEA) and transfemoral carotid artery stenting (TFCAS), potentially combining the benefits of a minimally invasive approach with a lower risk of procedural stroke compared with TFCAS. Emerging evidence shows TCAR to have excellent perioperative outcomes. However, the cost-effectiveness of TCAR is not well-understood. Incorporating data from Carotid Revascularization Endarterectomy vs Stenting Trial (CREST), the Vascular Quality Initiative Surveillance Project, and local cost data, we compared the cost-effectiveness of these three treatment modalities (TFCAS, CEA, and TCAR) for both symptomatic and asymptomatic carotid stenosis using a Markov state-transition model to quantify lifetime costs in United States dollars and effectiveness in quality-adjusted life-years (QALYs). We accounted for perioperative stroke and myocardial infarction, as well as long-term risks of stroke and restenosis. Based on CREST, we assumed a start age of 69 years and a cost-effectiveness acceptability threshold of $100,000/QALYs gained. Sensitivity analyses were performed. In the base-case scenario, TCAR cost $160,642/QALY gained compared with CEA, greater than the frequently cited $100,000/QALY gained threshold. TFCAS was more expensive and less effective than other strategies, largely due to a greater periprocedural stroke risk. In one-way sensitivity analysis, if TCAR stroke risk was <0.9% (base-case risk, 1.4%), than it was economically favorable compared with CEA at its current procedural cost. Alternatively, if TCAR procedural costs were reduced by approximately $2000 (base-case cost, $15,182), it would also become economically favorable. In a probabilistic sensitivity analysis, varying all parameters simultaneously over distributions, CEA was favored in 80% of model iterations at $100,000/QALY, with TCAR favored in 19%. At current cost and outcomes, TCAR does not meet a traditional cost-effectiveness threshold to replace CEA as the primary treatment modality for carotid stenosis. TFCAS is the least cost-effective strategy for carotid revascularization. Given these observations, TCAR should be limited to select patients, specifically those at high physiologic and anatomic risk from CEA. However, TCAR can become cost-effective if its cost is reduced. Given the current outcomes and cost, CEA remains the most cost-effective treatment for carotid revascularization. [ABSTRACT FROM AUTHOR]

A survey of nearly 1,000 social science students in Latvia was conducted to determine the effects of student employment on academic achievement. Findings show that employment has a significant negative impact on school performance, and this negative effect increases as the number of working hours increases. Reduced class attendance and reduced time spent in independent study were observed.

Despite multiple randomized trials, variation in practice remains regarding the most effective treatment for early-stage, favorable-risk Hodgkin lymphoma. With increasing emphasis on alternative payment models, we investigate the cost-effectiveness of chemotherapy alone versus combined modality therapy (CMT). A Markov model was formed to compared 2 cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) to 2 cycles of ABVD followed by 20 Gy in 10 fractions involved-site radiation therapy. Modalities were compared using the incremental cost-effectiveness ratio, with effectiveness measured in quality-adjusted life years (QALYs) and evaluated with a willingness to pay a threshold of $100,000 per QALY gained. The base case analysis showed that CMT is cost-effective compared with ABVD alone, with an incremental cost-effectiveness ratio of $8028 per QALY gained and an incremental cost of $236 gaining 0.029 QALYs. On sensitivity analyses, the results were the most sensitive to changes in recurrence rates. If the recurrence rate differences were ≥6%, CMT was cost-effective. CMT is a cost-effective strategy for early-stage, favorable-risk Hodgkin lymphoma based on currently available evidence. However, small variations in recurrence-rate estimates dramatically affect strategy cost-effectiveness. [ABSTRACT FROM AUTHOR]

• Childhood vaccination has decreased during the pandemic, potentially leading to increased pneumococcal disease. • As a result, changes to older adult pneumococcal vaccination recommendations could be considered. • Plausible pneumococcal illness increases do not favor heightened PCV13 use in older adults. • Current vaccination recommendations for older adults should not change based on pediatric vaccination rates. The COVID-19 pandemic is causing declines in childhood immunization rates. We examined potential COVID-19-related changes in pediatric 13-valent pneumococcal conjugate vaccine (PCV13) use, subsequent impact on childhood and adult pneumococcal disease rates, and how those changes might affect the favorability of PCV13 use in non-immunocompromised adults aged ≥65 years. A Markov model estimated pediatric disease resulting from decreased PCV13 use in children aged <5 years; absolute decreases from 10 to 50% for 1–2 years duration were examined, assuming no catch-up vaccination and that decreased vaccination led to proportionate increases in PCV13 serotype pneumococcal disease in children and seniors. Integrating pediatric model output into a second Markov model examining 65-year-olds, we estimated the cost effectiveness of older adult pneumococcal vaccination strategies while accounting for potential epidemiologic changes from decreased pediatric vaccination. One year of 10–50% absolute decreases in PCV13 use in <5-year-olds increased pneumococcal disease by an estimated 4–19% in seniors; 2 years of decreased use increased senior rates by 8–38%. In seniors, a >53% increase in pneumococcal disease was required to favor PCV13 use in non-immunocompromised seniors at a $200,000 per quality-adjusted life-year gained threshold, which corresponded to absolute decreases in pediatric PCV13 vaccination of >50% over a 2-year period. In sensitivity analyses, senior PCV13 vaccination was unfavorable if absolute decreases in pediatric PCV13 receipt were within plausible ranges, despite model assumptions favoring PCV13 use in seniors. COVID-19-related decreases in pediatric PCV13 use would need to be both substantial and prolonged to make heightened PCV13 use in non-immunocompromised seniors economically favorable. [ABSTRACT FROM AUTHOR]

Introduction: Use of the 13-valent pneumococcal conjugate vaccine in nonimmunocompromised adults aged ≥65 years is controversial. Higher-valency conjugate vaccines (15-valent and 20-valent ) are under development; their potential cost effectiveness in older adults is unknown, particularly when potential indirect (herd immunity) effects from childhood vaccination are considered.Methods: A Markov model estimated the cost effectiveness of current U.S. recommendations and alternative strategies using currently available and in-development pneumococcal conjugate vaccines in seniors. Separately, strategies using a hypothetical 20-valent vaccine adding the 7 most common disease-causing non-13-valent vaccine serotypes were considered. Sensitivity analyses were performed and alternative scenarios were examined. Data were gathered and the analyses were performed in 2020.Results: In analyses considering only existing and in-development vaccines, sole 20-valent vaccine use cost $172,491/quality-adjusted life year gained compared with current U.S. recommendations under baseline assumptions (equal serotype effectiveness and no childhood vaccination indirect effects). Strategies using 15-valent vaccine were more costly and less effective. When 13-valent/20-valent vaccines were assumed ineffective against pneumococcal serotype 3 and 15-valent vaccine was fully effective, 15-valent vaccine cost $237,431/quality-adjusted life year gained. With indirect effects considered, 15-valent or 20-valent vaccine cost >$449,000/quality-adjusted life year gained. When adding hypothetical 20-valent vaccine under baseline assumptions, hypothetical 20-valent vaccine cost $139,348/quality-adjusted life year gained.Conclusions: In-development pneumococcal conjugate vaccines may be economically unreasonable in older adults, regardless of serotype effectiveness assumptions, particularly when considering potential indirect effects from use of those vaccines in children. Adult vaccines containing high-risk serotypes not contained in childhood vaccines may be more promising. [ABSTRACT FROM AUTHOR]

Background Teduglutide use in pediatric patients with short bowel syndrome can aid in the achievement of enteral autonomy, but with a price of >$400,000 per y. Objective The current study evaluated the cost-effectiveness of using teduglutide in conjunction with offering intestinal transplantation in US pediatric patients with short bowel syndrome. Design A Markov model was used to evaluate the costs (in US dollars) and effectiveness [in quality-adjusted life years (QALYs)] of using teduglutide compared with offering intestinal transplantation. Parameters were estimated from published data where available. The primary effect modeled was the probability of weaning from parenteral nutrition while on teduglutide. Sensitivity analyses were performed on all model parameters. Results Compared with offering only intestinal transplantation, adding teduglutide cost |${\$}$| 124,353/QALY gained. Reducing the cost of the medication by 16% allowed the cost to reach the typical benchmark of |${\$}$| 100,000/QALY gained. Probabilistic sensitivity analysis favored transplantation without offering teduglutide in 68% of iterations at a |${\$}$| 100,000/QALY threshold. Never using teduglutide created an opportunity cost of over |${\$}$| 100,000 per patient. Conclusions At its current price, teduglutide does not provide a cost-effective addition to transplantation in the treatment of pediatric short bowel syndrome. Further work should look to identify cost-reducing strategies, including alternative dosing regimens. [ABSTRACT FROM AUTHOR]

The use of artificial intelligence (AI) computer software to interpret data has become part of our everyday lives, and these AI algorithms are becoming part of our everyday laboratory practices. Many AI tools are beginning to demonstrate their real or potential utility in clinical microbiology laboratory practice. In this introduction to applications of AI in clinical microbiology diagnostic testing, the authors introduce AI and machine learning to those familiar with routine clinical microbiology practice. The discussion explores the role of AI for image analysis including Gram stains, ova and parasite exam, and digital plate reading of bacterial cultures. AI's role in advanced analysis of matrix-assisted laser desorption-ionization/time of flight mass spectrometry (MALDI-TOF) mass spectral data and whole genome sequence data of microbes is also discussed. In the future, computers and clinical laboratory scientists will work more closely together to provide optimal efficiency and quality in clinical microbiology laboratory practice, and this close collaboration between humans and machines is expected to improve patient care. [ABSTRACT FROM AUTHOR]

Symptomatic hypocalcemia is a common complication of total thyroidectomy. Management strategies include responsive treatment initiation for symptoms or prevention by routine or parathyroid hormone-directed calcium supplementation. The comparative cost-effectiveness of even the most often utilized strategies is unclear. A Markov cohort model was created to compare routine supplementation with calcium alone (RS), postoperative parathyroid hormone-based selective supplementation with calcium and calcitriol (SS), and no supplementation (NS) in asymptomatic patients. Patients could remain asymptomatic or develop symptomatic hypocalcemia, managed with outpatient oral supplementation or intravenous calcium infusion and administered either inpatient or outpatient. Effectiveness was measured in quality-adjusted life years. Sensitivity analyses were performed to test model parameter assumptions. RS was the preferred strategy, costing $329/patient and resulting in 0.497 quality-adjusted life years, which was only marginally better compared to SS ($373 for 0.495 quality-adjusted life years). NS was most costly at $4,955 for 0.491 quality-adjusted life years. Preference for RS over SS was sensitive to the probability of developing symptoms and the probability of symptom treatment with intravenous supplementation. On probabilistic sensitivity analysis, RS was preferred in 75.4% of scenarios. After total thyroidectomy, a preventative calcium supplementation strategy should be strongly considered. In this data-driven theoretical model, RS was the least costly option and resulted in an incremental gain in quality-adjusted life years. [ABSTRACT FROM AUTHOR]

Background Adults with short bowel syndrome have a high mortality and significant morbidity due to unsuccessful attempts at rehabilitation that necessitate chronic use of parenteral nutrition (PN). Teduglutide is a novel therapy that promotes intestinal adaptation to improve rehabilitation but with a price >$400,000/y. Objective The current study evaluated the cost-effectiveness of using teduglutide in US adult patients with short bowel syndrome. Methods A Markov model evaluated the costs (in US dollars) and effectiveness (in quality-adjusted life years, or QALYs) of treatment compared with no teduglutide use, with a presumed starting age of 40 y. Parameters were obtained from published data or estimation. The primary effect modeled was the increased likelihood of reduced PN days per week when using teduglutide, leading to greater quality of life and lower PN costs. Sensitivity analyses were performed on all model parameters. Results In the base scenario, teduglutide cost $949,910/QALY gained. In 1-way sensitivity analyses, only reducing teduglutide cost decreased the cost/QALY gained to below the typical threshold of $100,000/QALY gained. Specifically, teduglutide cost would need to be reduced by >65% for it to reach the threshold value. Probabilistic sensitivity analysis favored no teduglutide use in 80% of iterations at a $100,000/QALY threshold. However, teduglutide therapy was cost-saving in 13% of model iterations. Conclusions Teduglutide does not meet a traditional cost-effectiveness threshold as treatment for PN reduction in adult patients with short bowel syndrome compared with standard intestinal rehabilitation. Subpopulations that demonstrate maximum benefit could be cost-saving, and complete nonuse could lead to financial loss. Teduglutide becomes economically reasonable only if its cost is substantially reduced. [ABSTRACT FROM AUTHOR]

Both microvascular decompression (MVD) and Gamma Knife radiosurgery (GKRS) are time-tested treatment modalities for trigeminal neuralgia (TN). There is little evidence in the literature studying these modalities head to head in a cost-effectiveness comparison. To evaluate the cost-effectiveness of MVD compared with GKRS for treating patients with TN. We developed a Markov cost-effectiveness model for the U.S. health care system to account for all costs related to MVD and GKRS as treatment modalities for TN, from the health care system perspective, over a patient lifetime horizon. A base case was estimated using data from previous studies, from our own GKRS experience, and from a current data analysis of patients undergoing MVD. We derived model inputs, including health care costs, survival, and utility estimates, from the literature. We used age-specific, sex-specific, and race-specific mortality from national registries. Costs studied included those for MVD, for GKRS, for treating complications from either procedure, and for medications throughout patient lifetimes. We performed multiple 1-way, 2-way, and probabilistic sensitivity analyses to confirm the robustness of model assumptions and results. The incremental cost-effectiveness ratio (ICER), with a threshold of $50,000 per quality-adjusted life-year (QALY) gained, defined cost-effectiveness. The base case had an ICER of $12,154 per QALY for MVD compared with GKRS. Probabilistic sensitivity (Monte Carlo) analysis showed that MVD was cost-effective in 70% of model iterations. GKRS was favored when the willingness to pay threshold was <$12,000 per QALY gained. In patients medically eligible for either procedure, we found MVD to be the most cost-effective modality to treat TN, primarily because of its reported greater durability. MVD remained the most cost-effective strategy across a broad range of model input values in sensitivity analyses. [ABSTRACT FROM AUTHOR]

• Fish oil supplementation in older females activated angiogenesis-related genes. • Mitochondrial genes in muscle were not influenced by fish oil in older females. • Cocoa supplementation in older males did not alter muscle angiogenesis genes. • 7 day cocoa supplementation in older males caused changes in ECM genes in muscle. Cocoa flavanols and fish oil omega-3 fatty acids are two bio-active nutrients that may improve muscle microvascular function, insulin sensitivity and mitochondrial function in older adults. We assessed changes in gene expression of these pathways in muscle from two nutritional intervention studies in older healthy volunteers: (i) 6-weeks daily fish oil supplementation in older females (3.4 g/d; age: 64.4 ± 0.8 y, BMI: 26.2 ± 0.7 kg/m2), and (ii) 7-day daily cocoa flavanol supplementation in older males (1050 mg/d; age: 70.1 ± 0.9 y, BMI: 25.7 ± 0.6 kg/m2). There was a main effect of 6-weeks fish oil supplementation on angiogenesis gene expression, with no overall changes in mitochondrial or insulin signaling genes. 7-day cocoa supplementation elicited changes in extracellular matrix (ECM) related genes. Thus, the effects of fish oil supplementation on vascular remodeling in skeletal muscle, and ECM remodeling with cocoa supplementation have emerged as areas for future study. [ABSTRACT FROM AUTHOR]

Introduction: Tradeoffs exist between efforts to increase influenza vaccine uptake, including early season vaccination, and potential decreased vaccine effectiveness if protection wanes during influenza season. U.S. older adults increasingly receive vaccination before October. Influenza illness peaks vary from December to April.Methods: A Markov model compared influenza likelihood in older adults with (1) status quo vaccination (August-May) to maximize vaccine uptake or (2) vaccination compressed to October-May (to decrease waning vaccine effectiveness impact). The Centers for Disease Control and Prevention data were used for influenza incidence and vaccination parameters. Prior analyses showed that absolute vaccine effectiveness decreased by 6%-11% per month, favoring later season vaccination. However, compressed vaccination could decrease overall vaccine uptake. Influenza incidence was based on average monthly incidence with earlier and later peaks also examined. Influenza strain distributions from two seasons were modeled in separate scenarios. Sensitivity analyses were performed to test result robustness. Data were collected and analyzed in 2018.Results: Compressed vaccination would avert ≥11,400 influenza cases in older adults during a typical season if it does not decrease vaccine uptake. However, if compressed vaccination decreases vaccine uptake or there is an early season influenza peak, more influenza can result. In probabilistic sensitivity analyses, compressed vaccination was never favored if it decreased absolute vaccine uptake by >5.5% in any scenario; when influenza peaked early, status quo vaccination was favored.Conclusions: Compressed vaccination could decrease waning vaccine effectiveness and decrease influenza cases in older adults. However, this positive effect is negated when early season influenza peaks occur and diminished by decreased vaccine uptake that could occur with shortening the vaccination season. [ABSTRACT FROM AUTHOR]

Background Patients undergoing posterior spinal fusion surgery can lose a substantial amount of blood. This can prolong operative time and require transfusion of allogeneic blood components, which increases the risk of infection and can be the harbinger of serious complications. Does a saline-irrigated bipolar radiofrequency hemostatic sealer (RFHS) help reduce transfusion requirements? Methods In an observational cohort study, we compared transfusion requirements in 30 patients undergoing surgery for adult spinal deformity using the RFHS with that of a historical control group of 30 patients in which traditional hemostasis was obtained with bipolar electrocautery and matched them for blood loss–related variables. Total expense to the hospital for the RFHS, laboratory expenses, and blood transfusions was used for cost calculations. The incremental cost-effectiveness ratio was calculated using the number of blood transfusions avoided as the effectiveness payoff. Results Using a multivariable linear regression model, we found that only estimated blood loss (EBL) was an independent significant predictor of transfusion requirement in both groups. We evaluated the variables of age, EBL, time duration of surgery, preoperative hemoglobin, hemoglobin nadir during surgery, body mass index, length of stay, and number of levels operated on. Mean EBL was greater in the control group (2201 vs. 1416 mL, P = 0.0099). The number of transfusions also was greater in the control group (14.5 vs. 6.5, P = 0.0008). In the cost-effectiveness analysis, we found that the RFHS cost $108 more (compared with not using the RFHS) to avoid 1 unit of blood transfusion. Conclusions The cost-effectiveness analysis revealed that if we are willing to pay $108 to avoid 1 unit of blood transfusion, the use of the RFHS is a reasonable choice to use in open surgery for adult spinal deformity. [ABSTRACT FROM AUTHOR]

Summary Background & aims Impaired anabolic responses to nutrition and exercise contribute to loss of skeletal muscle mass with ageing (sarcopenia). Here, we tested responses of muscle protein synthesis (MPS), in the under represented group of older women, to leucine-enriched essential amino acids (EAA) in comparison to a large bolus of whey protein (WP). Methods Twenty-four older women (65 ± 1 y) received (N = 8/group) 1.5 g leucine-enriched EAA supplements (LEAA_1.5), 6 g LEAA (LEAA_6) in comparison to 40 g WP. A primed constant I.V infusion of 13C 6 -phenylalanine was used to determine MPS at baseline and in response to feeding (FED) and feeding-plus-exercise (FED-EX; 6 × 8 unilateral leg extensions; 75%1-RM). We quantified plasma insulin/AA concentrations, leg femoral blood flow (LBF)/muscle microvascular blood flow (MBF), and anabolic signalling via immunoblotting. Results Plasma insulineamia and EAAemia were greater and more prolonged with WP than LEAA, although LEAA_6 peaked at similar levels to WP. Neither LEAA or WP modified LBF or MBF. FED increased MPS similarly in the LEAA_1.5, LEAA_6 and WP (P < 0.05) groups over 0–2 h, with MPS significantly higher than basal in the LEAA_6 and WP groups only over 0–4 h. However, FED-EX increased MPS similarly across all the groups from 0 to 4 h (P < 0.05). Only p-p70S6K1 increased with WP at 2 h in FED (P < 0.05), and at 2/4 h in FED-EX (P < 0.05). Conclusions In conclusion, LEAA_1.5, despite only providing 0.6 g of leucine, robustly (perhaps maximally) stimulated MPS, with negligible trophic advantage of greater doses of LEAA or even to 40 g WP. Highlighting that composition of EAA, in particular the presence of leucine rather than amount is most crucial for anabolism. [ABSTRACT FROM AUTHOR]

Suboptimal responses to a primary vaccination course have been reported in the elderly, but there is little information regarding the impact of age on responses to booster third doses. Here, we show that individuals 70 years or older (median age 73, range 70–75) who received a primary two-dose schedule with AZD1222 and booster third dose with mRNA vaccine achieve significantly lower neutralizing antibody responses against SARS-CoV-2 spike pseudotyped virus compared with those younger than 70 (median age 66, range 54–69) at 1 month post booster. Impaired neutralization potency and breadth post third dose in the elderly is associated with circulating "atypical" spike-specific B cells expressing CD11c and FCRL5. However, when considering individuals who received three doses of mRNA vaccine, we did not observe differences in neutralization or enrichment in atypical B cells. This work highlights the finding that AdV and mRNA COVID-19 vaccine formats differentially instruct the memory B cell response. [Display omitted] • Two doses AZD1222 and BNT162b2 dose 3 show lower neutralization in older individuals • Reduced neutralization is not related to binding antibody or spike-specific B cell frequency • Reduced neutralization associates with circulating "atypical" B cells in the elderly • T cell responses, especially IL-2 secretion, show age-associated impairment post dose 3 Ferreira et al. show that older individuals vaccinated with two doses of AZD1222 and a third dose with mRNA achieve lower neutralizing antibody responses against SARS-CoV-2 compared with younger individuals and associate with spike-specific atypical B cells. Age-related differences in serum neutralization are not observed following three mRNA vaccine doses. [ABSTRACT FROM AUTHOR]

Aims Cannulated surgical instruments may retain biologic debris after routine cleaning and sterilization. Residual debris after cleaning is assumed to be sterile; however, there is no experimental basis for this assumption. The purpose of this study was to determine the sterility of retained biodebris found within cannulated surgical instruments after autoclave sterilization. Materials and Methods Fifteen cannulated drill bits were used to drill pig scapulae to create a plug of bone that was exposed to a mixture of Bacillus cereus , Pseudomonas aeruginosa , and methicillin-resistant Staphylococcus aureus for 60, 120, or 180 minutes prior to sterilization. The drill bits were autoclave sterilized using standard settings. The “sterilized” bone cores were then incubated in solution and streak-plated on blood agar. Results All 3 positive controls were positive for the experimental bacteria. Two negative controls were positive for contaminant bacteria. A B. cereus strain was recovered from 1 of the experimental group drill bits in the 180-minute group. Pulsed-field gel electrophoresis confirmed that the recovered B. cereus strain was identical to the experimental inoculate. Conclusion Retained biodebris in cannulated drills may not be sterile after standard autoclave sterilization. In addition, delay of surgical instrument reprocessing may increase the risk of resistant contamination. [ABSTRACT FROM AUTHOR]

Background Annual influenza vaccination is a key to preventing widespread influenza infections. Recent reports of influenza vaccine effectiveness (VE) indicate that vaccination in prior years may reduce VE in the current season, suggesting vaccine interference. The purpose of this study is to evaluate the potential effect of repeat influenza vaccinations in the presence of vaccine interference. Methods Using literature-based parameters, an age-structured influenza equation-based transmission model was used to determine the optimal vaccination strategy, while considering the effect of varying levels of interference. Results The model shows that, even in the presence of vaccine interference, revaccination reduces the influenza attack rate and provides individual benefits. Specifically, annual vaccination is a favored strategy over vaccination in alternate years, as long as the level of residual protection is less than 58% or vaccine interference effect is minimal. Furthermore, the negative impact of vaccine interference may be offset by increased vaccine coverage levels. Conclusions Even in the presence of potential vaccine interference, our work provides a population-level perspective on the potential merits of repeated influenza vaccination. This is because repeat vaccination groups had lower attack rates than groups that omitted the second vaccination unless vaccine interference was at very high, perhaps implausible, levels. [ABSTRACT FROM AUTHOR]

Objective Drug-coated balloons (DCBs) may increase durability of endovascular treatment of superficial femoral artery (SFA) disease while avoiding stent-related risks. The purpose of this study was to use meta-analytic data of DCB studies to compare the cost-effectiveness of potential SFA treatments: DCB, drug-eluting stent (DES), plain old balloon angioplasty (POBA), or bare-metal stent (BMS). Methods A search for randomized controlled trials comparing DCB with POBA for treatment of SFA disease was performed. Hazard ratios were extracted to account for the time-to-event primary outcome of target lesion revascularization. Odds ratios were calculated for the secondary outcomes of primary patency (PP) and major amputation. Incorporating pooled data from the meta-analysis, cost-effectiveness analysis, assuming a payer perspective, used a decision model to simulate patency at 1 year and 2 years for each index treatment modality: POBA, BMS, DCB, or DES. Costs were based on current Medicare outpatient reimbursement rates. Results Eight studies (1352 patients) met inclusion criteria for meta-analysis. DCB outperformed POBA with respect to target lesion revascularization over time (pooled hazard ratio, 0.41; P < .001). Risk of major amputation at 12 months was not significantly different between groups. There was significantly improved 1-year PP in the DCB group compared with POBA (pooled odds ratio, 3.30; P < .001). In the decision model, the highest PP at 1 year was seen in the DES index therapy strategy (79%), followed by DCB (74%), BMS (71%), and POBA (64%). With a baseline cost of $9259.39 per patent limb at 1 year in the POBA-first group, the incremental cost per patent limb for each other strategy compared with POBA was calculated: $14,136.10/additional patent limb for DCB, $38,549.80/limb for DES, and $59,748,85/limb for BMS. The primary BMS option is dominated by being more expensive and less effective than DCB. Compared directly with DCB, DES costs $87,377.20 per additional patent limb at 1 year. Based on the projected PP at 1 year in the decision model, the number needed to treat for DES compared with DCB is 20. At current reimbursement, the use of more than two DCBs per procedure would no longer be cost-effective compared with DES. At 2 years, DCB emerges as the most cost-effective index strategy with the lowest overall cost and highest patency rates over that time horizon. Conclusions Current data and reimbursements support the use of DCB as a cost-effective strategy for endovascular intervention in the SFA; any additional effectiveness of DES comes at a high price. Use of more than one DCB per intervention significantly decreases cost-effectiveness. [ABSTRACT FROM AUTHOR]

Summary Postprandial limb blood flow and skeletal muscle microvascular perfusion reduce with aging. Here we tested the impact of providing bolus essential amino acids (EAA) in the presence and absence of the nitric oxide precursor, l -Arginine (ARG), upon skeletal muscle blood flow and anabolism in older men. Healthy young (YOUNG: 19.7 ± 0.5 y, N = 8) and older men (OLD, 70 ± 0.8 y, N = 8) received 15 g EAA or (older only) 15 g EAA +3 g ARG (OLD-ARG, 69.2 ± 1.2 y, N = 8). We quantified responses in muscle protein synthesis (MPS; incorporation of 13 C phenylalanine into myofibrillar proteins), leg and muscle microvascular blood flow (Doppler/contrast enhanced ultrasound (CEUS)) and insulin/EAA in response to EEA ± ARG. Plasma EAA increased similarly across groups but argininemia was evident solely in OLD-ARG (∼320 mmol, 65 min post feed); increases in plasma insulin (to ∼13 IU ml −1 ) were similar across groups. Increases in femoral flow were evident in YOUNG >2 h after feeding; these effects were blunted in OLD and OLD-ARG. Increases in microvascular blood volume (MBV) occurred only in YOUNG and these effects were isolated to the early postprandial phase (+45% at ∼45 min after feeding) coinciding with detectable arterio-venous differences in EAA reflecting net uptake by muscle. Increases in microvascular flow velocity (MFV) and tissue perfusion (MBV × MFV) occurred (∼2 h) in YOUNG and OLD-ARG, but not OLD. Postprandial protein accretion was greater in YOUNG than OLD or OLD-ARG; the latter two groups being indistinguishable. Therefore, ARG rescues aspects of muscle perfusion in OLD without impacting anabolic blunting, perhaps due to the “rescue” being beyond the period of active EAA-uptake. [ABSTRACT FROM AUTHOR]

Tibiotalocalcaneal arthrodesis is a salvage procedure for various end-stage foot and ankle pathologic entities. Several factors are known to influence the union rate after these procedures, including construct rigidity. The data on locked plates as a fixation technique have been inconclusive, with variable union rates reported. One recent study suggested that locking plates can lead to high nonunion rates owing to excessive rigidity. The purpose of the present study was to retrospectively examine the outcomes of locking plate fixation. We retrospectively reviewed the cases of 15 patients (7 [46.7%] male, 8 [53.3%] female) who underwent tibiotalocalcaneal, tibiocalcaneal, or tibiotalar arthrodesis fixed with a locking plate from January 2013 to January 2014. The average age was 52.19 ± 5.8 years. The mean follow-up period was 17 ± 5.3 months. We examined the overall union rates and the effects of smoking, diabetes, and rheumatologic status on the union rate. Of the 15 cases, 11 (73.3%) did not achieve union. The mean time to failure was 10 ± 5.3 months. Age, gender, smoking, diabetes, use of augmentation screws outside the plate, and operating surgeon did not have an effect on the failure rate ( p > .50). In addition, gender, smoking, and diabetes did not predict for nonunion. The high failure rate of rigid locking plate fixation reported might be attributable to the high incidence of smoking and diabetic comorbidities in our study. However, excessive construct rigidity might play an important role. Larger studies are needed to establish more reliable union rates with the use of locking plates in foot and ankle fusion. [ABSTRACT FROM AUTHOR]

Purpose High-dose trivalent inactivated influenza vaccine (HD-IIV3) or recombinant trivalent influenza vaccine (RIV) may increase influenza vaccine effectiveness (VE) in adults with conditions that place them at high risk for influenza complications. This analysis models the public health impact and cost-effectiveness (CE) of these vaccines for 50–64 year-olds. Methods Markov model CE analysis compared 5 strategies in 50–64 year-olds: no vaccination; only standard-dose IIV3 offered (SD-IIV3 only), only quadrivalent influenza vaccine offered (SD-IIV4 only); high-risk patients receiving HD-IIV3, others receiving SD-IIV3 (HD-IIV3 & SD-IIV3); and high-risk patients receiving HD-IIV3, others receiving SD-IIV4 (HD-IIV3 & SD-IIV4). In a secondary analysis, RIV replaced HD-IIV3. Parameters were obtained from U.S. databases, the medical literature and extrapolations from VE estimates. Effectiveness was measured as 3%/year discounted quality adjusted life year (QALY) losses avoided. Results The least expensive strategy was SD-IIV3 only, with total costs of $99.84/person. The SD-IIV4 only strategy cost an additional $0.91/person, or $37,700/QALY gained. The HD-IIV3 & SD-IIV4 strategy cost $1.06 more than SD-IIV4 only, or $71,500/QALY gained. No vaccination and HD-IIV3 & SD-IIV3 strategies were dominated. Results were sensitive to influenza incidence, vaccine cost, standard-dose VE in the entire population and high-dose VE in high-risk patients. The CE of RIV for high-risk patients was dependent on as yet unknown parameter values. Conclusions Based on available data, using high-dose influenza vaccine or RIV in middle-aged, high-risk patients may be an economically favorable vaccination strategy with public health benefits. Clinical trials of these vaccines in this population may be warranted. [ABSTRACT FROM AUTHOR]

Introduction: Decreased live attenuated influenza vaccine (LAIV) effectiveness in the U.S. prompted the Advisory Committee on Immunization Practices in August 2016 to recommend against this vaccine's use. However, overall influenza uptake increases when LAIV is available and, unlike the U.S., LAIV has retained its effectiveness in other countries. These opposing countercurrents create a dilemma.Methods: To examine the potential consequences of the decision to not recommend LAIV, which may result in decreased influenza vaccination coverage in the U.S. population, a Markov decision analysis model was used to examine influenza vaccination options in U.S. children aged 2-8 years. Data were compiled and analyzed in 2016.Results: Using recently observed low LAIV effectiveness values, fewer influenza cases will occur if LAIV is not used compared with having LAIV as a vaccine option. However, having the option to use LAIV may be favored if LAIV effectiveness returns to prior levels or if the absence of vaccine choice substantially decreases overall vaccine uptake.Conclusions: Continued surveillance of LAIV effectiveness and influenza vaccine uptake is warranted, given their importance in influenza vaccination policy decisions. [ABSTRACT FROM AUTHOR]

Certain serum proteins, including C-reactive protein (CRP) and D-dimer, have prognostic value in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Nonetheless, these factors are non-specific, providing limited mechanistic insight into the peripheral blood mononuclear cell (PBMC) populations that drive the pathogenesis of severe COVID-19. To identify cellular phenotypes associated with disease, we performed a comprehensive, unbiased analysis of total and plasma-membrane PBMC proteomes from 40 unvaccinated individuals with SARS-CoV-2, spanning the whole disease spectrum. Combined with RNA sequencing (RNA-seq) and flow cytometry from the same donors, we define a comprehensive multi-omic profile for each severity level, revealing that immune-cell dysregulation progresses with increasing disease. The cell-surface proteins CEACAMs1, 6, and 8, CD177, CD63, and CD89 are strongly associated with severe COVID-19, corresponding to the emergence of atypical CD3+CD4+CEACAM1/6/8+CD177+CD63+CD89+ and CD16+CEACAM1/6/8+ mononuclear cells. Utilization of these markers may facilitate real-time patient assessment by flow cytometry and identify immune populations that could be targeted to ameliorate immunopathology. [Display omitted] • Proteomic analysis of immune cells across the COVID-19 severity spectrum • Both whole-cell and plasma-membrane proteomes are quantified • Surface markers associated with severe COVID-19 include CEACAMs, CD177, CD63, CD89 • Unusual marker-expressing T cell and monocyte populations emerge in severe disease Potts et al. describe a multiplexed proteomic analysis of immune cells obtained from individuals with COVID-19, identifying CEACAMs 1/6/8, CD177, CD63, and CD89 as cell-surface markers upregulated in severe disease. Phenotyping identifies emergence of unusual CD4+ T cell and CD16+ monocyte populations expressing these markers in severe disease. [ABSTRACT FROM AUTHOR]