Safety of baclofen versus tizanidine for older adults with musculoskeletal pain.

BACKGROUND: Baclofen and tizanidine are both muscle relaxants that carry the risk for neuropsychiatric events in older adults but there is a lack of data directly comparing their safety. This study aimed to investigate the relative risk between these two medications in causing injury and delirium in older adults. METHODS: This was a retrospective cohort study that was completed in an integrated healthcare system in the United States and included patients aged 65 years or older who started baclofen or tizanidine for the treatment of musculoskeletal pain from January 2016 through December 2018. Outcomes included new incidence of injury (concussion, contusion, dislocation, fall, fracture, or other injuries) and delirium. The cohort was followed from the initiation of therapy until the first occurrence of any of the following events: end of the index drug exposure, end of health plan membership, death, or the study end date of December 31st, 2019. Descriptive statistics were used to compare baseline patient characteristics between baclofen and tizanidine treatment groups. Cox proportional hazards model was used to calculate adjusted hazard ratios (HRs) with 95% confidence intervals. RESULTS: The final study cohort included 12,101 and 6,027 older adults in the baclofen and tizanidine group respectively (mean age 72.2 ± 6.2 years old, 59% female). Older adults newly started on baclofen had a greater risk of injury (HR = 1.54, 95% CI = 1.21-1.96, P = < 0.001) and delirium (HR = 3.33, 95% CI = 2.11-5.26, p = <0.001) compared to those started on tizanidine. CONCLUSION: The results of this study suggest that baclofen is associated with higher incidences of injury and delirium compared to tizanidine when used for the treatment of musculoskeletal pain. Future studies should investigate if these risks are dose-related and include a comparison group not exposed to either drug.

Mixed methods approach to understanding the influence of changes in successive versions of the advanced trauma life support training program on student performance.

BACKGROUND: The Advanced Trauma Life Support course is the American College of Surgeons' standard of care for physicians who provide initial care to trauma victims. In addition to content updates, Advanced Trauma Life Support version 10 adopted contemporary learning theory and practice into the format and conduct of the training. METHODS: The study used a mixed-methods approach wherein a one-group post-test-only study of student and student refresher exam score differences was followed up with a faculty survey to qualitatively explore the quantitative findings. Mann-Whitney U tests were used to test the null hypotheses that student and student refresher test scores on version 9 (2018) and version 10 (2019) were the same. χ2 tests of independence were conducted to test the null hypotheses that student and student refresher initial assessment pass rates under versions 9 and 10 were the same. Faculty survey responses were analyzed descriptively. RESULTS: For the student written tests, the null hypothesis was retained. For the student refresher written tests the null hypothesis was rejected; the 2019 cohort performed worse than the 2018 cohort. Student initial assessment and student refresher initial assessment pass rates in 2018 and 2019 were statistically the same. The majority of faculty reported less motivation for teaching version 10. CONCLUSION: Although a quadrennial review of the format and conduct of Advanced Trauma Life Support courses above and beyond content updates is appropriate, it may be prudent to require strong evidence of improved student performance and value before implementing changes to the training.

Drug discovery for X-linked adrenoleukodystrophy: An unbiased screen for compounds that lower very long-chain fatty acids.

X-linked adrenoleukodystrophy (XALD) is a genetic neurologic disorder with multiple phenotypic presentations and limited therapeutic options. The childhood cerebral phenotype (CCALD), a fatal demyelinating disorder affecting about 35% of patients, and the adult-onset adrenomyeloneuropathy (AMN), a peripheral neuropathy affecting 40%-45% of patients, are both caused by mutations in the ABCD1 gene. Both phenotypes are characterized biochemically by elevated tissue and plasma levels of saturated very long-chain fatty acids (VLCFA), and an increase in plasma cerotic acid (C26:0), along with the clinical presentation, is diagnostic. Administration of oils containing monounsaturated fatty acids, for example, Lorenzo's oil, lowers patient VLCFA levels and reduced the frequency of development of CCALD in presymptomatic boys. However, this therapy is not currently available. Hematopoietic stem cell transplant and gene therapy remain viable therapies for boys with early progressive cerebral disease. We asked whether any existing approved drugs can lower VLCFA and thus open new therapeutic possibilities for XALD. Using SV40-transformed and telomerase-immortalized skin fibroblasts from an XALD patient, we conducted an unbiased screen of a library of approved drugs and natural products for their ability to decrease VLCFA, using measurement of C26:0 in lysophosphatidyl choline (C26-LPC) by tandem mass spectrometry as the readout. While several candidate drugs were initially identified, further testing in primary fibroblast cell lines from multiple CCALD and AMN patients narrowed the list to one drug, the anti-hypertensive drug irbesartan. In addition to lowering C26-LPC, levels of C26:0 and C28:0 in total fibroblast lipids were reduced. The effect of irbesartan was dose dependent between 2 and 10 µM. When male XALD mice received orally administered irbesartan at a dose of 10 mg/kg/day, there was no reduction in plasma C26-LPC. However, irbesartan failed to lower mouse fibroblast C26-LPC consistently. The results of these studies indicate a potential therapeutic benefit of irbesartan in XALD that should be validated by further study.

A Randomized Trial Comparing Antibiotics with Appendectomy for Appendicitis.

BACKGROUND: Antibiotic therapy has been proposed as an alternative to surgery for the treatment of appendicitis. METHODS: We conducted a pragmatic, nonblinded, noninferiority, randomized trial comparing antibiotic therapy (10-day course) with appendectomy in patients with appendicitis at 25 U.S. centers. The primary outcome was 30-day health status, as assessed with the European Quality of Life-5 Dimensions (EQ-5D) questionnaire (scores range from 0 to 1, with higher scores indicating better health status; noninferiority margin, 0.05 points). Secondary outcomes included appendectomy in the antibiotics group and complications through 90 days; analyses were prespecified in subgroups defined according to the presence or absence of an appendicolith. RESULTS: In total, 1552 adults (414 with an appendicolith) underwent randomization; 776 were assigned to receive antibiotics (47% of whom were not hospitalized for the index treatment) and 776 to undergo appendectomy (96% of whom underwent a laparoscopic procedure). Antibiotics were noninferior to appendectomy on the basis of 30-day EQ-5D scores (mean difference, 0.01 points; 95% confidence interval [CI], -0.001 to 0.03). In the antibiotics group, 29% had undergone appendectomy by 90 days, including 41% of those with an appendicolith and 25% of those without an appendicolith. Complications were more common in the antibiotics group than in the appendectomy group (8.1 vs. 3.5 per 100 participants; rate ratio, 2.28; 95% CI, 1.30 to 3.98); the higher rate in the antibiotics group could be attributed to those with an appendicolith (20.2 vs. 3.6 per 100 participants; rate ratio, 5.69; 95% CI, 2.11 to 15.38) and not to those without an appendicolith (3.7 vs. 3.5 per 100 participants; rate ratio, 1.05; 95% CI, 0.45 to 2.43). The rate of serious adverse events was 4.0 per 100 participants in the antibiotics group and 3.0 per 100 participants in the appendectomy group (rate ratio, 1.29; 95% CI, 0.67 to 2.50). CONCLUSIONS: For the treatment of appendicitis, antibiotics were noninferior to appendectomy on the basis of results of a standard health-status measure. In the antibiotics group, nearly 3 in 10 participants had undergone appendectomy by 90 days. Participants with an appendicolith were at a higher risk for appendectomy and for complications than those without an appendicolith. (Funded by the Patient-Centered Outcomes Research Institute; CODA ClinicalTrials.gov number, NCT02800785.).

Risk of Overdose with Exposure to Prescription Opioids, Benzodiazepines, and Non-benzodiazepine Sedative-Hypnotics in Adults: a Retrospective Cohort Study.

BACKGROUND: Concurrent use of benzodiazepines in opioid users has been linked to a higher risk of an emergency room visit or inpatient admission for opioid overdose and death from drug overdose. Further research is needed to confirm the findings and analyze contributing risk factors for opioid overdoses in a large commercially insured population. OBJECTIVES: To estimate the risk of opioid overdose associated with opioid users exposed to various combinations of opioid, benzodiazepine, and non-benzodiazepine sedative-hypnotic therapy. To identify other factors that are associated with increased risk for opioid overdose. DESIGN: Retrospective cohort study. PATIENTS: New start adult users of opioids, defined as naïve to opioids for 6 months, in Kaiser Permanente California regions from January 2013 through September 2017. MAIN MEASURES: Inpatient or emergency department admissions due to opioid-related overdose. KEY RESULTS: A total of 2,241,530 patients were included in this study. Patients exposed to opioids, benzodiazepines, and non-benzodiazepine sedative-hypnotics at any point during their follow-up were 60% more likely to overdose than those who were only exposed to opioids (p < 0.0001). Those exposed to opioids and benzodiazepines were 20% more likely to have an opioid-related overdose than those exposed to opioids only (p < 0.0001). Significant risk factors for opioid overdose included exposure to all three medication classes, higher opioid dosage strengths, elderly age (age ≥ 65 years), history of previous overdose, and substance use disorder. CONCLUSIONS: Results from this study demonstrate a significant increase in risk of opioid overdose in patients exposed to combinations of sedative-hypnotics with opioids compared to those only taking opioids. Findings from this study provide evidence that opioids should be avoided in combination with benzodiazepines and non-benzodiazepine sedative-hypnotics, used at the lowest dose possible, and used with caution in the elderly, those with previous history of overdose, and those with substance use disorder at baseline.

Refining the Definition of Polypharmacy and Its Link to Disability in Older Adults: Conceptualizing Necessary Polypharmacy, Unnecessary Polypharmacy, and Polypharmacy of Unclear Benefit.

The term polypharmacy in older adults is generally used in a pejorative context in the medical literature. Because of its link to geriatric syndromes and disability, the avoidance of polypharmacy is usually recommended in older adults as a strategy to optimize functional status. However, there are many polypharmacy regimens based on high-quality trials that clearly reduce the risk of disability in older adults. Other guidelines for older adults recommend the use of additional medications that may or may not be evidence based and that may or may not reduce disability. Therefore, we propose that, in the geriatric literature, polypharmacy now be categorized as "necessary polypharmacy," "unnecessary polypharmacy," or "polypharmacy of unclear benefit." In this article, we discuss the 3 categories of polypharmacy and give examples on each polypharmacy regimen and its potential relationship to disability in older adults.

Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Peroxisomal disorders are a clinically and genetically heterogeneous group of diseases caused by defects in peroxisomal biogenesis or function, usually impairing several metabolic pathways. Peroxisomal disorders are rare; however, the incidence may be underestimated due to the broad spectrum of clinical presentations. The inclusion of X-linked adrenoleukodystrophy to the Recommended Uniform Screening Panel for newborn screening programs in the United States may increase detection of this and other peroxisomal disorders. The current diagnostic approach relies heavily on biochemical genetic tests measuring peroxisomal metabolites, including very long-chain and branched-chain fatty acids in plasma and plasmalogens in red blood cells. Molecular testing can confirm biochemical findings and identify the specific genetic defect, usually utilizing a multiple-gene panel or exome/genome approach. When next-generation sequencing is used as a first-tier test, evaluation of peroxisome metabolism is often necessary to assess the significance of unknown variants and establish the extent of peroxisome dysfunction. This document provides a resource for laboratories developing and implementing clinical biochemical genetic testing for peroxisomal disorders, emphasizing technical considerations for sample collection, test performance, and result interpretation. Additionally, considerations on confirmatory molecular testing are discussed.

Operation continued care: A large mass-casualty, full-scale exercise as a test of regional preparedness.

BACKGROUND: Our regional trauma organization, which comprises 7 trauma centers, 30 acute care hospitals and free-standing emergency departments, and 42 emergency medical services agencies, conducted possibly the largest mass-casualty drill to date, totaling 445 victims at 3 sites involving 11 hospitals and 25 agencies and organizations. METHODS: The drill was preceded by a tabletop exercise 4 months beforehand called Operation Continued Care Full-Scale Exercise, which consisted of simulated terrorist events at 3 sites to wound 445 moulaged patients. Four law enforcement and 5 fire and emergency medical services departments and 16 supporting organizations and agencies were involved in transporting patients to 11 different hospitals. The 7 objectives for the event addressed coordinating emergency operations, sustaining adequate communications, updating regional bed status, processing resource requests, triaging patients, tracking patients, and patient identification. RESULTS: Of the 445 transported patients, 270 (60%) were entered correctly into the state patient tracking system; 68 (25.2%) upgrades and 34 (12.6%) downgrades from scene triage categories were noted. Multiple opportunities for improvement were identified, with major weaknesses noted in communication and coordination from event sites to the regional trauma organizations and hospitals. CONCLUSION: The size and complexity of the drill provided experience and knowledge to facilitate future disaster preparedness and highlighted weaknesses in communication and coordination. Large, multijurisdictional, multiagency exercises provide opportunities to stress, evaluate, and improve regional disaster preparedness.

Is Your Career Hurting You? The Ergonomic Consequences of Surgery in 701 Urologists Worldwide.

Purpose: Our objective was to seek correlations between the type, volume, and duration of surgical work performed, surgeon habits and characteristics, and the prevalence of neck and back musculoskeletal complaint and intervention across career from training to retirement. Materials and Methods: An anonymous web-based multinational survey of urologists was conducted. The primary outcome measured was pain. Secondary outcomes included pain requiring intervention and surgery. Responses were subgrouped according to geography, practice patterns, and demographics. Student t test, Fisher's exact test, and chi-square test were used for analysis. Results: A total of 701 complete responses were received from this multinational survey. Gender, pain distribution, and private or academic practice did not correlate with pain, whereas exercise, lower weight, and body mass index (BMI) were protective. Dose-response of surgical type was assessed with high- and low-volume density quartiles and frequency of each pain severity; no correlation was found. Secondary analysis showed that female practitioners seek invasive therapy less than male counterparts, and practitioners of direct optical cystoscopy report no more neck trouble than others. Length of career since residency shows little relationship to pain or pain-free rates. Conclusions: In this, the largest surgical ergonomic study to date: surgical type, duration, volume, setting, and physician gender were unrelated to surgeon pain throughout career. Exercise was associated with lower prevalence of pain in a dose-related manner; increasing weight and BMI were positively associated with pain. Although 47% of urologists with spinal pain blame their career, we are unable to identify any dose-response relationship that supports that assumption.

Efficacy and Safety of a Tofacitinib-based Immunosuppressive Regimen After Kidney Transplantation: Results From a Long-term Extension Trial.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. This open-label, long-term extension (LTE) study (NCT00658359) evaluated long-term tofacitinib treatment in stable kidney transplant recipients (n = 178) posttransplant. METHODS: Patients who completed 12 months of cyclosporine (CsA) or tofacitinib treatment in the phase IIb parent study (NCT00483756) were enrolled into this LTE study, evaluating long-term tofacitinib treatment over months 12 to 72 posttransplant. Patients were analyzed by tofacitinib less-intensive (LI) or more-intensive (MI) regimens received in the parent study. For both groups, tofacitinib dose was reduced from 10 to 5 mg twice daily by 6 months into the LTE. Patients were followed up through month 72 posttransplant, with a focus on month 36 results. RESULTS: Tofacitinib demonstrated similar 36-month patient and graft survival rates to CsA. Biopsy-proven acute rejection rates at month 36 were 11.2% for CsA, versus 10.0% and 7.4% (both P > 0.05) for tofacitinib LI and MI, respectively. Least squares mean estimated glomerular filtration rates were 9 to 15 mL/min per 1.73 m2 higher for tofacitinib versus CsA at month 36. The proportions of patients with grade 2/3 interstitial fibrosis and tubular atrophy in month 36 protocol biopsies were 20.0% for LI and 18.2% for MI (both P > 0.05) versus 33.3% for CsA. Kaplan-Meier cumulative serious infection rates at month 36 were numerically higher for tofacitinib LI (43.9%; P = 0.45) and significantly higher for MI (55.9%; P < 0.05) versus CsA (37.1%). CONCLUSIONS: Long-term tofacitinib continued to be effective in preventing renal allograft acute rejection and preserving renal function. However, long-term tofacitinib and mycophenolic acid product combination was associated with persistent serious infection risk.

Risk of acute kidney injury in critically ill surgical patients with presumed pneumonia is not impacted by choice of methicillin-resistant staphylococcus aureus therapy.

BACKGROUND: Vancomycin and linezolid are standard treatment options for nosocomial methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. While acute kidney injury (AKI) is commonly attributed to vancomycin, existing data has not definitely confirmed vancomycin as an independent risk factor for AKI. AIMS: This study aimed to quantify the incidence of AKI in Surgical Intensive Care Unit (ICU) patients receiving empiric vancomycin or linezolid for nosocomial pneumonia and to identify risk factors for AKI with a focus on MRSA antibiotic therapy. MATERIALS AND METHODS: A retrospective cohort analysis of surgical ICU patients who received at least 48 h of vancomycin or linezolid for pneumonia was performed. Patients who received vancomycin were compared to those who received linezolid with a primary endpoint of AKI as defined by the risk/injury/failure/loss/end-stage renal disease (RIFLE) criteria. A modified RIFLE criteria assessing only changes in serum creatinine was also used. RESULTS: One hundred one patients were evaluated (63 vancomycin and 38 linezolid). AKI occurred in 51 (81.0%) and 32 (84.2%) patients in the vancomycin and linezolid groups (P = 0.79), respectively. Using the modified RIFLE criteria, AKI occurred in 19 (30.2%) and 14 (36.8%) patients in the vancomycin and linezolid groups (P = 0.448). After adjustment for age, diabetes mellitus, Charlson comorbidity index, and concomitant nephrotoxins, there was no difference in risk of AKI between groups (P = 0.773). CONCLUSIONS: Patients who received empiric vancomycin or linezolid for nosocomial pneumonia experienced high, but similar rates of AKI. The results suggest MRSA antibacterial therapy in this setting may not be independently indicative of AKI risk, rather the risk is likely multifactorial.

Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder.

Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3' untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C>T, did not show AEI and were homozygous for the 3' UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.

X-linked adrenoleukodystrophy in a chimpanzee due to an ABCD1 mutation reported in multiple unrelated humans.

BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is a genetic disorder leading to the accumulation of very long chain fatty acids (VLCFA) due to a mutation in the ABCD1 gene. ABCD1 mutations lead to a variety of phenotypes, including cerebral X-ALD and adrenomyeloneuropathy (AMN) in affected males and 80% of carrier females. There is no definite genotype-phenotype correlation with intrafamilial variability. Cerebral X-ALD typically presents in childhood, but can also present in juveniles and adults. The most affected tissues are the white matter of the brain and adrenal cortex. MRI demonstrates a characteristic imaging appearance in cerebral X-ALD that is used as a diagnostic tool. OBJECTIVES: We aim to correlate a mutation in the ABCD1 gene in a chimpanzee to the human disease X-ALD based on MRI features, neurologic symptoms, and plasma levels of VLCFA. METHODS: Diagnosis of X-ALD made using MRI, blood lipid profiling, and DNA sequencing. RESULTS: An 11-year-old chimpanzee showed remarkably similar features to juvenile onset cerebral X-ALD in humans including demyelination of frontal lobes and corpus callosum on MRI, elevated plasma levels of C24:0 and C26:0, and identification of the c.1661G>A ABCD1 variant. CONCLUSIONS: This case study presents the first reported case of a leukodystrophy in a great ape, and underscores the fidelity of MRI pattern recognition in this disorder across species.

Acute Illness Among Surfers After Exposure to Seawater in Dry- and Wet-Weather Conditions.

Rainstorms increase levels of fecal indicator bacteria in urban coastal waters, but it is unknown whether exposure to seawater after rainstorms increases rates of acute illness. Our objective was to provide the first estimates of rates of acute illness after seawater exposure during both dry- and wet-weather periods and to determine the relationship between levels of indicator bacteria and illness among surfers, a population with a high potential for exposure after rain. We enrolled 654 surfers in San Diego, California, and followed them longitudinally during the 2013-2014 and 2014-2015 winters (33,377 days of observation, 10,081 surf sessions). We measured daily surf activities and illness symptoms (gastrointestinal illness, sinus infections, ear infections, infected wounds). Compared with no exposure, exposure to seawater during dry weather increased incidence rates of all outcomes (e.g., for earache or infection, adjusted incidence rate ratio (IRR) = 1.86, 95% confidence interval (CI): 1.27, 2.71; for infected wounds, IRR = 3.04, 95% CI: 1.54, 5.98); exposure during wet weather further increased rates (e.g., for earache or infection, IRR = 3.28, 95% CI: 1.95, 5.51; for infected wounds, IRR = 4.96, 95% CI: 2.18, 11.29). Fecal indicator bacteria measured in seawater (Enterococcus species, fecal coliforms, total coliforms) were strongly associated with incident illness only during wet weather. Urban coastal seawater exposure increases the incidence rates of many acute illnesses among surfers, with higher incidence rates after rainstorms.