Trait groups as management entities in a complex, multispecies reef fishery.

Localized stressors compound the ongoing climate-driven decline of coral reefs, requiring natural resource managers to work with rapidly shifting paradigms. Trait-based adaptive management (TBAM) is a new framework to help address changing conditions by choosing and implementing management actions specific to species groups that share key traits, vulnerabilities, and management responses. In TBAM maintenance of functioning ecosystems is balanced with provisioning for human subsistence and livelihoods. We first identified trait-based groups of food fish in a Pacific coral reef with hierarchical clustering. Positing that trait-based groups performing comparable functions respond similarly to both stressors and management actions, we ascertained biophysical and socioeconomic drivers of trait-group biomass and evaluated their vulnerabilities with generalized additive models. Clustering identified 7 trait groups from 131 species. Groups responded to different drivers and displayed divergent vulnerabilities; human activities emerged as important predictors of community structuring. Biomass of small, solitary reef-associated species increased with distance from key fishing ports, and large, solitary piscivores exhibited a decline in biomass with distance from a port. Group biomass also varied in response to different habitat types, the presence or absence of reported dynamite fishing activity, and exposure to wave energy. The differential vulnerabilities of trait groups revealed how the community structure of food fishes is driven by different aspects of resource use and habitat. This inherent variability in the responses of trait-based groups presents opportunities to apply selective TBAM strategies for complex, multispecies fisheries. This approach can be widely adjusted to suit local contexts and priorities.

Grupos de Atributos como Entidades de Manejo en una Pesquería de Arrecife Compleja y Multiespecie Resumen Los estresantes localizados agravan la continua declinación de los arrecifes de coral causada por el clima, lo que requiere que los administradores de recursos naturales trabajen con paradigmas en constante cambio. El manejo adaptativo basado en caracteres (TBAM, en inglés) es un marco de trabajo nuevo que ayuda a enfrentar las condiciones cambiantes mediante la selección e implementación de acciones de manejo específicas para grupos de especies que comparten atributos, vulnerabilidades y respuestas al manejo esenciales. En el TBAM, el mantenimiento de los ecosistemas funcionales está balanceado con el suministro para la subsistencia humana. Identificamos mediante un agrupamiento jerárquico los grupos basados en atributos de peces para la alimentación en un arrecife de coral del Pacífico. Al plantear que los grupos basados en atributos que desempeñan funciones comparables responden similarmente a los estresantes y las acciones de manejo, determinamos los impulsores biofísicos y socioeconómicos de la biomasa de un grupo de atributos y evaluamos sus vulnerabilidades mediante modelos aditivos generalizados. Identificamos siete grupos de atributos a partir de 131 especies. Los grupos respondieron a diferentes impulsores y desplegaron vulnerabilidades divergentes; las actividades humanas aparecieron como predictores importantes de la estructuración de la comunidad. La biomasa de las especies solitarias asociadas al arrecife incrementó con la distancia desde puertos importantes de pesca y los piscívoros solitarios de gran tamaño exhibieron una declinación en la biomasa junto con la distancia desde un puerto. La biomasa de los grupos también varió en respuesta a los diferentes tipos de hábitat, la presencia o ausencia reportada de actividad pesquera con dinamita y la exposición a la energía del oleaje. Las vulnerabilidades diferenciales de los grupos de atributos revelaron cómo la estructura de la comunidad de peces para la alimentación está impulsada por aspectos diferentes del uso de recursos y del hábitat. Esta variabilidad inherente en las respuestas de los grupos basados en atributos presenta la oportunidad de aplicar estrategias selectivas de manejo basado en atributos en las pesquerías complejas y multiespecie. Este enfoque puede ajustarse abiertamente para adaptarse a los contextos y las prioridades locales.

Improved outcomes in CABG patients with atrial fibrillation associated with surgical left atrial appendage exclusion.

BACKGROUND: We sought to determine the impact of left atrial appendage clip exclusion (LAACE) on coronary artery bypass grafting (CABG) outcomes among patients with pre-existing atrial fibrillation (AF). METHODS: From October 1, 2015 to October 1, 2017, 4210 Medicare beneficiaries with pre-existing AF underwent isolated CABG (i.e., without ablation) with (n = 931) or without (n = 3279) LAACE. Inverse probability of treatment weighting was used to evaluate the effect of concomitant LAACE on short- and long-term outcomes after CABG. Long term risks of thromboembolism and mortality were assessed using competing-risk regression and Cox proportional hazard models. RESULTS: Operative mortality, length of stay, and 30-day readmission did not differ between groups. Thromboembolism risk was 26% lower for the CABG + LAACE group compared with isolated CABG over a 2-year time-to-event analysis (sub hazard ratio [sHR] 0.74, 95% confidence interval [CI] 0.54-1.00, p = .049). There were no differences in ischemic stroke rates. All-cause mortality risk was 45% lower for CABG + LAACE during the late follow-up period (91-730 days; HR 0.55, 95% CI 0.32-0.95, p = .031). The late period annual absolute all-cause mortality rate was 3.7% for CABG + LAACE and 6.9% for isolated CABG. There were lower readmission rates (31% vs. 43%, p < .001) and total inpatient days (4.0 days vs. 7.2 days, p < .01.) for the CABG + LAACE during follow-up. Total hospital in and out-patient treatment costs were similar between groups through one year. CONCLUSIONS: Concomitant LAA exclusion via an epicardial closure device is associated with reduced CABG mortality, thromboembolic events, and readmissions in patients with pre-existing atrial fibrillation.

A Cenozoic record of the equatorial Pacific carbonate compensation depth.

Atmospheric carbon dioxide concentrations and climate are regulated on geological timescales by the balance between carbon input from volcanic and metamorphic outgassing and its removal by weathering feedbacks; these feedbacks involve the erosion of silicate rocks and organic-carbon-bearing rocks. The integrated effect of these processes is reflected in the calcium carbonate compensation depth, which is the oceanic depth at which calcium carbonate is dissolved. Here we present a carbonate accumulation record that covers the past 53 million years from a depth transect in the equatorial Pacific Ocean. The carbonate compensation depth tracks long-term ocean cooling, deepening from 3.0-3.5 kilometres during the early Cenozoic (approximately 55 million years ago) to 4.6 kilometres at present, consistent with an overall Cenozoic increase in weathering. We find large superimposed fluctuations in carbonate compensation depth during the middle and late Eocene. Using Earth system models, we identify changes in weathering and the mode of organic-carbon delivery as two key processes to explain these large-scale Eocene fluctuations of the carbonate compensation depth.

Endovascular Interventions for Femoropopliteal Peripheral Artery Disease: A Network Meta-Analysis of Current Technologies.

PURPOSE: To use network meta-analysis (NMA) to determine the optimal endovascular strategy for management of femoropopliteal peripheral artery disease (PAD) given the lack of multiple prospective randomized trials to guide treatment decisions. MATERIALS AND METHODS: NMA is a new meta-analytic method that permits comparisons among any 2 therapies by combining results of a collection of clinical trials conducted in the same or similar patient population. NMA was used to analyze data from 15 randomized controlled trials (RCTs) and 10 prospective, multicenter, single-arm trials (combined evidence [CE] NMA) that evaluated target lesion revascularization (TLR) for 5 endovascular strategies: bare metal stent (BMS), polymer-covered metal stent (CMS), drug-eluting stent (DES), drug-coated balloon (DCB) and percutaneous transluminal angioplasty (PTA). RESULTS: The RCT and CE NMAs included 2,912 (6,091) patients with 3,151 (6,786) person-years of follow-up. In the CE NMA, DCB provided a statistically significant 68% reduction in TLR compared with PTA and a statistically significant 53% reduction in TLR compared with BMS. BMS, CMS, and DES provided reductions in TLR of 33%, 48%, and 58% compared with PTA, with statistical significance achieved for CMS and DES. The significant reductions in TLR for DCB compared with PTA and BMS were replicated in the RCT NMA. CONCLUSIONS: This NMA demonstrated that DCB provided better reduction in TLR rates compared with PTA and BMS.

Cost effectiveness of radiofrequency microremodeling for stress urinary incontinence.

INTRODUCTION AND HYPOTHESIS: Stress urinary incontinence (SUI) is a common and growing problem among adult women and affects individuals and society through decreased quality of life (QoL), decreased work productivity, and increased health care costs. A new, nonsurgical treatment option has become available for women who have failed conservative therapy, but its cost effectiveness has not been evaluated. This study examined the cost effectiveness of transurethral radiofrequency microremodeling of the female bladder neck and proximal urethra compared with synthetic transobturator tape (TOT), retropubic transvaginal tape (TVT) sling, and Burch colposuspension surgeries for treating SUI. METHODS: A Markov model was used to compare the cost effectiveness of five strategies for treating SUI for patients who had previously failed conservative therapy. The strategies were designed to compare the value of starting with a less invasive treatment. The cost-effectiveness analysis was conducted from the health care system perspective. Efficacy and adverse event rates were obtained from the literature; reimbursement costs were based on Medicare fee schedule. The model cycle was 3 months, with a 3-year time horizon. Single-variable sensitivity analyses were conducted to assess stability of base-case results. RESULTS: Two of the five strategies employed the use of transurethral radiofrequency microremodeling and achieved 17-30 % lower mean costs relative to their comparative sling or Burch strategies. CONCLUSIONS: Superior safety and cost effectiveness are recognized when patients are offered a sequential approach to SUI management that employs transurethral radiofrequency microremodeling before invasive surgical procedures. This sequential approach is consistent with treatment strategies for other conditions and offers a solution for women with SUI who want to avoid the inherent risks and costs of invasive continence surgery.

Corrigendum: Perceptions and experiences of community-based healthcare professionals in the state of Qatar having do not attempt resuscitation discussions during the COVID-19 pandemic.

[This corrects the article DOI: 10.3389/fmed.2023.1232954.].

Perceptions and experiences of community-based healthcare professionals in the state of Qatar having do not attempt resuscitation discussions during the COVID-19 pandemic.

Introduction: The values and attitudes of healthcare professionals influence their handling of "do-not-attempt-resuscitation" (DNAR) orders, as does that of the families they interact with. The aim of this study was to describe attitudes, perceptions, and practices among community-based medical practitioners towards discussing cardiopulmonary resuscitation and DNAR orders with patients and their relatives, and to investigate if the COVID-19 pandemic affected their practice in having these discussions. Methods: This is a researcher-developed online survey-based study which aimed to recruit a convenience sample of respondents from a total population of 106 healthcare professionals working for the Mobile Healthcare Service (MHS), Hamad Medical Corporation Ambulance Service in the State of Qatar. Results: 33 family physicians, 38 nurses, and 20 paramedics (n = 91) responded to the questionnaire, of who around 40, 8, and 50%, respectively, had engaged in Do Not Attempt Resuscitation discussions during their work with MHS. 15% of physicians who had experience with Do Not Attempt Resuscitation discussions in Qatar felt that the family or patient were not open to having such discussions. 90% of paramedics thought that Do Not Attempt Resuscitation was a taboo topic for their patients in Qatar, and this view was shared by 75% of physicians and 50% of nurses. Per the responses, the COVID-19 pandemic had not affected the likelihood of most of the physicians or nurses (and 50% of the paramedics) identifying patients with whom having a Do Not Attempt Resuscitation discussion would be clinically appropriate. Discussion: Overall, for all three groups, the COVID-19 pandemic did not affect the likelihood of identifying patients with whom a Do Not Attempt Resuscitation discussion would be clinically appropriate. We found that the greatest barriers in having Do Not Attempt Resuscitation discussions were perceived to be the religious or cultural beliefs of the patient and/or their family, along with the factor of feeling the staff member did not know the patient or their family well enough. All three groups said they would be more likely to have a conversation about Do Not Attempt Resuscitation if barriers were addressed.

Trends in quality during medical home transformation.

PURPOSE We describe changes over time in performance on measures of technical quality and patient experience as a group of primary care clinics transformed themselves into level III patient-centered medical homes. METHODS A group of 21 Minnesota primary care clinics achieving level III recognition as medical homes by the National Committee for Quality Assurance has been tracking a variety of quality and patient satisfaction measures for years. We analyzed trends in these measures and compared them with those of other medical groups in the community to estimate what we might expect as other primary care sites gear up to achieve medical home status. RESULTS The clinics in this group achieved a 1% to 3% increase per year in patient satisfaction and a 2% to 7% increase per year in performance on quality measures for diabetes, coronary artery disease, preventive services, and generic medication use. When compared with the average for other medical groups in the region, the rates of increase were greater for satisfaction, but similar for the quality measures. CONCLUSIONS Achieving medical home recognition was associated with improvements in quality and patient satisfaction for these clinics, but the rate of improvement is slow and does not always exceed levels in the surrounding community in Minnesota (which are also improving). Expectations for large and rapid change are probably unrealistic.

Dysferlin associates with the developing T-tubule system in rodent and human skeletal muscle.

Mutations in the dysferlin gene cause limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, and distal anterior compartment myopathy. Dysferlin mainly localizes to the sarcolemma in mature skeletal muscle where it is implicated in membrane fusion and repair. In different forms of muscular dystrophy, a predominantly cytoplasmic localization of dysferlin can be observed in regenerating myofibers, but the subcellular compartment responsible for this labeling pattern is not yet known. We have previously demonstrated an association of dysferlin with the developing T-tubule system in vitro. To investigate the role of dysferlin in adult skeletal muscle regeneration, we studied dysferlin localization at high resolution in a rat model of regeneration and found that the subcellular labeling of dysferlin colocalizes with the developing T-tubule system. Furthermore, ultrastructural analysis of dysferlin-deficient muscle revealed primary T-tubule anomalies similar to those seen in caveolin-3-deficient muscle. These findings indicate that dysferlin is necessary for correct T-tubule formation, and dysferlin-deficient skeletal muscle is characterized by abnormally configured T-tubules.

Monte Carlo simulations of single- and multistep enzyme-catalyzed reaction sequences: effects of diffusion, cell size, enzyme fluctuations, colocalization, and segregation.

Following the discovery of slow fluctuations in the catalytic activity of an enzyme in single-molecule experiments, it has been shown that the classical Michaelis-Menten (MM) equation relating the average enzymatic velocity and the substrate concentration may hold even for slowly fluctuating enzymes. In many cases, the average velocity is that given by the MM equation with time-averaged values of the fluctuating rate constants and the effect of enzyme fluctuations is simply averaged out. The situation is quite different for a sequence of reactions. For colocalization of a pair of enzymes in a sequence to be effective in promoting reaction, the second must be active when the first is active or soon after. If the enzymes are slowly varying and only rarely active, the product of the first reaction may diffuse away before the second enzyme is active, and colocalization may have little value. Even for single-step reactions the interplay of reaction and diffusion with enzyme fluctuations leads to added complexities, but for multistep reactions the interplay of reaction and diffusion, cell size, compartmentalization, enzyme fluctuations, colocalization, and segregation is far more complex than for single-step reactions. In this paper, we report the use of stochastic simulations at the level of whole cells to explore, understand, and predict the behavior of single- and multistep enzyme-catalyzed reaction systems exhibiting some of these complexities. Results for single-step reactions confirm several earlier observations by others. The MM relationship, with altered constants, is found to hold for single-step reactions slowed by diffusion. For single-step reactions, the distribution of enzymes in a regular grid is slightly more effective than a random distribution. Fluctuations of enzyme activity, with average activity fixed, have no observed effects for simple single-step reactions slowed by diffusion. Two-step sequential reactions are seen to be slowed by segregation of the enzymes for each step, and results of the calculations suggest limits for cell size. Colocalization of enzymes for a two-step sequence is seen to promote reaction, and rates fall rapidly with increasing distance between enzymes. Low frequency fluctuations of the activities of colocalized enzymes, with average activities fixed, can greatly reduce reaction rates for sequential reactions.

Association of Ambulatory Ability on Complications and Medical Costs in Patients with Traumatic Spinal Cord Injury: A Decision-analytic Model.

Purpose  The objective of this study was to determine the independent association of ambulatory ability with complications and medical costs in patients with spinal cord injury (SCI). Methods Patients with SCI between T1-T12 enrolled in the National Spinal Cord Injury Database (NSCID) provided a minimum one-year follow-up. Covariate-adjusted annual rates of important medical complications (pressure sore, urinary tract infection, hospitalization) and associated medical costs were determined over five years post-injury.  Results A total of 1,753 patients provided data at one-year follow-up and 1,340 patients provided five-year data. At one-year post-injury, 82% of patients were non-ambulatory and 18% were ambulatory. After adjusting for important covariates, ambulatory status was associated with a lower annual probability of urinary tract infection (43% vs. 68%), pressure sore (12% vs. 35%), and hospitalization (23% vs. 34%). Covariate-adjusted base-case medical costs due to urinary tract infection, pressure sore, and hospitalization were 34% lower in ambulatory vs. non-ambulatory patients ($31,358 vs. $47,266) over five years. Probabilistic sensitivity analyses confirmed the base-case results. Conclusion In spinal cord-injured individuals, the ability to ambulate is independently associated with lower complication risks and associated medical costs over the five-year period following injury. Long-term clinical benefit and cost savings may be realized with assisted or unassisted ambulation in spinal cord-injured patients.

Comparison of perioperative costs with fast-track vs standard endovascular aneurysm repair.

BACKGROUND: Perioperative health care utilization and costs in patients undergoing elective fast-track vs standard endovascular aneurysm repair (EVAR) remain unclear. METHODS: The fast-track EVAR group included patients treated with a 14 Fr stent graft, bilateral percutaneous access, no general anesthesia or intensive care monitoring, and next-day hospital discharge. The standard EVAR group was identified from Medicare administrative claims using a matching algorithm to adjust for imbalances in patient characteristics. Hospital outcomes included operating room time, intensive care monitoring, hospital stay, secondary interventions, and major adverse events (MAEs). Perioperative outcomes occurring from hospital discharge to 30 days postdischarge included MAE, secondary interventions, and unrelated readmissions. RESULTS: Among 1000 matched patients (250 fast-track; 750 standard), hospital outcomes favored the fast-track EVAR group, including shorter operating room time (2.30 vs 2.83 hrs, P<0.001), shorter hospital stay (1.16 vs 1.69 d, P<0.001), less need for intensive care monitoring (4.4% vs 48.0%, P<0.001), and lower secondary intervention rate (0% vs 2.4%, P=0.01). Postdischarge outcomes also favored fast-track EVAR with a lower rate of MAE (0% vs 7.2%, P<0.001) and all-cause readmission (1.6% vs 6.8%, P=0.001). The total cost to the health care system during the perioperative period was $26,730 with fast-track EVAR vs $30,730 with standard EVAR. Total perioperative health care costs were $4000 (95% CI: $3130-$4830) lower with fast-track EVAR vs standard EVAR, with $2980 in savings to hospitals and $1030 savings to health care payers. CONCLUSION: A fast-track EVAR protocol using a 14 Fr stent graft resulted in shorter procedure time, lower intensive care utilization, faster discharge, lower incidence of MAE, lower readmission rates, and lower perioperative costs compared to standard EVAR.

AHNAK, a novel component of the dysferlin protein complex, redistributes to the cytoplasm with dysferlin during skeletal muscle regeneration.

Mutations in dysferlin cause limb girdle muscular dystrophy 2B, Miyoshi myopathy and distal anterior compartment myopathy. Dysferlin is proposed to play a role in muscle membrane repair. To gain functional insight into the molecular mechanisms of dysferlin, we have searched for dysferlin-interacting proteins in skeletal muscle. By coimmunoprecipitation coupled with mass spectrometry, we demonstrate that AHNAK interacts with dysferlin. We defined the binding sites in dysferlin and AHNAK as the C2A domain in dysferlin and the carboxyterminal domain of AHNAK by glutathione S-transferase (GST)-pull down assays. As expected, the N-terminal domain of myoferlin also interacts with the carboxyterminal domain of AHNAK. In normal skeletal muscle, dysferlin and AHNAK colocalize at the sarcolemmal membrane and T-tubules. In dysferlinopathies, reduction or absence of dysferlin correlates with a secondary muscle-specific loss of AHNAK. Moreover, in regenerating rat muscle, dysferlin and AHNAK showed a marked increase and cytoplasmic localization, consistent with the direct interaction between them. Our data suggest that dysferlin participates in the recruitment and stabilization of AHNAK to the sarcolemma and that AHNAK plays a role in dysferlin membrane repair process. It may also have significant implications for understanding the biology of AHNAK-containing exocytotic vesicles, "enlargosomes," in plasma membrane remodeling and repair.

Analysis of the UK diagnostic strategy for limb girdle muscular dystrophy 2A.

Diagnosis of limb girdle muscular dystrophy type 2A can be complex due to phenotypic variability, lack of precision of protein analysis in muscle biopsies, and absence of mutational hot spots in the CAPN3 gene. The aim of this study was to review clinical and biopsy data from a group of patients with known CAPN3 genetic status to validate and refine our current diagnostic strategy, which combines clinical information and protein analysis to direct gene testing. We analysed 85 patients in whom CAPN3 gene sequencing had been performed. Forty-two patients had two mutations, 15 a single mutation and in 28 no mutation was found. We identified clinical features that clearly discriminated the LGMD2A patients. These were: presence of scapular winging, contractures and normal respiratory function. In addition, a typical pattern of muscle weakness on manual muscle testing could be confirmed. Interpretation of protein expression obtained by Western blot was complex and involved the analysis of a number of bands detected by two antibodies for calpain 3. Loss of all calpain 3 bands was 100% specific for LGMD2A, but this pattern was found in only 23%. Absence or reduction of the approximately 60 kDa bands was also highly specific for LGMD2A, while increased abundance was highly predictive of no mutations being found even where other bands were reduced, suggesting that this is the most sensitive marker of artefactual protein degradation. Twenty-three percent of the patients with two mutations had normal full-sized calpain 3 protein, consistent with the finding of mutations localized in parts of the gene likely or proven to be involved in autolytic activity. Clinical and biochemical findings in patients with only one mutation were similar to patients with two mutations, indicating that other gene analysis techniques should be used before excluding the diagnosis. Our analysis confirms that our strategy is still valid to prioritize genetic testing in this complex group of patients, provided patients with normal protein but a suggestive clinical phenotype are not excluded from genetic testing.

A new evidence for the maintenance of the sarcoglycan complex in muscle sarcolemma in spite of the primary absence of delta-SG protein.

delta-Sarcoglycan (delta-SG) is one of the first proteins of the sarcoglycan complex (SGC) to be expressed during muscle development, and it has been considered fundamental for the assembling and insertion of the SGC in the sarcolemma. Studies using heterologous cell systems and co-precipitation have demonstrated that SGC assembly was dependent on the simultaneous synthesis of all four sarcoglycan proteins. Mutations in any one of sarcoglycan genes, including the common disease causing mutation c.656delC in the delta-SG gene, block complex formation and its insertion in the plasma membrane. Failure in complex assembly in patients with this mutation would be therefore expected. In this study, we provide evidence for the possibility of preservation of part of the SG complex in the sarcolemma, even in the absence of delta-SG. This is based on the study of one mildly affected patient with limb-girdle muscular dystrophy type 2F (LGMD2F) due to the homozygous c.656delC mutation in the delta-SG gene. Protein analysis in his muscle biopsy presented a significant deficiency of only delta-SG with retention of the other three SG proteins in the sarcolemma. RNA expression analysis showed that zeta-SG, a functionally homologous to delta-SG, is not atypically upregulated in his muscle and would not replace the absent delta-SG, retaining the complex alpha-beta-gamma-zeta. The patient started clinical manifestation at age 25, with frequent falls, but he is currently able to walk unassisted at age 42. His clinical course is significantly milder when compared to several other affected patients carrying the same mutation associated with a total deficiency of the four SG proteins in the muscle studied by our group and confirmed in other patients. Therefore, our results add a new in vivo evidence that alpha-, beta-, and gamma-SG proteins can be maintained in the sarcolemma without delta-SG. Additionally, LGMD2F, with retention of the part of the SGC, might be associated to a milder clinical course, which has important implications for clinical prognosis and genetic counseling of the family.

Protein studies in dysferlinopathy patients using llama-derived antibody fragments selected by phage display.

Mutations in dysferlin, a member of the fer1-like protein family that plays a role in membrane integrity and repair, can give rise to a spectrum of neuromuscular disorders with phenotypic variability including limb-girdle muscular dystrophy 2B, Myoshi myopathy and distal anterior compartment myopathy. To improve the tools available for understanding the pathogenesis of the dysferlinopathies, we have established a large source of highly specific antibody reagents against dysferlin by selection of heavy-chain antibody fragments originating from a nonimmune llama-derived phage-display library. By utilizing different truncated forms of recombinant dysferlin for selection and diverse selection methodologies, antibody fragments with specificity for two different dysferlin domains could be identified. The selected llama antibody fragments are functional in Western blotting, immunofluorescence microscopy and immunoprecipitation applications. Using these antibody fragments, we found that calpain 3, which shows a secondary reduction in the dysferlinopathies, interacts with dysferlin.

The differential gene expression profiles of proximal and distal muscle groups are altered in pre-pathological dysferlin-deficient mice.

The selective pattern of muscle involvement is a key feature of muscular dystrophies. Dysferlinopathy is a good model for studying this process since it shows variable muscle involvement that can be highly selective even in individual patients. The transcriptomes of proximal and distal muscles from wildtype C57BL/10 and dysferlin deficient C57BL/10.SJL-Dysf mice at a prepathological stage were assessed using the Affymetrix oligonucleotide-microarray system. We detected significant variation in gene expression between proximal and distal muscle in wildtype mice. Dysferlin defiency, even in the absence of pathological changes, altered this proximal distal difference but with little specific overlap with previous microarray analyses of dysferlinopathy. In conclusion, proximal and distal muscle groups show distinct patterns of gene expression and respond differently to dysferlin deficiency. This has implications for the selection of muscles for future microarray analyses, and also offers new routes for investigating the selectivity of muscle involvement in muscular dystrophies.

Making improvements in the management of patients with type 2 diabetes: a possible role for the control of variation in glycated hemoglobin.

Glucose level varies over time due to a number of complex physiologic processes. Evidence suggests variation in glucose level contributes to risk of complications. The timescale associated with variation in glucose level is on the order of seconds to minutes, yet diabetes complications stem from years of cumulative effects. This difference between timescale suggests a slower timescale may better represent the influential component of variation. We hypothesize variation in glycated hemoglobin captures the component of variation associated with future complications. Moreover, we hypothesize that patient-management strategies influence variation in glycated hemoglobin level. From a systems control perspective, increasing variation may well reflect a policy of closed loop feedback control where changes in patient glycated hemoglobin are addressed after the fact. Such a strategy attends to problems as they arise. In contrast, decreasing variation may result from a clinical strategy that is anticipatory and proactive. A physician using a proactive strategy will base current moves on anticipation of future states, controlling variation in patient outcomes such as glycated hemoglobin. We motivate our discussion using observational data from a large multispecialty medical group in Minnesota: we characterize the within-patient trend and variation of glycated hemoglobin in adults with type 2 diabetes, describe patterns of variation, and identify factors associated with variation. Our hypotheses imply: (1) patterns of variation in glycated hemoglobin reflect physician treatment strategy; (2) variation provides an independent contribution to risk of diabetes complications; (3) the development of treatment strategies that control variation may be a beneficial goal in the management of type 2 diabetes.

Health care charges associated with physical inactivity, overweight, and obesity.

INTRODUCTION: Physical inactivity, overweight, and obesity are associated with increased morbidity and mortality. The objective of this study was to estimate the proportion of total health care charges associated with physical inactivity, overweight, and obesity among U.S. populations aged 40 years and older. METHODS: A predictive model of health care charges was developed using data from a cohort of 8000 health plan members aged 40 and older. Model cells were defined by physical activity status, body mass index, age, sex, smoking status, and selected chronic diseases. Total health care charges were estimated by multiplying the percentage of the population in each cell by the predicted charges per cell. Counterfactual estimates were computed by reclassifying all individuals as physically active and of normal weight while leaving other characteristics unchanged. Charges associated with physical inactivity, overweight, and obesity were computed as the difference between current risk profile total charges and counterfactual total charges. National population percentage estimates were derived from the National Health Interview Survey; those estimates were multiplied by the predicted charges per cell from the health plan analysis. RESULTS: Physical inactivity, overweight, and obesity were associated with 23% (95% confidence interval [CI], 10%-34%) of health plan health care charges and 27% (95% CI, 10%-37%) of national health care charges. Although charges associated with these risk factors were highest for the oldest group (aged 65 years and older) and for individuals with chronic conditions, nearly half of aggregate charges were generated from the group aged 40 to 64 years without chronic disease. CONCLUSION: Charges associated with physical inactivity, overweight, and obesity constitute a significant portion of total medical expenditures. The results underscore the importance of addressing these risk factors in all segments of the population.

Human Skin Allograft for Patients With Diabetic Foot Ulcers, Venous Leg Ulcers, or Surgical/Traumatic Wounds Retrospective, Descriptive Study.

Chronic wounds such as diabetic foot ulcers (DFU) and venous leg ulcers (VLU) may take a long time to heal and increase the risk of complications. Previous studies have suggested human skin allograft may facilitate healing of these chronic wounds. A retrospective, descriptive study was conducted among outpatients with nonhealing DFU, VLU, surgical, or traumatic wounds managed with a meshed, partial-thickness, cryopreserved human skin allograft. Charts of all patients who received an allograft from 2011 to 2013 were abstracted if the wound was >1 cm2, had a duration>30 days, was adequately debrided, and was free of infection before the first allograft application. Primary outcome was percentage of wounds healed (ie, 100% epithelialized) at 12 and 20 weeks. Secondary outcome was the number of recorded adverse events. Wound measurements (area--calculated as width x length in cm2), wound type and duration, number of allograft applications, number of adverse events, and race, smoking status, and body mass index were abstracted. Of the 49 patients (average age 64.3 [SD 15.0]; 64% male) who met the inclusion criteria, 13 did not have medical follow-up through the primary outcomes at 12 and 20 weeks, leaving 36 patients (average age 65.1 [SD 15.4]; 67% male) available for analysis. The most common diagnoses were VLU (18 patients, 50%) and traumatic wounds (9 patients, 25%). Average wound size was 19.4 cm2 (SD 29.3, range 1.2-156, median 9.5), and average wound duration at initial treatment was 17.2 (SD 17.0, range 4-72, excluding outlier) weeks. Seventeen (17) wounds (47%) healed by 12 weeks, and 21 (58%) were healed by week 20 with an average of 3.3 (SD 2.0) allograft applications. No serious adverse events occurred. The results of this study are encouraging and add to the currently available literature on the use of allograft skin for chronic wounds, but the study design and sample size limit the ability to interpret the observations. Prospective, controlled clinical studies are needed to compare the efficacy, effectiveness, and cost-effectiveness of human skin allograft to standard care and to other advanced care modalities.