Rasch analysis of clinical outcome measures in spinal muscular atrophy

Introduction: Trial design for SMA depends on meaningful rating scales to assess outcomes. In this study Rasch methodology was applied to 9 motor scales in spinal muscular atrophy (SMA). Methods: Data from all 3 SMA types were provided by research groups for 9 commonly used scales. Rasch methodology assessed the ordering of response option thresholds, tests of fit, spread of item locations, residual correlations, and person separation index. Results: Each scale had good reliability. However, several issues impacting scale validity were identified, including the extent that items defined clinically meaningful constructs and how well each scale measured performance across the SMA spectrum. Conclusions: The sensitivity and potential utility of each SMA scale as outcome measures for trials could be improved by establishing clear definitions of what is measured, reconsidering items that misfit and items whose response categories have reversed thresholds, and adding new items at the extremes of scale ranges. Muscle Nerve 49 :422–430, 2014     

Alcohol and other risk factors for drowning among male active duty U.S. army soldiers.

BACKGROUND: Risk factors for drowning are largely undocumented among military populations. Hypothesis: Accident report narratives will provide important information about the role of alcohol use and other behaviors in drownings among active duty male U.S. Army soldiers. METHODS: Using a case series design, we describe drowning deaths reported to the U.S. Army Safety Center (1980-1997), documenting associated demographic factors, alcohol use, and other risk-taking behaviors. RESULTS: Drowning victims (n = 352) were disproportionately young, black, and single, with less time-in-service, and no college experience. Most drownings occurred off-duty (89%). Alcohol use was involved in at least 31% of the cases overall. Alcohol use was also associated with a 10-fold increase in reckless behavior (OR 9.6, 95% Cl 4.5-20.7) and was most common among drownings in Europe (OR = 4.3, 95% Cl 1.5-13.4). Most drownings occurred where no lifeguard was present (68%), but almost two-thirds occurred in the presence of others, with CPR initiated in less than one-third of these cases. Drownings involving minority victims were less likely to involve alcohol, but more likely to occur in unauthorized swimming areas. While most drownings did not involve violations of safety rules, over one-third of the cases involved some form of reckless behavior, particularly for those under age 21. CONCLUSIONS: Intervention programs should be tailored to meet the needs of the demographic subgroups at highest risk since behavioral risk factors vary by race and age. CPR training and skills maintenance can improve survival rates. Narrative data are important for developing hypotheses and understanding risk factors for injuries.     

What is the risk associated with being a qualified military parachutist?

Military parachuting has been recognized as a hazardous activity since it was first introduced in World War II. Other risks associated with military service include actual war-fighting, training with weapons and explosives, operating with armoured vehicles or deployment to climatic extremes. These other hazards should be considered in any assessment of the additional risk associated with military parachuting. The aim of this study was to identify the risk attributable to parachuting amongst US Army enlisted soldiers. This study identified a cohort of infantry soldiers who served between 1990-94. They were separated by receipt of parachute hazardous duty pay. There was a total of 329,794 person-years (PY) available for study of which 18% were in the exposed group. The rate of hospitalization was very similar in both groups [123.9 per 1,000 PYs for the exposed group, 127 in the non-exposed group: relative risk (RR) = 0.98, 95% confidence interval (CI) = 0.96-1.00). The exposed group was 1.49 times (CI = 1.42-1.57) more likely to be admitted as a result of an injury as compared with the non-exposed group. Military parachuting was 20 times (CI = 16.6-24.3) more likely to be the cause of an injury. This study has shown that receipt of hazardous duty pay for military parachuting can be used as a marker in identifying significant additional risks to the health of infantry soldiers associated with military parachuting. This was reflected in an increased incidence of admission for acute injury and musculoskeletal trauma (particularly a trauma pattern associated with parachuting) as a result of military parachuting. Other risks, which are associated with parachute pay, are admission for the effects of heat, battle injury and helicopter accidents.     

Burn disasters in the middle belt of Ghana from 2007 to 2008 and their consequences

Aim

To study the survival and mortality trends in four fire disasters in the middle belt of Ghana from 2007 to 2008 and to explore measures that could minimize the risk of future disasters.

Methods

Data were collected from clinical records from the Burns Intensive Care Unit and the Casualty Unit of the Komfo Anokye Teaching Hospital, Kumasi, Ghana and from the various disaster sites and the Ghana Police Service.

Results

A total of 212 were injured from four burn disasters; 37 (17%) died on the spot; 175 (83%) reported to the Casualty Unit out of which 46 (26%) were admitted. The victims admitted had mean age 24.6 years with male to female ratio 2.3:1; 25 (54%) of the admitted victims died. The average burned surface area of the admitted victims was 63%, with a mean survival rate of 46%. Statistical analysis for mortality when the surface area of the burn was >70% was 0.0005 (P-value).

Conclusion

The four petrol-related fire disasters showed variable mortality rates. Death and severe disability of victims of future disasters can be avoided if intensive road accident preventive measures and massive public education are encouraged.     

Reliability and validity of the instrument used in BRFSS to assess physical activity

INTRODUCTION: State-level statistics of adherence to the physical activity objectives in Healthy People 2010 are derived from the Behavioral Risk Factor Surveillance System (BRFSS) data. BRFSS physical activity questions were updated in 2001 to include domains of leisure time, household, and transportation-related activity of moderate- and vigorous intensity, and walking questions. This article reports the reliability and validity of these questions. METHODS: The BRFSS Physical Activity Study (BPAS) was conducted from September 2000 to May 2001 in Columbia, SC. Sixty participants were followed for 22 d; they answered the physical activity questions three times via telephone, wore a pedometer and accelerometer, and completed a daily physical activity log for 1 wk. Measures for moderate, vigorous, recommended (i.e., met the criteria for moderate or vigorous), and strengthening activities were created according to Healthy People 2010 operational definitions. Reliability and validity were assessed using Cohen's kappa (kappa) and Pearson correlation coefficients. RESULTS: Seventy-three percent of participants met the recommended activity criteria compared with 45% in the total U.S. population. Test-retest reliability (kappa) was 0.35-0.53 for moderate activity, 0.80-0.86 for vigorous activity, 0.67-0.84 for recommended activity, and 0.85-0.92 for strengthening. Validity (kappa) of the survey (using the accelerometer as the standard) was 0.17-0.22 for recommended activity. Validity (kappa) of the survey (using the physical activity log as the standard) was 0.40-0.52 for recommended activity. CONCLUSIONS: The validity and reliability of the BRFSS physical activity questions suggests that this instrument can classify groups of adults into the levels of recommended and vigorous activity as defined by Healthy People 2010. Repeated administration of these questions over time will help to identify trends in physical activity.     

Squamous cell carcinoma of bladder after successful intravesical therapy with Bacillus Calmette-Guérin

A case of invasive squamous cell carcinoma of the bladder following intravesical immunotherapy with Bacillus Calmette-Guérin in a patient with pre-existing squamous dysplasia of the bladder is presented.     

Retinol binding protein 4 primes the NLRP3 inflammasome by signaling through Toll-like receptors 2 and 4

Adipose tissue (AT) inflammation contributes to systemic insulin resistance. In obesity and type 2 diabetes (T2D), retinol binding protein 4 (RBP4), the major retinol carrier in serum, is elevated in AT and has proinflammatory effects which are mediated partially through Toll-like receptor 4 (TLR4). We now show that RBP4 primes the NLRP3 inflammasome for interleukin-1β (IL1β) release, in a glucose-dependent manner, through the TLR4/MD2 receptor complex and TLR2. This impairs insulin signaling in adipocytes. IL1β is elevated in perigonadal white AT (PGWAT) of chow-fed RBP4-overexpressing mice and in serum and PGWAT of high-fat diet-fed RBP4-overexpressing mice vs. wild-type mice. Holo- or apo-RBP4 injection in wild-type mice causes insulin resistance and elevates PGWAT inflammatory markers, including IL1β. TLR4 inhibition in RBP4-overexpressing mice reduces PGWAT inflammation, including IL1β levels and improves insulin sensitivity. Thus, the proinflammatory effects of RBP4 require NLRP3-inflammasome priming. These studies may provide approaches to reduce AT inflammation and insulin resistance in obesity and diabetes.

The incidence of type 2 diabetes (T2D) continues to increase worldwide and constitutes a major global health threat (1). Insulin resistance in muscle, adipose tissue (AT), and liver is a hallmark of T2D, which is associated with low-grade chronic inflammation, characterized by increased serum cytokine levels and a proinflammatory immune profile in AT (2–4). Pattern recognition receptors including Toll-like receptors (TLRs) sense pathogenic microbial components (pathogen-associated molecular patterns, PAMPs) and also host-derived damage-associated molecular patterns (DAMPs), which results in nonpathogen-initiated inflammation often referred to as “sterile inflammation” (5). In obesity, TLR2 and TLR4 are implicated in inflammation-induced insulin resistance in AT, and genetic deletion of TLR2 or TLR4 in mice results in improved insulin sensitivity (6, 7). In obese, insulin-resistant humans, TLR2 and TLR4 expression and activation are increased in AT compared to healthy controls (8) and some evidence suggests that people taking an antiinflammatory agent (abatacept, also known as CTLA4-Ig) which blocks antigen presentation, may have improved insulin sensitivity (9, 10). TLR2 and TLR4 signal through the adaptor proteins myeloid differentiation primary response gene 88 (MyD88) and TIR-domain-containing adaptor-inducing IFN (TRIF) to activate proinflammatory signaling cascades including nuclear factor kappa B (NFκB) and c-Jun N-terminal kinase (JNK) (5, 11). This results in AT immune cell migration, activation, and cytokine secretion which augments insulin resistance in adipocytes (12). Thus, TLR2 and TLR4 contribute to AT inflammation and insulin resistance and their targeting may provide treatment strategies for T2D.Retinol binding protein 4 (RBP4), the major serum retinol transporter, is secreted by the liver and AT (13, 14). Serum RBP4 levels are elevated in obese, insulin-resistant mice and humans (15, 16). Genetic and pharmacological elevation of RBP4 induces insulin resistance in wild-type (WT) mice (16, 17) and reducing RBP4 levels improves insulin sensitivity (16, 18). In humans, RBP4 levels are elevated with prediabetes and correlate positively with many metabolic syndrome-related components, including increased waist/hip ratio, intraabdominal fat mass, dyslipidemia, hypertension, and cardiovascular disease in large epidemiological studies (15, 19–21). A gain-of-function polymorphism in the RBP4 promoter which increases adipose RBP4 expression is associated with an 80% increased risk of T2D in humans (19, 22).Inflammation is critical for RBP4-induced insulin resistance which is partially mediated through TLR4 (17, 18, 23). RBP4 induces insulin resistance in adipocytes indirectly by increasing proinflammatory cytokine secretion from macrophages (23). Insulin resistance and AT inflammation have been observed in two mouse models of RBP4 overexpression. Mice overexpressing RBP4 driven by a muscle-specific promoter (RBP4-Ox) have elevated serum and perigonadal white adipose tissue (PGWAT) RBP4 protein levels and PGWAT inflammation (17). Elevated AT RBP4 in these mice activates antigen presentation through the JNK pathway which results in proinflammatory CD4 T cell proliferation and Th1 polarization (17). Mice overexpressing RBP4 selectively in adipocytes also have AT inflammation and glucose intolerance even on a chow diet (14). Transfer of RBP4-activated dendritic cells into normal mice is sufficient to cause AT inflammation and insulin resistance (17). Interestingly, overexpression of RBP4 selectively in hepatocytes has been reported not to cause elevated circulating RBP4 levels and is not associated with insulin resistance (24) even though hepatocytes are thought to be the major site for RBP4 secretion (25). Adipocytes can contribute to circulating RBP4 levels especially in obesity (14). Taken together, these data suggest that RBP4 in AT may be an obesity and insulin-resistance-related damage-associated molecule pattern.Activation of PAMP and DAMP receptors in immune cells leads to the assembly of inflammasomes, which are multiprotein complexes that cleave and activate interleukin-1 beta (IL1β) and interleukin-18 (IL18) (26). The nucleotide-binding domain and leucine-rich repeat containing protein 3 (NLRP3) inflammasome plays a role in the pathogenesis of obesity, type 1 diabetes, type 2 diabetes, and metabolic syndrome (26–28). NLRP3 knockout (KO) protects against insulin resistance in mice (27). NLRP3 activation requires a two-step process. The first “priming” occurs in response to TLR-mediated activation of the NFκB pathway resulting in expression of pro-IL1β (26). The second “activating” step directly induces inflammasome assembly which recruits and cleaves procaspase-1 to its active form caspase-1 (26). Caspase-1 mediates the cleavage of pro-IL1β resulting in IL1β release (26). The NLRP3 inflammasome can be activated by metabolites which are elevated in obesity and insulin resistance, such as palmitate (29). While an ever-expanding list of several metabolites is known to provide the second signal in inflammasome activation, there is a paucity of data on the endogenous proteins and metabolites that provide the first priming signal in obesity and T2D. Here we show that RBP4 is an endogenous NLRP3-inflammasome priming agent and we investigate its upstream signaling pathways.Our data show that elevating RBP4 levels by RBP4 injection in WT mice or genetically induced RBP4 overexpression markedly elevates adipose IL1β expression, which leads to PGWAT inflammation and insulin resistance. IL1β is elevated in PGWAT of chow-fed RBP4-Ox mice and in serum and PGWAT of HFD-fed RBP4-Ox mice compared to WT mice. The RBP4-mediated proinflammatory effects are mediated specifically through TLR2 and a TLR4/MD2 receptor complex, which does not require the other adaptor proteins LPS-binding protein and CD14. The activation of macrophages by RBP4 through TLR2 and TLR4/MD2 requires signaling through the downstream pathways MyD88 and TRIF. TLR4 inhibition in RBP4-Ox reduces IL1β levels in PGWAT and improves insulin sensitivity. The RBP4-mediated increase in IL1β release from macrophages is glucose dependent. Thus, targeting the NLRP3 inflammasome or the upstream activating receptors or pathways may provide therapeutic avenues to ameliorate RBP4-mediated insulin resistance and T2D.