Association between anaemia and hospital readmissions in patients undergoing major surgery requiring postoperative intensive care.

Anaemia is a common sequela of surgery, although its relationship with patient recovery is unclear. The goal of this investigation was to assess the associations between haemoglobin concentrations at the time of hospital discharge following major surgery and early post-hospitalisation outcomes, with a primary outcome of 30 day unanticipated hospital readmissions. This investigation includes data from two independent population-based observational cohorts of adult surgical patients (aged ≥ 18 years) requiring postoperative intensive care unit admission between 1 January 2010 and 31 December 2019 in hospitals in Olmsted County, Minnesota, and between 1 July 2010 and 30 June 2017 in the Kaiser Permanente Northern California integrated healthcare system, California. Cox proportional hazards models assessed the associations between discharge haemoglobin concentrations (per 10 g.l-1 ) and outcomes, with prespecified multivariable adjustment. A total of 3260 patients were included from Olmsted County hospitals and 29,452 from Kaiser Permanente Northern California. In adjusted analyses, each 10 g.l-1 decrease in haemoglobin at hospital discharge was associated with a 9% (hazard ratio 1.09, 95%CI 1.02-1.18; p = 0.014) and 8% increase (hazard ratio 1.08, 95%CI 1.06-1.11; p < 0.001) in the hazard for readmission within 30 days in Olmsted County and Kaiser Permanente Northern California, respectively. In a sensitivity analysis exploring relationships across varying levels of pre-operative anaemia severity, these associations remained consistent, with lower discharge haemoglobin concentrations associated with higher readmissions irrespective of pre-operative anaemia severity. Anaemia at hospital discharge in surgical patients requiring postoperative intensive care is associated with increased rates of hospital readmission in two large independent cohorts. Future studies are necessary to evaluate strategies to prevent and/or treat anaemia in these patients for the improvement of post-hospitalisation outcomes.

Increasing comparability among coral bleaching experiments.

Coral bleaching is the single largest global threat to coral reefs worldwide. Integrating the diverse body of work on coral bleaching is critical to understanding and combating this global problem. Yet investigating the drivers, patterns, and processes of coral bleaching poses a major challenge. A recent review of published experiments revealed a wide range of experimental variables used across studies. Such a wide range of approaches enhances discovery, but without full transparency in the experimental and analytical methods used, can also make comparisons among studies challenging. To increase comparability but not stifle innovation, we propose a common framework for coral bleaching experiments that includes consideration of coral provenance, experimental conditions, and husbandry. For example, reporting the number of genets used, collection site conditions, the experimental temperature offset(s) from the maximum monthly mean (MMM) of the collection site, experimental light conditions, flow, and the feeding regime will greatly facilitate comparability across studies. Similarly, quantifying common response variables of endosymbiont (Symbiodiniaceae) and holobiont phenotypes (i.e., color, chlorophyll, endosymbiont cell density, mortality, and skeletal growth) could further facilitate cross-study comparisons. While no single bleaching experiment can provide the data necessary to determine global coral responses of all corals to current and future ocean warming, linking studies through a common framework as outlined here, would help increase comparability among experiments, facilitate synthetic insights into the causes and underlying mechanisms of coral bleaching, and reveal unique bleaching responses among genets, species, and regions. Such a collaborative framework that fosters transparency in methods used would strengthen comparisons among studies that can help inform coral reef management and facilitate conservation strategies to mitigate coral bleaching worldwide.

Estrogen receptor ß controls proliferation of enteric glia and differentiation of neurons in the myenteric plexus after damage.

Injury to the enteric nervous system (ENS) can cause several gastrointestinal (GI) disorders including achalasia, irritable bowel syndrome, and gastroparesis. Recently, a subpopulation of enteric glial cells with neuronal stem/progenitor properties (ENSCs) has been identified in the adult ENS. ENSCs have the ability of reconstituting the enteric neuronal pool after damage of the myenteric plexus. Since the estrogen receptor ß (ERß) is expressed in enteric glial cells and neurons, we investigated whether a selective ERß agonist, LY3201, can influence neuronal and glial cell differentiation. Myenteric ganglia from the murine muscularis externa were isolated and cultured in either glial cell medium or neuronal medium. In glial cell medium, the number of glial progenitor cells (Sox10+) was increased by fourfold in the presence of LY3201. In the neuronal medium supplemented with an antimitotic agent to block glial cell proliferation, LY3201 elicited a 2.7-fold increase in the number of neurons (neurofilament+ or HuC/D+). In addition, the effect of LY3201 was evaluated in vivo in two murine models of enteric neuronal damage and loss, namely, high-fat diet and topical application of the cationic detergent benzalkonium chloride (BAC) on the intestinal serosa, respectively. In both models, treatment with LY3201 significantly increased the recovery of neurons after damage. Thus, LY3201 was able to stimulate glial-to-neuron cell differentiation in vitro and promoted neurogenesis in the damaged myenteric plexus in vivo. Overall, our study suggests that selective ERß agonists may represent a therapeutic tool to treat patients suffering from GI disorders, caused by excessive neuronal/glial cell damage.

Real-world outcomes of unrestricted direct-acting antiviral treatment for hepatitis C in Australia: The South Australian statewide experience.

In March 2016, the Australian government offered unrestricted access to direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) to the entire population. This included prescription by any medical practitioner in consultation with specialists until sufficient experience was attained. We sought to determine the outcomes and experience over the first twelve months for the entire state of South Australia. We performed a prospective, observational study following outcomes of all treatments associated with the state's four main tertiary centres. A total of 1909 subjects initiating DAA therapy were included, representing an estimated 90% of all treatments in the state. Overall, SVR12 was 80.4% in all subjects intended for treatment and 95.7% in those completing treatment and follow-up. 14.2% were lost to follow-up (LTFU) and did not complete SVR12 testing. LTFU was independently associated with community treatment via remote consultation (OR 1.50, 95% CI 1.04-2.18, P = .03), prison-based treatment (OR 2.02, 95% CI 1.08-3.79, P = .03) and younger age (OR 0.98, 95% CI 0.97-0.99, P = .05). Of the 1534 subjects completing treatment and follow-up, decreased likelihood of SVR12 was associated with genotype 2 (OR 0.23, 95% CI 0.07-0.74, P = .01) and genotype 3 (OR 0.23, 95% CI 0.12-0.43, P ≤ .01). A significant decrease in treatment initiation was observed over the twelve-month period in conjunction with a shift from hospital to community-based treatment. Our findings support the high responses observed in clinical trials; however, a significant gap exists in SVR12 in our real-world cohort due to LTFU. A declining treatment initiation rate and shift to community-based treatment highlight the need to explore additional strategies to identify, treat and follow-up remaining patients in order to achieve elimination targets.

A prospective surveillance study of inhibitor development in haemophilia A patients following a population switch to a third-generation B-domain-deleted recombinant factor VIII.

INTRODUCTION: Following a provincial tender, most subjects with haemophilia A in Quebec switched their treatment to a third-generation recombinant B-domain-deleted factor VIII (FVIII). AIM: Our objective was to evaluate the incidence of inhibitor development and FVIII recovery in patients following the switch of factor replacement therapy. METHODS: One hundred and thirty-five subjects were enrolled and tested for FVIII activity and inhibitors every 6 months during 1 year. Subjects with mild haemophilia A or current inhibitors were excluded. Data on demographics, bleeds and FVIII usage were collected. RESULTS: A total of 125 switchers and 10 non-switchers were enrolled. Most subjects had severe haemophilia A (95.6%) and were on prophylaxis (89.6%). Mean FVIII recovery was similar at 0, 6 and 12 months postswitch. Two switchers developed de novo inhibitors in the 6 months postswitch, one of which was transient. No recurrent inhibitor was observed. A small but significant increase in FVIII usage was observed for adult switchers and the whole cohort of switchers and non-switchers. There was an increase in the annualized bleeding rate (ABR) for non-joint bleeds for the whole cohort of switchers. However, no significant differences were observed in ABR for joint bleeds. CONCLUSION: Our surveillance study shows comparable inhibitor development to similar published studies. A significant increase in FVIII utilization was noted for the whole cohort, switchers and non-switchers. Lastly, no clinically significant changes were observed in ABR for joint bleeds, but a difference for non-joint bleed ABRs was observed in switchers.

Liver X receptors regulate cerebrospinal fluid production.

Of the two isoforms of Liver X receptor (LXR), LXRß has been shown to have major effects in the central nervous system (CNS) and on the regulation of aquaporins while LXRα has its most marked effects on cholesterol homeostasis. Both receptors have immunomodulatory functions. In LXRαß knockout (ko) mice, the CNS phenotype is much more severe than in the LXRß ko mice, suggesting a contribution of LXRα in CNS functions. One of the most striking abnormalities in the brains of LXRαß ko mice is the occlusion of the lateral ventricles with age. In the present study, we have found by immunohistochemical staining that both LXRα and LXRß are expressed in the cell nuclei of the epithelium of the choroid plexus and in the ependymal cells surrounding the lateral ventricles. The two receptors regulate several genes and can compensate for each other on expression of genes involved in structural integrity (E-cadherin, P-cadherin and ß-catenin) and function (aquaporin 1 and carbonic anhydrase IX). Aquaporin 4 (AQ4) is not expressed in the choroid plexus but is expressed in the astrocytic end feet and ependymal cells. AQP4 expression was increased in white matter around lateral ventricles but not in neurons of LXRαß ko mice. The data show that LXR is a regulator of cerebrospinal fluid (CSF) both at the choroid plexus and at the astrocytic end feet and defects in the synthesis of cerebrospinal fluid may be targeted by LXR agonists to facilitate CSF production, turnover and clearance in CNS diseases.

Proteomic signatures differentiating Bacillus anthracis Sterne sporulation on soil relative to laboratory media.

The process of sporulation is vital for the stability and infectious cycle of Bacillus anthracis. The spore is the infectious form of the organism and therefore relevant to biodefense. While the morphological and molecular events occurring during sporulation have been well studied, the influence of growth medium and temperature on the proteins expressed in sporulated cultures is not well understood. Understanding the features of B. anthracis sporulation specific to natural vs. laboratory production will address an important question in microbial forensics. In an effort to bridge this knowledge gap, a system for sporulation on two types of agar-immobilized soils was used for comparison to cultures sporulated on two common types of solid laboratory media, and one liquid sporulation medium. The total number of proteins identified as well as their identity differed between samples generated in each medium and growth temperature, demonstrating that sporulation environment significantly impacts the protein content of the spore. In addition, a subset of proteins common in all of the soil-cultivated samples was distinct from the expression profiles in laboratory medium (and vice versa). These differences included proteins involved in thiamine and phosphate metabolism in the sporulated cultures produced on soils with a notable increase in expression of ATP binding cassette (ABC) transporters annotated to be for phosphate and antimicrobial peptides. A distinct set of ABC transporters for amino acids, sugars and oligopeptides were found in cultures produced on laboratory media as well as increases in carbon and amino acid metabolism-related proteins. These protein expression changes indicate that the sporulation environment impacts the protein profiles in specific ways that are reflected in the metabolic and membrane transporter proteins present in sporulated cultures.

siRNA targeting the κ light chain constant region: preclinical testing of an approach to nonfibrillar and fibrillar light chain deposition diseases.

Treatment of light chain (LC) deposition diseases both nonfibrillar and fibrillar is aimed at eliminating LC production but success is limited. We report on the testing of an small interfering RNA pool targeting the κ LC constant region mRNA (si[IGKC]) designed for use against all κ plasma cell clones. To test for changes in κ LC message and protein production we used real-time PCR, immunoblot, intracellular mean fluorescence intensity and κ LC secretion by enzyme-linked immunosorbent assay. In vitro we employed 4 human cell lines that make κ LCs and 20 specimens of CD138-selected marrow plasma cells from patients with κ plasma cell diseases. In vivo, we used a murine flank plasmacytoma xenograft model. In vitro and in vivo, there were significant reductions in message and protein production by all modalities in all cell types despite diversity in variable region sequence. In addition, in clones producing intact immunoglobulin, caspase 3/7 activity with si[IGKC] was significantly increased compared with clones producing κ LC only, consistent with the triggering of a terminal unfolded protein response by excess unpaired heavy chains. In conclusion, si[IGKC] can significantly reduce κ LC production by κ plasma cells. Further preclinical development is needed to optimize delivery.

Estrogen receptor ß and Liver X receptor ß: biology and therapeutic potential in CNS diseases.

In the last decade of the twentieth century, two nuclear receptors were discovered in our laboratory and, very surprisingly, were found to have key roles in the central nervous system. These receptors have provided some novel insights into the etiology and progression of neurodegenerative diseases and anxiety disorders. The two receptors are estrogen receptor beta (ERß) and liver X receptor beta (LXRß). Both ERß and LXRß have potent anti-inflammatory activities and, in addition, LXRß is involved in the genesis of dopaminergic neurons during development and protection of these neurons against neurodegeneration in adult life. ERß is involved in migration of cortical neurons and calretinin-positive GABAergic interneurons during development and maintenance of serotonergic neurons in adults. Both receptors are present in magnocellular neurons of the hypothalamic preoptic area including those expressing vasopressin and oxytocin. As both ERß and LXRß are ligand-activated transcription factors, their ligands hold great potential in the treatment of diseases of the CNS.

A comparison of high vs standard tidal volumes in ventilator weaning for individuals with sub-acute spinal cord injuries: a site-specific randomized clinical trial.

STUDY DESIGN: Prospective, randomized, controlled parallel group trial with single-blinded data analysis. OBJECTIVES: To determine the safety and efficacy of higher (20 ml kg(-1) ideal body weight (IBW)) vs standard (10 ml kg(-1) IBW) tidal volumes (Vt) for patients with sub-acute traumatic tetraplegia during ventilator weaning using a 14-day (minimum) weaning protocol. SETTING: United States regional spinal cord injury treatment center. METHODS: Thirty-three ventilator requiring inpatients were randomized to either the higher (Group 1) or the standard (Group 2) Vt protocol. Initially, all patients were ventilated at 10 ml kg(-1) IBW Vt and 5 cm H(2)O [corrected] of PEEP for 72 h. For Group 1, Vt was raised 100 ml kg(-1) until reaching target Vt of 20 ml kg(-1) IBW. Group 2 was maintained at Vt of 10 ml kg(-1) IBW. Plateau pressures were kept at or below 30 cm H(2)O. [corrected]. Safety outcomes included incidence of adverse events. RESULTS: Because of smaller than expected enrollment, evaluation of efficacy was not possible. Therefore, we report the safety outcomes of 33 study participants. The 16 patients in Group 1 and 17 patients in Group 2 were demographically similar at baseline, except for age. The average age was 39.3 years in Group 1 and 27.2 years in Group 2, (P=0.002). There was no difference in median days to wean: 14.5 days in Group 1 and 14 days in Group 2. The incidence of adverse pulmonary events was similar between groups. CONCLUSION: Higher tidal volumes can be safely utilized during weaning of patients with tetraplegia from mechanical ventilation using a 14-day weaning protocol.

Liver X receptor ß is essential for the differentiation of radial glial cells to oligodendrocytes in the dorsal cortex.

Several psychiatric disorders are associated with aberrant white matter development, suggesting oligodendrocyte and myelin dysfunction in these diseases. There are indications that radial glial cells (RGCs) are involved in initiating myelination, and may contribute to the production of oligodendrocyte progenitor cells (OPCs) in the dorsal cortex. Liver X receptors (LXRs) are involved in maintaining normal myelin in the central nervous system (CNS), however, their function in oligodendrogenesis and myelination is not well understood. Here, we demonstrate that loss of LXRß function leads to abnormality in locomotor activity and exploratory behavior, signs of anxiety and hypomyelination in the corpus callosum and optic nerve, providing in vivo evidence that LXRß deletion delays both oligodendrocyte differentiation and maturation. Remarkably, along the germinal ventricular zone-subventricular zone and corpus callosum there is reduced OPC production from RGCs in LXRß(-/-) mice. Conversely, in cultured RGC an LXR agonist led to increased differentiation into OPCs. Collectively, these results suggest that LXRß, by driving RGCs to become OPCs in the dorsal cortex, is critical for white matter development and CNS myelination, and point to the involvement of LXRß in psychiatric disorders.

Pharmacokinetics of oral amantadine in greyhound dogs.

This study reports the pharmacokinetics of amantadine in greyhound dogs after oral administration. Five healthy greyhound dogs were used. A single oral dose of 100 mg amantadine hydrochloride (mean dose 2.8 mg/kg as amantadine hydrochloride) was administered to nonfasted subjects. Blood samples were collected at predetermined time points from 0 to 24 h after administration, and plasma concentrations of amantadine were measured by liquid chromatography with triple quadrupole mass spectrometry. Noncompartmental pharmacokinetic analyses were performed. Amantadine was well tolerated in all dogs with no adverse effects observed. The mean (range) amantadine CMAX was 275 ng/mL (225-351 ng/mL) at 2.6 h (1-4 h) with a terminal half-life of 4.96 h (4.11-6.59 h). The results of this study can be used to design dosages to assess multidose pharmacokinetics and dosages designed to achieve targeted concentrations in order to assess the clinical effects of amantadine in a variety of conditions including chronic pain. Further studies should also assess the pharmacokinetics of amantadine in other dog breeds or using population pharmacokinetics studies including multiple dog breeds to assess potential breed-specific differences in the pharmacokinetics of amantadine in dogs.

Involvement of estrogen receptor ß in maintenance of serotonergic neurons of the dorsal raphe.

The serotonergic neurons of the dorsal raphe (DR) nucleus in the CNS are involved in fear, anxiety and depression. Depression and anxiety occur quite frequently in postmenopausal women, but estrogen replacement to correct these CNS disorders is at present not favored because estrogen carries with it an increased risk for breast cancer. Serotonin synthesis, release and reuptake in the DR are targets of pharmaceuticals in the treatment of depression. In the present study we have examined by immunohistochemistry, the expression of two nuclear receptors, that is, the estrogen receptors ERα and ERß. We found that ERß but not ERα is strongly expressed in the DR and there is no sex difference and no change with ageing in the number of tryptophan hydroxylase (TPH)-positive neurons in the DR of wild-type (WT) mice. However, in ovariectomized (OVX) WT and in ERß(-/-) mice, there was a marked reduction in the number of TPH-positive normal-looking neurons and a marked increase in TPH-positive spindle-shaped cells. These neuronal changes were prevented in mice 1-3 weeks (but not 10 weeks) after OVX by the selective ERß agonist, LY3201, given as continuous release pellets for 3 days. The ERß agonist had no effects on glucose homeostasis. Thus, the onset of action of the ERß agonist is rapid but there is a limited window in time after estrogen loss when the drug is useful. We conclude that, rather than estradiol, ERß agonists could be useful pharmaceuticals in maintaining functional DR neurons to treat postmenopausal depression.

Efficacy of neuromuscular exercises to promote movement quality and reduce musculoskeletal injury during initial military training in Royal Navy recruits.

INTRODUCTION: Musculoskeletal injuries (MSKIs) are a significant problem in the Royal Navy, contributing to 48% of all medical discharges from service between 2019 and 2020. The objective of the study was to assess efficacy of implementing a neuromuscular training intervention to improve movement quality and reduce MSKIs in Royal Navy recruits undertaking initial military training. METHODS: Neuromuscular training (pre-activation exercises, focusing on hip control) was integrated into the warm-up exercise regimen preceding physical training during the 10-week initial naval training (recruits) programme (January-March 2020) at HMS Raleigh (intervention group; n=162). A control group comprised (n=90) of recruits entering training from January 2019, who completed the standard warm-up programme prior to physical training. Movement control of the intervention group (intervention) was assessed before and after the 10-week programme using the Hip and Lower-Limb Movement Screen (HLLMS). Injury incidence proportion for both groups was determined retrospectively by review of medical notes. RESULTS: The control group's MSKI incidence proportion was 31%, which was higher (p<0.05) than the 8% reported in the intervention group. The majority of MSKIs were of the lower limb, and were reported in weeks 1, 2 and 5 of the 10-week training programme. Movement control, as assessed by the HLLMS score, improved (pretraining (week 1) and post-training (week 10) HLLMS score (mean (SD) pre: 11.2 (5.6); post: 8.4 (3.9); t=5.829, p<0.001) following the neuromuscular training in the intervention group but was not assessed in the control group. CONCLUSION: A neuromuscular control intervention was successfully implemented during the initial military training in the Royal Navy. The cohort undertaking the intervention demonstrated lower injury incidence compared with an equivalent cohort of recruits who undertook standard training. Movement control improved following the intervention, indicating better movement quality. Continued use of the programme may reduce military training attrition in the Royal Navy.

Women-Focused Cardiac Rehabilitation Delivery Around the World and Program Enablers to Support Broader Implementation.

Background: Women are less likely than men to use cardiac rehabilitation (CR); thus, women-focused (W-F) CR was developed. Implementation of W-F CR globally was investigated, as well as barriers and enablers to its delivery. Methods: In this cross-sectional study, a survey was administered to CR programs via Research Electronic Data Capture (REDCap) from May to July, 2023. Potential respondents were identified via the International Council of Cardiovascular Prevention and Rehabilitation's network. Results: A total of 223 responses were received from 52 of 111 countries (46.8% country response rate) in the world that have any CR, across all 6 World Health Organization regions. Thirty-three programs (14.8%) from 30 countries reported offering any W-F programming. Programs commonly did offer elements preferred by women and recommended, namely, the following: patient choice of session time (n = 151; 70.6%); invitations for informal care providers and/or partners to attend sessions (n = 121; 57.1%); CR staff that have expertise in women and heart diseases (n = 112; 53.3%); separate changerooms for women (n = 38; 52.8%); and discussion of CR referral with patients (n = 112; 52.1%). Main barriers to delivery of W-F exercise were physical resources (n = 33; 14.8%), space (n = 30; 13.5%), and staff time (n = 26; 11.7%) and expertise (n = 33; 10.3%). Main barriers to delivery of W-F education were human resources (n = 114; 51.1%), educational resources (n = 26; 11.7%), and expertise in the content (n = 74; 33.2%). Enablers of W-F education delivery were availability of materials, in multiple modalities, as well as educated staff and financial resources. Conclusions: Despite the benefits, W-F CR is not commonly offered globally. Considering the barriers and enablers identified, the International Council of Cardiovascular Prevention and Rehabilitation is developing resources to expand delivery.

Contexte: Les femmes étant moins susceptibles que les hommes d'avoir recours à la réadaptation cardiaque (RC), il convient d'élaborer des programmes de RC qui sont mieux adaptés à leurs besoins. Le recours à de tels programmes dans le monde a fait l'objet d'une étude, laquelle portait également sur les obstacles à leur prestation et les facteurs qui les favorisent. Méthodologie: Dans cette étude transversale, un sondage a été mené auprès de programmes de RC via la REDCap (Research Electronic Data Capture) de mai à juillet 2023. Les participants potentiels au sondage ont été sélectionnés par le réseau de l'International Council of Cardiovascular Prevention and Rehabilitation. Résultats: Au total, 223 réponses ont été reçues de 52 pays sur 111 qui ont un programme de RC (taux de réponse des pays de 46,8 %), dans les 6 régions de l'Organisation mondiale de la Santé. Selon les résultats, trente-trois programmes (14,8 %) de 30 pays offrent des services axés sur les femmes. Les programmes offraient habituellement des éléments privilégiés par les femmes et recommandaient notamment des séances au moment choisi par les patientes (n = 151; 70,6 %); la possibilité de se faire accompagner par un aidant naturel et/ou un(e) partenaire (n = 121; 57,1 %); du personnel de RC possédant une expertise auprès des femmes et en matière de maladies cardiaques (n = 112; 53,3 %); des vestiaires réservés aux femmes (n = 38; 52,8 %); et une discussion avec les patientes sur leur orientation vers des spécialistes en RC (n = 112; 52,1 %). Les principaux obstacles à la prestation de services pour les femmes étaient les ressources physiques (n = 33; 14,8 %), l'espace (n = 30; 13,5 %) ainsi que la disponibilité du personnel (n = 26; 11,7 %) et son expertise (n = 33; 10,3 %). Les principaux obstacles à l'éducation destinée aux femmes étaient les ressources humaines (n = 114; 51,1 %), les ressources éducatives (n = 26; 11,7 %) et l'expertise liée au contenu (n = 74; 33,2 %). Les facteurs qui favorisent l'éducation destinée aux femmes étaient la disponibilité du matériel, sous plusieurs formes, de même que le personnel formé et les ressources financières. Conclusions: En dépit des bienfaits, la RC axée sur les femmes n'est pas couramment offerte dans le monde. En tenant compte des obstacles et des facteurs favorisant la prestation des services cités, l'International Council of Cardiovascular Prevention and Rehabilitation s'affaire à concevoir des ressources pour élargir la portée des programmes destinés aux femmes.

Treatment strategies in patients with statin intolerance: the Cleveland Clinic experience.

BACKGROUND: Statin therapy is a proven effective treatment of hyperlipidemia. However, a significant number of patients cannot tolerate statins. This study was conducted to review treatment strategies for patients intolerant to statin therapy with a focus on intermittent statin dosing. METHODS AND RESULTS: We performed a retrospective analysis of medical records of 1,605 patients referred to the Cleveland Clinic Preventive Cardiology Section for statin intolerance between January 1995 and March 2010 with at least a 6-month follow-up. The changes in lipid profile, achievement of low-density lipoprotein cholesterol (LDL-C) goals, and statin tolerance rate were analyzed. Most (72.5%) of patients with prior statin intolerance were able to tolerate a statin for the median follow-up time of 31 months. Patients on intermittent statin dosing (n = 149) had significantly lower LDL-C reduction compared with daily dosing group (n = 1,014; 21.3% ± 4.0% vs 27.7% ± 1.4%, P < .04). However, compared with the statin discontinued group (n = 442), they had a significantly higher LDL-C reduction (21.3% ± 4.0% vs 8.3 ± 2.2%, P < .001), and a significantly higher portion achieved their Adult Treatment Panel III goal of LDL-C (61% vs 44%, P < .05). There was a trend toward a decrease in all-cause mortality at 8 years for patients on daily and intermittent statin dosing compared with those who discontinued statin (P = .08). CONCLUSIONS: Most patients with previous statin intolerance can tolerate subsequent trial of statin. A strategy of intermittent statin dosing can be an effective therapeutic option in some patients and may result in reduction in LDL-C and achievement of LDL-C goals.

Chronic myopathy due to immunoglobulin light chain amyloidosis.

Amyloid myopathy associated with a plasma cell dyscrasia is a rare cause of muscle hypertrophy. It can be a challenging diagnosis, since pathological findings are often elusive. In addition, the mechanism by which immunoglobulin light-chain deposition stimulates muscle overgrowth remains poorly understood. We present a 53-year old female with a 10-year history of progressive generalized muscle overgrowth. Congo-red staining and immunohistochemistry revealed perivascular lambda light chain amyloid deposits, apparent only in a second muscle biopsy. The numbers of central nuclei and satellite cells were increased, suggesting enhanced muscle progenitor cell formation. Despite the chronicity of the light chain disease, the patient showed complete resolution of hematologic findings and significant improvement of her muscle symptoms following autologous bone marrow transplantation. This case highlights the importance of early diagnosis and therapy for this treatable cause of a chronic myopathy with muscle hypertrophy.

Fellowships and defence engagement: from clinical niches to strategic impact.

Medical fellowships have traditionally developed the individual rather than furthering military or national strategic objectives. This paper describes a medical fellowship with the British Antarctic Survey to illustrate the benefits to the individual, to the military and to wider international defence engagement efforts.By rebranding such fellowships as Defence Healthcare Engagement and by treating international organisations on a par with partner nations, the humble fellowship can facilitate enduring, mutually beneficial healthcare engagement at low cost and with minimal additional resources.

Assessing injury risk in male and female Royal Navy recruits: does the Functional Movement Screen provide understanding to inform effective injury mitigation?

INTRODUCTION: Musculoskeletal injuries (MSKIs) are common during military and other occupational physical training programmes, and employers have a duty of care to mitigate this injury risk. MSKIs account for a high number of working days lost during initial military training, contribute to training attrition and impact training costs. Poorer movement quality may be associated with increased MSKI risk. METHODS: The present study evaluated the relationship between the Functional Movement Screen (FMS) Score, as a measure of movement quality, and injury risk in Royal Navy (RN) recruits. A cohort of 957 recruits was assessed using the FMS prior to the 10-week phase I training programme. Injury occurrence, time, type and severity were recorded prospectively during the training period. RESULTS: Total FMS Score was associated with injury risk (p≤0.001), where recruits scoring ≥13 were 2.6 times more likely to sustain an injury during training. However, FMS Score accounted for only 10% of the variance in injury risk (R2=0.1). Sex was the only additional variable to significantly affect the regression model. Mean FMS Scores for men (14.6±2.3) and women (14.4±2.4) were similar, but injury occurrence in women was 1.7 times greater than in men. Examining the influence of individual FMS movement tests on injury prediction did not improve the model, where those movements that significantly contributed to injury prediction only accounted for a small amount of the variance (R2=0.01). CONCLUSION: There was a weak relationship between FMS and injury risk in RN recruits. Evidence is provided that FMS score alone would not be appropriate to use as an injury prediction tool in military recruits.

Lack of upward creep of glycopeptide MICs for methicillin-resistant Staphylococcus aureus (MRSA) isolated in the UK and Ireland 2001-07.

OBJECTIVES: There have been several reports of upward creep in vancomycin MICs for Staphylococcus aureus [predominantly methicillin-resistant S. aureus (MRSA)] over recent years, but only in single centres or using contemporaneous results. We aimed to test the hypothesis of MIC creep in a multicentre study, testing all the isolates concurrently. METHODS: Nineteen laboratories in the UK and Ireland contributed isolates from blood to the BSAC Bacteraemia Resistance Surveillance Programme every year between 2001 and 2007. MICs for 271 MRSA from these sites were re-measured at a single central laboratory during a single week by the BSAC agar dilution method, but with √2-fold instead of conventional 2-fold dilutions. Re-test results were compared with the original results obtained each year at the same central laboratory. RESULTS: The re-test results were much less variable than the original results and avoided the confounding of experimental variation with year of collection. They demonstrated statistically significant but very slow downward trends in MICs of vancomycin and teicoplanin, at 0.027 and 0.055 doubling dilutions/year, respectively. The original results had suggested more rapid trends in MICs, upward for vancomycin and downward for teicoplanin. The proportion of EMRSA-16 fell from 21% to 9% over the study period, while EMRSA-15 rose from 76% to 85%. CONCLUSIONS: Historical data can give a misleading impression of trends in MIC values because of experimental variation between tests conducted at different times. There was no upward creep in glycopeptide MICs for MRSA in the UK and Ireland between 2001 and 2007.