Does muscle inflammation influence recovery of muscle strength and function in patients undergoing total hip replacement?

BackgroundGenetic markers of muscle inflammation (eg, tumour necrosis factor α [TNFα] and interleukin [IL] 6 are downregulated following repeated transient increases after bouts of exercise. Total hip replacement (THR) typically resolves preoperative pain, although strength deficits of 10–21% persist in the affected hip at 1 year postoperatively. This study assessed whether mRNA expression of TNFα and IL6 in the vastus lateralis (VL) of the operated leg was related to changes in the strength of the operated leg quadriceps in patients following THR.MethodsTen patients were recruited prospectively after ethical approval. Distal VL (5 cm proximal to lateral suprapatellar pouch) biopsy samples were obtained intraoperatively and at 6 weeks postoperatively, with maximal voluntary contraction of the operated leg quadriceps (MVCOLQ) in Newtons (N), assessed preoperatively and at 6 weeks postoperatively. RT-PCR was used to assess mRNA expression in the biopsy samples and associations evaluated with Spearman's correlation coefficient.FindingsMean mRNA relative quotient (RQ) for comparison of 6 week intraoperative VL samples was 6·23 [SD 12·85] for TNFα and 17·10 [47·46] for IL6. Preoperatively, mean MVCOLQ was 188·90 N [76·84] and at 6 weeks it was 217·00 N [53·91]. There was no significant relation between TNFα or IL-6 RQ and absolute MVCOLQ at 6 weeks (r=0·115 [p=0·376] and ?0·491 [p=0·075], respectively). No statistically significant relation existed between TNFα mRNA RQ and the improvement in MVCOLQ at 6 weeks (r=–0·498, p=0·071) nor with IL6 and the same measure (r=0·091, p=0·401).InterpretationThere is a trend to correlation that exists for improvement in MVCOLQ with a reduction in TNFα mRNA expression, as well as between absolute MVCOLQ and reduction in IL-6 mRNA expression at 6 weeks postoperatively. Improvement in muscle strength may be mediated by reduced muscle inflammation and the associated reduction in pain in patients with severe osteoarthritis.FundingWales Deanery and Betsi Cadwaladr University Health Board Small Grants Scheme.     

Estimating SARS-CoV-2 infections from deaths,confirmed cases,tests, and random surveys

There are multiple sources of data giving information about the number of SARS-CoV-2 infections in the population, but all have major drawbacks, including biases and delayed reporting. For example, the number of confirmed cases largely underestimates the number of infections, and deaths lag infections substantially, while test positivity rates tend to greatly overestimate prevalence. Representative random prevalence surveys, the only putatively unbiased source, are sparse in time and space, and the results can come with big delays. Reliable estimates of population prevalence are necessary for understanding the spread of the virus and the effectiveness of mitigation strategies. We develop a simple Bayesian framework to estimate viral prevalence by combining several of the main available data sources. It is based on a discrete-time Susceptible–Infected–Removed (SIR) model with time-varying reproductive parameter. Our model includes likelihood components that incorporate data on deaths due to the virus, confirmed cases, and the number of tests administered on each day. We anchor our inference with data from random-sample testing surveys in Indiana and Ohio. We use the results from these two states to calibrate the model on positive test counts and proceed to estimate the infection fatality rate and the number of new infections on each day in each state in the United States. We estimate the extent to which reported COVID cases have underestimated true infection counts, which was large, especially in the first months of the pandemic. We explore the implications of our results for progress toward herd immunity.

SARS-CoV-2 test data are fraught with biases that obscure the true rate of infection in the population. Lack of access to viral tests, which was particularly pronounced in the early days of the pandemic, in conjunction with selection bias due to asymptomatic and mild infections, yield case counts that tend to underestimate the true number of infections in the population. By the same token, test positivity rates tend to overestimate viral prevalence. Hospitalization rates and emergency room visits do not estimate the overall infection rate and are not comparable between states or counties, or over time. Reported deaths due to COVID are considered less problematic as an estimate of the true death count and provide a more accurate reflection of the course of the pandemic (1).We combine several of the main sources of data relevant to the number of infections using a simple Bayesian model that accounts for the biases and delays in the data. Our model relies on data on deaths due to COVID, confirmed cases, and testing reported by the COVID Tracking Project (2). We use a modified Susceptible–Infected–Removed (SIR) model, a compartmental epidemiological model widely used to simulate the spread of disease in a population. We combine this with a Poisson likelihood for death counts and a normal likelihood for estimates of viral and seroprevalence from random-sample testing surveys conducted in Indiana and Ohio (3, 4).With these data, we infer the infection fatality rate (IFR) and obtain statistically principled estimates of the number of new infections on each day since March 2020 in Indiana and Ohio. We then leverage our results from these states to build a model for confirmed cases that accounts for preferential testing as a function of the cumulative number of tests administered in each state. This allows us to pin down the IFR and infection counts for the vast majority of states that have not conducted representative testing surveys.Our simple Bayesian model takes inspiration from Johndrow et al. (5), although it differs in significant ways. Whereas Johndrow et al. model the effect of social distancing measures by allowing the SIR contact parameter to change prelockdown and postlockdown, we allow it to vary in time to account for fluctuation in the tightening and loosening of restrictions, as well as in adherence to the restrictions. Furthermore, we incorporate testing data, develop a statistical model for preferential testing, and include the IFR as a parameter in the model to be estimated, rather than a fixed constant. Finally, to simplify model implementation, we use a discrete-time SIR model, rather than a continuous-time model based on differential equations.     

Antenatal therapy of Smith-Lemli-Opitz syndrome.

OBJECTIVES: Smith-Lemli-Opitz syndrome (SLOS) is a recessively inherited disorder caused by an inborn error of cholesterol metabolism that results in deficiency of cholesterol and accumulation of the cholesterol precursor, 7-dehydrocholesterol (DHC) and its epimer, 8-DHC. Affected patients present with congenital anomalies, growth restriction, and mental retardation. Postnatal treatment with cholesterol supplementation has been shown to improve plasma sterol levels and has resulted in improved growth and development in many patients. We hypothesized that prenatal supplementation of cholesterol could potentially arrest some of the adverse consequences of cholesterol deficiency at an earlier stage of development. METHODS: SLOS was diagnosed in the third trimester in a fetus initially identified by sonography with intrauterine growth restriction and ambiguous genitalia and confirmed by elevated levels of 7- and 8-DHC in amniotic fluid. Antenatal supplementation of cholesterol was provided by fetal intravenous and intraperitoneal transfusions of fresh frozen plasma (cholesterol level = 219 mg/dl). RESULTS: The in utero transfusions resulted in increased levels of fetal cholesterol, as measured in blood samples obtained by cordocentesis. In addition, fetal red cell mean corpuscular volume rose, which further indicated that the exogenous cholesterol was incorporated into the fetal erythrocytes. CONCLUSIONS: Antenatal treatment of SLOS by cholesterol supplementation is feasible and results in improvement in fetal plasma cholesterol levels and fetal red cell volume. SLOS may be added to the growing list of human genetic disorders for which prenatal diagnosis is available and therapeutic intervention may be possible.     

Intra-stride belt-speed variation affects treadmill locomotion

For overground and treadmill locomotion to be mechanically similar, it is required that the belt speed of the treadmill is constant and the same to that of overground locomotion. Variation of the belt speed during a stride causes exchange of energy between the subject and the treadmill. This might be the cause of different kinematic patterns between overground and treadmill locomotion, which have been reported in literature. The aim of this study was to investigate whether the intra-stride belt-speed is variable, and whether differences in kinematic patterns can be attributed to these variations. Nine subjects walked and ran overground and on two treadmills that were differently susceptible to subjects' braking and accelerating forces. It was found that the speed variations during treadmill locomotion affect the kinematic parameters significantly. The amount of intra-stride belt-speed variation was found to depend on the power of the treadmill and the mass of the subject. Copyright 1998 Elsevier Science B.V.     

Further delineation of cardiac abnormalities in Costello syndrome

We review the cardiac abnormalities in 94 patients (27 new, 67 literature) with Costello syndrome, an increasingly recognized syndrome consisting of increased birth weight, postnatal growth retardation, and distinctive facial, skin, and musculoskeletal features (MIM 218040). A cardiac abnormality was found in 59 (63%) patients, with each of three categories occurring in approximately one-third of patients. A cardiovascular malformation (CVM) was noted in 30%, typically pulmonic stenosis (46% of those with a CVM). Cardiac hypertrophy was reported in 34%, which involved the left ventricle in 50% and was usually consistent with classic hypertrophic cardiomyopathy (HCM). A variety of rhythm disturbances were reported in 33%. Most (74%) were atrial tachycardia that was reported as supraventricular, chaotic, multifocal, or ectopic. Of 31 patients with a rhythm abnormality, 22 (68%) had an additional abnormality, i.e., CVM (4), cardiac hypertrophy (12), or both (6). Nine patients had isolated dysrhythmia, five (56%) of whom died. All of the 12 (13%) patients who died had a cardiac abnormality. One patient died of embryonal rhabdomyosarcoma, but in the remainder, a cardiac cause of death could not be disproved. All patients with Costello syndrome need a baseline cardiology evaluation with echocardiography and Holter monitoring. Additional prospective evaluations, even in patients without apparent cardiac abnormalities, would be prudent, although data are insufficient to propose a specific schedule.     

Altered hematopoietic stem cell development in male B6C3F1 mice following exposure to 1,3-butadiene

The effects of the murine lymphomagen, 1,3-butadiene (BD), on the proliferation and differentiation of hematopoietic stem cells were examined in male B6C3F1 mice. Exposure to 1250 ppm BD for 6 weeks resulted in no demonstrable alteration in the frequency of spleen colony-forming units (CFU-S); however, colonies derived from treated animals were smaller than those from controls. The absence of any difference in the frequency of CFU-GM after 6 weeks exposure suggests that BD produces an alteration in the relative proportion of immature to mature pluripotent stem cells in BD-exposed animals. This was confirmed by the examination of the effects of BD on stem cell development in long-term bone marrow culture. After 14 days, the number of CFU-GM derived from cultures of animals exposed for 6 weeks was reduced compared to controls. However, at 28 days an increase relative to controls was observed. This shift in the course of differentiation of the granulocyte/macrophage precursor cell, as assessed by the CFU-GM, provides further evidence that there is an increase in the relative frequency of primitive or immature stem cells in BD-treated mice. After a 30-31 week exposure to BD, a decrease in the numbers of both CFU-S and CFU-GM was observed. These findings indicate that BD causes alterations in stem cell development and suggest that alterations in bone marrow stem cells may play an essential role in the pathogenesis of BD-induced thymic lymphoma.     

The relationship between an orientation to the future and an orientation to the past: The role of future clarity

Some research shows that people who often contemplate their future tend to be healthier. Yet the burgeoning literature on mindfulness demonstrates that people who are more attuned to their immediate experiences also enjoy many benefits. To reconcile these principles, many scholars recommend that people should distribute their attention, somewhat evenly, across the past, present, and future—but have not clarified how people should achieve this goal. We test the possibility that people who perceive their future as vivid and certain, called future clarity, might be able to both orient their attention to the future as well as experience mindfulness. Specifically, future clarity could diminish the inclination of people to reach decisions prematurely and dismiss information that contradicts these decisions, called need for closure—tendencies that diminish consideration of future consequences and mindfulness, respectively. In this cross‐sectional study, 194 participants completed measures of mindfulness, consideration of future consequences, need for closure, and future clarity. Consistent with hypotheses, future clarity was positively associated with both mindfulness and consideration of future consequences. Need for closure partly mediated these relationships. Accordingly, interventions that empower people to shape and to clarify their future might generate the benefits of both mindfulness and a future orientation.     

Third-line agent selection for patients with type 2 diabetes mellitus uncontrolled with sulfonylureas and metformin

Patients with type 2 diabetes mellitus often begin treatment by taking oral agents, usually metformin or a sulfonylurea, and then progress to the combination of these two agents. Most patients often require three or more agents or a change to an insulin regimen. However, no guidelines are available to aid the clinician in the decision-making process for selecting the third agent. Many options are available for additional therapy, including thiazolidinediones, intermediate- and long-acting insulins, exenatide, and dipeptidyl peptidase-4 inhibitors. Although the American Diabetes Association recommends metformin as first-line therapy, it does not give exact specifications for second- and third-line agents but only summarizes clinical data and options about each therapeutic drug class. Guidelines from the American College of Endocrinology and American Association of Clinical Endocrinologists recommend several options depending on the patient's hemoglobin A(1c) level. Therefore, a standard of care cannot be provided; rather, clinicians must evaluate each patient to ascertain that patient's optimum therapy. In doing so, clinicians need to be familiar with the efficacy, safety, and cost of each agent.     

Allocation of health care resources in the neonatal and perinatal area �CCPS Symposium 1996

There have been publically expressed concerns about the costs and allocation of neonatal and perinatal health care resources in Canada and elsewhere for the past 15 years. This paper reports information from a symposium held during the 1996 Canadian Paediatric Society (CPS) annual meeting sponsored by the CPS Section on Perinatal Medicine. Experts in perinatal epidemiology, health care economics, public policy and finance, and consumer perspectives on the outcomes of neonatal and perinatal intensive care explored the following questions: How should the need for health care resources in the neonatal and perinatal area be objectively determined? When there are competing needs between the maternal-newborn area and other areas, how should these be rationalized? What evidence should be used (or should be available) to support the present use of resources? What evidence should be available (or is needed) to change or introduce new uses of resources? The conclusions indicated that there are no generally accepted methods to determine the allocation of health care resources but that considerations need to include population characteristics, desired outcomes, achievable results, values, ethics, legalities, cost-benefit analyses and political objectives. Information from families and adolescents who required the use of high technology and/or high cost programs will contribute individual, family and societal values that complement cost-efficacy analyses.