Intranasal neomycin evokes broad-spectrum antiviral immunity in the upper respiratory tract.

Respiratory virus infections in humans cause a broad-spectrum of diseases that result in substantial morbidity and mortality annually worldwide. To reduce the global burden of respiratory viral diseases, preventative and therapeutic interventions that are accessible and effective are urgently needed, especially in countries that are disproportionately affected. Repurposing generic medicine has the potential to bring new treatments for infectious diseases to patients efficiently and equitably. In this study, we found that intranasal delivery of neomycin, a generic aminoglycoside antibiotic, induces the expression of interferon-stimulated genes (ISGs) in the nasal mucosa that is independent of the commensal microbiota. Prophylactic or therapeutic administration of neomycin provided significant protection against upper respiratory infection and lethal disease in a mouse model of COVID-19. Furthermore, neomycin treatment protected Mx1 congenic mice from upper and lower respiratory infections with a highly virulent strain of influenza A virus. In Syrian hamsters, neomycin treatment potently mitigated contact transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In healthy humans, intranasal application of neomycin-containing Neosporin ointment was well tolerated and effective at inducing ISG expression in the nose in a subset of participants. These findings suggest that neomycin has the potential to be harnessed as a host-directed antiviral strategy for the prevention and treatment of respiratory viral infections.

Arterial dissection during peripheral vascular interventions.

OBJECTIVE: Arterial dissection (AD) is a known complication of peripheral vascular interventions (PVIs), but its incidence and significance have not been well-characterized. This study examines AD in the Vascular Quality Initiative database for patients treated for peripheral arterial disease. Our hypothesis is that AD is associated with decreased patency and worse limb outcomes. METHODS: The Vascular Quality Initiative PVI registry (2016-2021) was reviewed. Patients were divided based on the presence or absence of reported AD during the procedure. Trend of incidence and management of AD was derived. The characteristics and outcomes of patients with and without AD were compared. The primary endpoint was primary patency. RESULTS: There was a total of 177,790 cases, and 3% had AD. The incidence of AD significantly increased over the study period from 2.4% to 3.6% (P = .007). Endovascular therapy was used to treat AD in 83.7% of cases, 14.5% were treated medically, and only 1.8% required open surgery. Patients with AD were significantly more likely to be female (47.4% vs 39.7%; P < .001). Patient with AD were more likely to have a history of smoking (79.7% vs 77.2%; P < .001), but were significantly less likely to be on dialysis (8.2% vs 9.3%; P < .001) compared with patients without AD. Patients with AD were more likely to have femoropopliteal disease (45.2% vs 38.0%; P < .001) and undergo treatment of more complex disease as denoted by higher mean number of lesions treated (1.95 ± 1.01 vs 1.71 ± 0.89; P < .001), longer occlusion length (8 ± 16 vs 7 ± 15 cm; P < .001), and more severe TransAtlantic Inter-Society Consensus grade (Grade D: 36.2% vs 29.1%; P < .001). The proportion of stenting as a treatment modality was higher in the dissection group (55.4% vs 41.1%; P < .001). After a mean follow-up of 828 days, patients with AD had significantly lower primary patency than patients without AD. Kaplan-Meier curves demonstrated that the AD group had lower primary patency (86.9% vs 91%; P < .001) and reintervention-free survival (79.5 % vs 84.1%; P < .001) at 1 year with difference in amputation-free survival. Cox proportional hazard regression confirmed the independent association of AD with primary patency and reintervention-free survival. CONCLUSIONS: AD is more common in women and is more likely to occur during treatment of the femoropopliteal segment. AD is associated with decreased primary patency and reintervention-free survival after PVI for peripheral arterial disease.

Comparative Outcomes of Peripheral Vascular Interventions in Patients on Chronic Anticoagulation with Factor Xa Inhibitors and Vitamin K Antagonists.

BACKGROUND: In patients undergoing revascularization for peripheral arterial disease (PAD), low-dose Factor Xa inhibitors (FXaI) taken with aspirin improved limb and cardiovascular outcomes compared to aspirin alone. Furthermore, in atrial fibrillation and venous thromboembolism, FXaI are recommended over vitamin K antagonists (VKA) for chronic anticoagulation. While studies have evaluated different perioperative anticoagulation regimens in patients treated for PAD, the optimal regimen for chronic anticoagulation in patients with PAD undergoing peripheral vascular intervention (PVI) has not been determined. This analysis compares outcomes of patients after PVI that require chronic anticoagulation with FXaI and VKA. METHODS: The Vascular Quality Initiative-PVI database was used. Patients consistently treated with FXaI or VKA before the procedure, at discharge, and on long-term follow-up were defined as those receiving chronic anticoagulation. Patient demographics, procedural details, and perioperative and long-term outcomes were compared between FXaI and VKA groups. RESULTS: A total of 109,268 patients were analyzed, and 6,885 were chronically anticoagulated with FXaI (N = 2,427) or VKA (N = 4,458). Patients anticoagulated with VKA were more frequently males (65.3% vs. 61.0%, P < 0.001) with end-stage renal disease (9.7% vs. 4.6%, P < 0.001) and more likely to be treated for chronic limb-threatening ischemia (58.1% vs. 52.7%, P < 0.001). Rates of hematoma following PVI were significantly higher in patients taking VKA compared to FXaI (3.5% vs. 1.9%, P < 0.001). Multivariable logistic regression analysis showed that VKA were associated with increased perioperative hematoma than FXaI (odds ratio = 1.89 [1.30-2.82]). Compared to patients taking VKA, those receiving FXaI had lower rates of major amputation (6.7% vs. 8.4%, P = 0.020) and mortality (7.6% vs. 15.2%, P ≤ 0.001). Using Kaplan-Meier analysis, patients consistently anticoagulated with FXaI had improved amputation-free survival after PVI. Adjusting for significant patient and procedural characteristics, Cox proportional hazard regression demonstrated that there is an increased risk for major amputation or mortality in patients using VKA compared to FXaI (hazard ratio 1.61, [1.36-1.90]). CONCLUSIONS: Chronic anticoagulation with FXaI as compared to VKA was associated with superior perioperative and long-term outcomes in patients with PAD undergoing PVI. FXaI should be the preferred agents over VKA for chronic anticoagulation in patients with PAD undergoing PVI.

Clinical Implications of Low Body Mass Index on Endovascular Lower Extremity Revascularization.

BACKGROUND: The epidemic of obesity and associated cardiovascular morbidity continues to grow, attracting public attention and healthcare resources. However, the impact of malnutrition and being underweight continues to be overshadowed by obesity, especially in patients with peripheral arterial disease (PAD). This study assesses the characteristics and outcomes of patients with low body mass index (BMI ≤ 18.5) compared to patients with nonobese BMI undergoing peripheral vascular interventions (PVI). METHODS: A retrospective analysis of patients undergoing PVI due to PAD registered in the Vascular Quality Initiative database. Patients were categorized into underweight (BMI ≤ 18.5) and nonobese BMI (BMI = 18.5-30). Patients in both groups were matched 3:1 for baseline demographic characteristics, comorbidities, medications, and indications. Kaplan-Meier analysis was done for long-term outcomes. RESULTS: A total of 337,926 patients underwent PVI, of whom 12,935 (4%) were underweight, 215,728 (64%) were nonobese, and 109,263 (32%) were obese. Underweight patients were more likely to be older, female, smokers, with chronic obstructive pulmonary disorder, and more likely to present with chronic limb-threatening ischemia than nonobese patients. After propensity matching, there were 18,047 nonobese patients and 6,031 underweight patients. There were no significant differences in matched characteristics. Perioperatively, underweight patients were more likely to require a longer hospital length of stay. Underweight patients had statistically significantly higher 30-day mortality compared to patients with nonobese BMI (3% vs. 1.6%, P < 0.001) and a higher rate of thrombotic complications. As for long-term outcomes, underweight patients had a higher rate of reintervention (20% vs. 18%, P < 0.001) and major adverse limb events (27% vs. 22%, P < 0.001). The 4-year rate of amputation-free survival was significantly lower in underweight patients (70% vs. 82%, P < 0.001), and the 2-year freedom from major amputation (90% vs. 94%, P < 0.001) showed similar trends with worse outcomes in patients who were underweight. CONCLUSIONS: Underweight patients with PAD are disproportionally more likely to be African American, females, and smokers and suffer worse outcomes after PVI than PAD patients with nonobese BMI. When possible, increased scrutiny and optimization of nutrition and other factors contributing to low BMI should be addressed prior to PVI.

The Use and Impact of Cilostazol on Patients Undergoing Endovascular Peripheral Interventions.

BACKGROUND: Cilostazol is used for the treatment of intermittent claudication. The impact of cilostazol on the outcomes of peripheral vascular interventions (PVIs) remains controversial. This study assesses the use and impact of cilostazol on patients undergoing PVI for peripheral arterial disease (PAD). METHODS: The Vascular Quality Initiative (VQI) database files for PVI were reviewed. Patients with PAD who underwent PVI for chronic limb threatening-ischemia or claudication were included and divided based on the use of cilostazol preoperatively. After propensity matching for patient demographics and comorbidities, the short-term and long-term outcomes of the 2 groups (preoperative cilostazol use versus no preoperative cilostazol use) were compared. The Kaplan-Meier method was used to determine outcomes. RESULTS: A total of 245,309 patients underwent PVI procedures and 6.6% (N = 16,366) were on cilostazol prior to intervention. Patients that received cilostazol were more likely to be male (62% vs 60%; P < 0.001), White (77% vs. 75%; P < 0.001), and smokers (83% vs. 77%; P < 0.001). They were less likely to have diabetes mellitus (50% vs. 56%; P < 0.001) and congestive heart failure (14% vs. 23%; P < 0.001). Patient on cilostazol were more likely to be treated for claudication (63% vs. 40%, P < 0.001), undergo prior lower extremity revascularization (55% vs. 51%, P < 0.001) and less likely to have undergone prior minor and major amputation (10% vs. 19%; P < 0.001) compared with patients who did not receive cilostazol. After 3:1 propensity matching, there were 50,265 patients included in the analysis with no differences in baseline characteristics. Patients on cilostazol were less likely to develop renal complications and more likely to be discharged home. Patients on cilostazol had significantly lower rates of long-term mortality (11.5% vs. 13.4%, P < 0.001 and major amputation (4.0% vs. 4.7%, P = 0.022). However, there were no significant differences in rates of reintervention, major adverse limb events, or patency after PVI. Amputation-free survival rates were significantly higher for patients on cilostazol, after 4 years of follow up (89% vs. 87%, P = 0.03). CONCLUSIONS: Cilostazol is underutilized in the VQI database and seems to be associated with improved amputation-free survival. Cilostazol therapy should be considered in all patients with PAD who can tolerate it prior to PVI.

Insulin Requirement and Infrainguinal Bypass Outcomes in Patients with Peripheral Arterial Disease.

BACKGROUND: Diabetes mellitus (DM) is a major risk factor for peripheral artery disease. The association of DM with major adverse limb events (MALE) after lower extremity revascularization remains controversial, as patients with diabetes are typically analyzed as a single, homogenous group. Using a large national database, this study examines the impact of insulin use and glycemic control on the outcomes following infrainguinal bypass. The hypothesis is that prevalent insulin therapy and elevated hemoglobin A1c (HbA1c) are associated with an increased risk of MALEs after infrainguinal bypass in patients with DM and could therefore be used for risk stratification. METHODS: The Vascular Quality Initiative database files for infrainguinal bypass (2007-2021) were retrospectively reviewed. Patients with DM undergoing bypass for peripheral artery disease were included. Patients on dialysis or with prior kidney transplantation were excluded. The characteristics and outcomes of patients with insulin-requiring diabetes mellitus (IRDM) were compared to those of patients not requiring insulin (noninsulin-requiring diabetes mellitus [NIRDM]) prior to the bypass procedure. RESULTS: A total of 9,686 patients with DM (56% IRDM) underwent bypass. Patients with IRDM were significantly younger than patients with NIRDM, more likely to be female (P < 0.01), African American (P < 0.01), and Hispanic (P = 0.031), and more likely to have comorbidities and be categorized into American Society of Anesthesiologist classes IV-V. They were more likely to be treated for chronic limb-threatening ischemia (P < 0.001). Patients with IRDM had significantly higher perioperative complications with no difference in perioperative mortality between the 2 groups. Beyond the perioperative period, with a mean follow-up of 427 days, patients with IRDM had significantly lower crude rates of primary patency and higher crude rates of major amputation, MALE, and mortality compared to patients with NIRDM. Regression analyses demonstrated that insulin requirement, but not HbA1c, was independently associated with a higher risk of MALE (hazard ratio = 1.17 [1.06-1.29]) and mortality (hazard ratio = 1.28 [1.16-1.43]). CONCLUSIONS: Insulin requirement, but not HbA1c, is significantly associated with MALEs and survival after infrainguinal bypass in the Vascular Quality Initiative. Stratification of patients with DM based on their prevalent insulin use prior to infrainguinal bypass surgery could improve the prediction of outcomes of peripheral arterial bypass surgery in patients with diabetes.

The management of patients with popliteal artery aneurysms presenting with acute limb ischemia.

OBJECTIVE: Endovascular popliteal artery aneurysm (PAA) repair has acceptable outcomes compared with open repair for elective therapy. Endovascular repair for urgent PAA causing acute limb ischemia (ALI) has not been well-studied. This project compares outcomes of urgent endovascular and open repair of PAA with ALI. METHODS: The Vascular Quality Initiative database for peripheral vascular interventions (PVIs) and infrainguinal bypass were reviewed for PAAs with ALI from 2010 to 2021. Only patients entered as having symptoms of ALI in the PVI module and ALI as indication in the infrainguinal bypass module were included. In addition, patients undergoing elective treatment were excluded and the sample analyzed was restricted to patients undergoing urgent and emergent open and endovascular repair. Patient demographics and comorbidities as well as procedural details were compared between the two groups. Perioperative complications up to 30 days were compared as well as long-term outcomes including major amputation and mortality at 1 year. RESULTS: Urgent PAA repair for ALI constituted 10.5% (n = 571) of all PAAs. Most urgent repairs were open (80.6%; n = 460) with 19.4% (n = 111) endovascular. The proportion of endovascular repair significantly increased from 16.7% in 2010 to 85.7% in 2021. Patients undergoing endovascular repair were older (71.2 ± 12.5 vs 68.0 ± 11.8; P = .011) than patients undergoing open repair. They were also more likely to have coronary artery disease (32.4% vs 21.7%; P = .006). Open PAA repair was associated with more bleeding complications (20.8% vs 2.7%; P < .001), longer postoperative length of stay (8.1 ± 9.3 days vs 4.9 ± 5.6 days; P < .001), and less likelihood of discharge to home (64.9% vs 70.3%; P = .051). Perioperative major amputation rate was 7.5% with no difference between the two treatment strategies up to 1 year. However, patients receiving endovascular repair had higher inpatient (1.1% vs 0%; P < .001), 30-day (6.3% vs 0.4%; P < .001), and 1-year (16.5% vs 8.4%; P = .02) mortality. Multivariable regression analysis suggested that endovascular repair was possibly associated with increased 30-day mortality, but not 1-year mortality. CONCLUSIONS: Endovascular PAA has exponentially increased from 2010 to 2021. Endovascular repair is associated with decreased complications and hospital length of stay. The increased perioperative mortality seen in this group is likely due to selection bias.

WBAs in UME-How Many Are Needed? A Reliability Analysis of 5 AAMC Core EPAs Implemented in the Internal Medicine Clerkship.

BACKGROUND: Reliable assessments of clinical skills are important for undergraduate medical education, trustworthy handoffs to graduate medical programs, and safe, effective patient care. Entrustable professional activities (EPAs) for entering residency have been developed; research is needed to assess reliability of such assessments in authentic clinical workspaces. DESIGN: A student-driven mobile assessment platform was developed and used for clinical supervisors to record ad hoc entrustment decisions using the modified Ottawa scale on 5 core EPAs in an 8-week internal medicine (IM) clerkship. After a 12-month period, generalizability (G) theory analysis was performed to estimate the reliability of entrustment scores and determine the proportion of variance attributable to the student and the other facets, including particular EPA, evaluator type (attending versus resident), or case complexity. Decision (D) theory analysis determined the expected reliability based on the number of hypothetical observations. A g-coefficient of 0.7 was used as a generally agreed upon minimum reliability threshold. KEY RESULTS: A total of 1368 ratings over the 5 EPAs were completed on 94 students. Variance attributed to person (true variance) was high for all EPAs; EPA-5 had the lowest person variance (9.8% across cases and four blocks). Across cases, reliability ranged from 0.02 to 0.60. Applying this to the Decision study, the estimated number of observations needed to reach a reliability index of 0.7 ranged between 9 and 11 for all EPAs except EPA5 which was sensitive to case complexity. CONCLUSIONS: Work place-based clinical skills in IM clerkship students were assessed and logged using a convenient mobile platform. Our analysis suggests that 9-11 observations are needed for these EPA workplace-based assessments (WBAs) to achieve a reliability index of 0.7. Note writing was very sensitive to case complexity. Further reliability analyses of core EPAs are needed before US medical schools consider wider adoption into summative entrustment processes and GME handoffs.

SPLUNC1: a novel marker of cystic fibrosis exacerbations.

BACKGROUND: Acute pulmonary exacerbations (AE) are episodes of clinical worsening in cystic fibrosis (CF), often precipitated by infection. Timely detection is critical to minimise morbidity and lung function declines associated with acute inflammation during AE. Based on our previous observations that airway protein short palate lung nasal epithelium clone 1 (SPLUNC1) is regulated by inflammatory signals, we investigated the use of SPLUNC1 fluctuations to diagnose and predict AE in CF. METHODS: We enrolled CF participants from two independent cohorts to measure AE markers of inflammation in sputum and recorded clinical outcomes for a 1-year follow-up period. RESULTS: SPLUNC1 levels were high in healthy controls (n=9, 10.7 µg·mL-1), and significantly decreased in CF participants without AE (n=30, 5.7 µg·mL-1; p=0.016). SPLUNC1 levels were 71.9% lower during AE (n=14, 1.6 µg·mL-1; p=0.0034) regardless of age, sex, CF-causing mutation or microbiology findings. Cytokines interleukin-1ß and tumour necrosis factor-α were also increased in AE, whereas lung function did not decrease consistently. Stable CF participants with lower SPLUNC1 levels were much more likely to have an AE at 60 days (hazard ratio (HR)±se 11.49±0.83; p=0.0033). Low-SPLUNC1 stable participants remained at higher AE risk even 1 year after sputum collection (HR±se 3.21±0.47; p=0.0125). SPLUNC1 was downregulated by inflammatory cytokines and proteases increased in sputum during AE. CONCLUSION: In acute CF care, low SPLUNC1 levels could support a decision to increase airway clearance or to initiate pharmacological interventions. In asymptomatic, stable patients, low SPLUNC1 levels could inform changes in clinical management to improve long-term disease control and clinical outcomes in CF.

JAK-inhibitor and type I interferon ability to produce favorable clinical outcomes in COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: The spread of a highly pathogenic, novel coronavirus (SARS-CoV-2) has emerged as a once-in-a-century pandemic, having already infected over 63 million people worldwide. Novel therapies are urgently needed. Janus kinase-inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients due to their proven efficacy against diseases with excessive cytokine release and their direct antiviral ability against viruses including coronaviruses, respectively. METHODS: A search of MEDLINE and MedRxiv was conducted by three investigators from inception until July 30th 2020 and included any study type that compared treatment outcomes of humans treated with Janus kinase-inhibitor or Type I interferon against controls. Inclusion necessitated data with clearly indicated risk estimates or those that permitted their back-calculation. Outcomes were synthesized using RevMan. RESULTS: Of 733 searched studies, we included four randomized and eleven non-randomized trials. Five of the studies were unpublished. Those who received Janus kinase-inhibitor had significantly reduced odds of mortality (OR, 0.12; 95% CI, 0.03-0.39, p< 0.001) and ICU admission (OR, 0.05; 95% CI, 0.01-0.26, p< 0.001), and had significantly increased odds of hospital discharge (OR, 22.76; 95% CI, 10.68-48.54, p< 0.00001) when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95% CI, 0.04-0.85, p< 0.05), and increased odds of discharge bordering significance (OR, 1.89; 95% CI, 1.00-3.59, p=0.05). CONCLUSIONS: Janus kinase-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes in regard to mortality and discharge. While these data show promise, additional well-conducted RCTs are needed to further elucidate the relationship between clinical outcomes and Janus kinase-inhibitors and Type I interferons in COVID-19 patients.

Predictors for Matriculation into Geriatric Psychiatry Fellowship: Data from a 2019-2020 National Survey of U.S. Program Directors.

OBJECTIVE: With the number of geriatric psychiatry fellows declining from a peak of 106 during 2002-2003 to 48 during 2020-2021, this study aims to investigate characteristics of the geriatric psychiatry training requirement across U.S. psychiatry residency programs and to identify specific factors which may influence residents to pursue geriatric psychiatry subspecialty training. METHODS: The authors queried the American Medical Association's Fellowship and Residency Electronic Interactive Database Access system to compile a list of program directors from the Accreditation Council for Graduate Medical Education sponsored general adult psychiatry residency programs. Program directors were emailed an anonymous multiple-choice survey to ascertain specific characteristics of their program's geriatric psychiatry training experiences. This study's primary outcome was the percentage of residents entering geriatric psychiatry fellowship after completion of general psychiatry training. Linear regression analysis determined which variables may be associated with this primary outcome. RESULTS: Of 248 surveyed, 60 programs (24%) responded to the survey. Only one of the independent variables revealed a statistically significant association with the percent of residents that became geriatric psychiatry fellows: the number of geriatric psychiatrists at the residents' home institution (p=0.002). CONCLUSIONS: Consistent with previous data, the presence of geriatric psychiatry faculty members is strongly associated with the decision to pursue subspecialty training in geriatric psychiatry.

BPIFA1 regulates lung neutrophil recruitment and interferon signaling during acute inflammation.

Bpifa1 (BPI fold-containing group A member 1) is an airway host-protective protein with immunomodulatory properties that binds to LPS and is regulated by infectious and inflammatory signals. Differential expression of Bpifa1 has been widely reported in lung disease, yet the biological significance of this observation is unclear. We sought to understand the role of Bpifa1 fluctuations in modulating lung inflammation. We treated wild-type (WT) and Bpifa1-/- mice with intranasal LPS and performed immunological and transcriptomic analyses of lung tissue to determine the immune effects of Bpifa1 deficiency. We show that neutrophil (polymorphonuclear cells, PMNs) lung recruitment and transmigration to the airways in response to LPS is impaired in Bpifa1-/- mice. Transcriptomic analysis revealed a signature of 379 genes that differentiated Bpifa1-/- from WT mice. During acute lung inflammation, the most downregulated genes in Bpifa1-/- mice were Cxcl9 and Cxcl10. Bpifa1-/- mice had lower bronchoalveolar lavage concentrations of C-X-C motif chemokine ligand 10 (Cxcl10) and Cxcl9, interferon-inducible PMN chemokines. This was consistent with lower expression of IFNγ, IFNλ, downstream IFN-stimulated genes, and IFN-regulatory factors, which are important for the innate immune response. Administration of Cxcl10 before LPS treatment restored the inflammatory response in Bpifa1-/- mice. Our results identify a novel role for Bpifa1 in the regulation of Cxcl10-mediated PMN recruitment to the lungs via IFNγ and -λ signaling during acute inflammation.

Early hearing slope as a predictor of subsequent hearing trajectory in a noise-exposed occupational cohort.

Variations in individual susceptibility to noise-induced hearing loss have been observed among workers exposed to similar ambient noise levels but the reasons for this observation are poorly understood. Many workers are exposed to hazardous levels of occupational noise throughout their entire careers. Therefore, a mechanism to identify workers at risk for accelerated hearing loss early in their career may offer a time-sensitive window for targeted intervention. Using available longitudinal data for an occupationally noise-exposed cohort of manufacturing workers, this study aims to examine whether change in an individual's high frequency hearing level during the initial years of occupational noise exposure can predict subsequent high frequency hearing loss. General linear mixed modeling was used to model later hearing slope in the worse ear for the combined frequencies of 3, 4, and 6 kHz as a function of early hearing slope in the worse ear, age at baseline, sex, race/ethnicity, mean ambient workplace noise exposure, and self-reported non-occupational noise exposure. Those with accelerated early hearing loss were more likely to experience a greater rate of subsequent hearing loss, thus offering a potentially important opportunity for meaningful intervention among those at greatest risk of future hearing loss.

Extracellular Mitochondrial DNA Is Generated by Fibroblasts and Predicts Death in Idiopathic Pulmonary Fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) involves the accumulation of α-smooth muscle actin-expressing myofibroblasts arising from interactions with soluble mediators such as transforming growth factor-ß1 (TGF-ß1) and mechanical influences such as local tissue stiffness. Whereas IPF fibroblasts are enriched for aerobic glycolysis and innate immune receptor activation, innate immune ligands related to mitochondrial injury, such as extracellular mitochondrial DNA (mtDNA), have not been identified in IPF. OBJECTIVES: We aimed to define an association between mtDNA and fibroblast responses in IPF. METHODS: We evaluated the response of normal human lung fibroblasts (NHLFs) to stimulation with mtDNA and determined whether the glycolytic reprogramming that occurs in response to TGF-ß1 stimulation and direct contact with stiff substrates, and spontaneously in IPF fibroblasts, is associated with excessive levels of mtDNA. We measured mtDNA concentrations in bronchoalveolar lavage (BAL) from subjects with and without IPF, as well as in plasma samples from two longitudinal IPF cohorts and demographically matched control subjects. MEASUREMENTS AND MAIN RESULTS: Exposure to mtDNA augments α-smooth muscle actin expression in NHLFs. The metabolic changes in NHLFs that are induced by interactions with TGF-ß1 or stiff hydrogels are accompanied by the accumulation of extracellular mtDNA. These findings replicate the spontaneous phenotype of IPF fibroblasts. mtDNA concentrations are increased in IPF BAL and plasma, and in the latter compartment, they display robust associations with disease progression and reduced event-free survival. CONCLUSIONS: These findings demonstrate a previously unrecognized and highly novel connection between metabolic reprogramming, mtDNA, fibroblast activation, and clinical outcomes that provides new insight into IPF.

Injury, illness, and disability risk in American seafarers.

BACKGROUND: Seafarers are an understudied and essential workforce, isolated from medical care. This study describes injuries, illness, and risk factors for resultant disability in one shipping company with a majority of American seafarers. METHODS: The study used a telemedicine database of injury and illness incidence in seafarers, and applied descriptive statistical methods and logistic regression modeling. RESULTS: Illnesses were more frequently reported than injuries (860 vs 479). The overall injury rate was 113 per 1000 person-years, and the overall illness rate was 211 per 1000 person-years. Seafarer ratings had higher risk for disability compared to officers (OR = 1.60; 95%CI 1.17, 2.18), and incidents on dry cargo ships (OR = 2.70; 95%CI 1.49, 4.91) and articulated tug-barges (ATBs) (OR = 2.21; 95%CI 1.26, 3.86) had higher disability risk compared to container vessels. CONCLUSION: Additional research in this vital American workforce may be useful to confirm these findings forming a basis for preventive interventions.

Preventing Episodic Migraine With Caloric Vestibular Stimulation: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the safety and efficacy of a novel solid-state, caloric vestibular stimulation (CVS) device to provide adjuvant therapy for the prevention of episodic migraine in adult migraineurs. BACKGROUND: Migraine causes significant disability in ∼12% of the world population. No current migraine preventive treatment provides full clinical relief, and many exhibit high rates of discontinuation due to adverse events. Thus, new therapeutic options are needed. CVS may be an effective and safe adjuvant-therapy for the prevention of episodic migraine. METHODS: In a multicenter, parallel-arm, block-randomized, placebo-controlled clinical trial (clinicaltrials.gov: NCT01899040), subjects completed a 3-month treatment with the TNM™ device for CVS (refer to Fig. 2 for patient enrollment and allocation). The primary endpoint was the change in monthly migraine days from baseline to the third treatment month. Secondary endpoints were 50% responder rates, change in prescription analgesic usage and difference in total subjective headache-related pain scores. Device safety assessments included evaluation of any impact on mood, cognition, or balance. RESULTS: Per-protocol, active-arm subjects showed immediate and continued steady declines in migraine frequency over the treatment period. After 3 months of treatment, active-arm subjects exhibited significantly fewer migraine days (-3.9 ± 0.6 from a baseline burden of 7.7 ± 0.5 migraine days). These improvements were significantly greater than those observed in control subjects (-1.1 ± 0.6 from a baseline burden = 6.9 ± 0.7 migraine days) and represented a therapeutic gain of -2.8 migraine days, CI = -0.9 to -4.7, P = .012. Active arm subjects also reported greater reductions in acute medication usage and monthly pain scores compared to controls. No adverse effects on mood, cognition, or balance were reported. Subjects completed the trial with an average rate of 90% treatment adherence. No serious or unexpected adverse events were recorded. The rate of expected adverse events was similar across the active and the placebo groups, and evaluation confirmed that subject blinding remained intact. CONCLUSION: The TNM™ device for CVS appears to provide a clinically efficacious and highly tolerable adjuvant therapy for the prevention of episodic migraine.

Validation of the prognostic value of MMP-7 in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and variable clinical course. Although matrix metalloproteinase-7 (MMP-7) is emerging as an important IPF biomarker, reproducibility across studies is unclear. We aimed to determine whether a previously reported prognostic threshold for MMP-7 was predictive of mortality in an independent cohort of IPF patients. METHODS: MMP-7 concentrations obtained from heparinized plasma samples were determined by ELISA in 97 patients with IPF and 41 healthy controls. The association of the previously published heparin plasma MMP-7 threshold of 12.1 ng/mL with all-cause mortality or transplant-free survival (TFS) was determined, either as an independent biomarker or as part of the modified personal clinical and molecular mortality index (m-PCMI). RESULTS: MMP-7 plasma concentrations were significantly higher in IPF patients compared to healthy controls (14.40 ± 6.55 ng/mL vs 6.03 ± 2.51 ng/mL, P < 0.001). The plasma MMP-7 threshold of 12.1 ng/mL was significantly associated with both all-cause mortality and TFS (unadjusted Cox proportional hazard ratio (HR) = 25.85 and 15.49, 95% CI: 10.91-61.23 and 5.41-44.34, respectively, P < 0.001). MMP-7 concentrations, split by 12.1 ng/mL, were significantly (P < 0.05) predictive of mortality and TFS after adjusting for age, gender, smoking and baseline pulmonary function parameters, in a multivariate Cox proportional hazards model. MMP-7 concentrations were negatively correlated with diffusing lung capacity of carbon monoxide (DLCO ) (r = -0.21, P = 0.02), and positively with a mortality risk scoring system (GAP) that combines age, gender, forced vital capacity (FVC) and DLCO (r = 0.32, P = 0.001). CONCLUSION: This study confirms that MMP-7 concentrations could be used to accurately predict outcomes across cohorts and centres, when similar collection protocols are applied.

The Impact of Functional Status on the Outcomes of Endovascular Lower Extremity Revascularization for Critical Limb Ischemia in the Elderly.

BACKGROUND: Functional status is an important predictor of outcomes after infrainguinal bypass surgery. There are little data on the effect of functional status on the outcomes of endovascular lower extremity interventions, especially in the elderly frail population. METHODS: This is a retrospective analysis of the American College of Surgeons - National Surgical Quality Improvement Program files for the years 2011-2013 to assess the impact of functional status on outcome after endovascular intervention for critical limb ischemia (CLI). Elderly patients (age ≥70) undergoing revascularization for CLI were included. The patients were divided into 2 groups based on functional status prior to surgery: independent (IND) or dependent (DEP), which included partially dependent as well as totally dependent patients. The 2 groups were compared with respect to demographics, comorbidities, complications, length of stay, limb loss, and mortality. Statistical analysis was performed using Student's t-test for continuous variables and Fisher's exact test for categorical variables. RESULTS: There were 1,055 patients (DEP = 253, 24%). There was no difference in gender or race but DEP patients were older than IND (P = 0.008). DEP patients were significantly more likely to have history of congestive heart failure (P = 0.003), hypertension (P = 0.042), and diabetes (P <0.001). There was no difference in emergent surgeries between the 2 groups (P = 1.00). DEP patients had more tibial interventions compared with IND (P <0.001). DEP developed more pneumonia (P <0.001) and septic shock (P = 0.016) and had a trend toward more urinary tract infections (P = 0.051) after endovascular revascularization. There was no significant difference in operating time (P = 0.232) or major amputation (P = 0.092). DEP had significantly longer length of hospital stay (P = 0.0068). DEP had significantly higher mortality (5.98% vs. 2.01%, P = 0.002). On multivariate analysis, DEP status, emergency procedure, congestive heart failure, cardiac arrest requiring cardiopulmonary resuscitation, myocardial infarction, sepsis, and septic shock were independently associated with 30 days of mortality. Irrespective of age, DEP functional status was the most significant preoperative predictor of mortality with an odd ratio of 5.16 [1.93-13.83], P = 0.001 (parsimonious model). CONCLUSIONS: Functional status should be carefully assessed when considering endovascular revascularization in the elderly as DEP has significantly higher morbidity and mortality.

Evaluation of safety climate and employee injury rates in healthcare.

OBJECTIVES: Safety climates that support safety-related behaviour are associated with fewer work-related injuries, and prior research in industry suggests that safety knowledge and motivation are strongly related to safety performance behaviours; this relationship is not well studied in healthcare settings. METHODS: We performed analyses of survey results from a Veterans Health Administration (VHA) Safety Barometer employee perception survey, conducted among VHA employees in 2012. The employee perception survey assessed 6 safety programme categories, including management participation, supervisor participation, employee participation, safety support activities, safety support climate and organisational climate. We examined the relationship between safety climate from the survey results on VHA employee injury and illness rates. RESULTS: Among VHA facilities in the VA New England Healthcare System, work-related injury rate was significantly and inversely related to overall employee perception of safety climate, and all 6 safety programme categories, including employee perception of employee participation, management participation, organisational climate, supervisor participation, safety support activities and safety support climate. CONCLUSIONS: Positive employee perceptions of safety climate in VHA facilities are associated with lower work-related injury and illness rates. Employee perception of employee participation, management participation, organisational climate, supervisor participation, safety support activities and safety support climate were all associated with lower work-related injury rates. Future implications include fostering a robust safety climate for patients and healthcare workers to reduce healthcare worker injuries.

Expert ratings of job demand and job control as predictors of injury and musculoskeletal disorder risk in a manufacturing cohort.

OBJECTIVE: To examine associations between workplace injury and musculoskeletal disorder (MSD) risk and expert ratings of job-level psychosocial demand and job control, adjusting for job-level physical demand. METHODS: Among a cohort of 9260 aluminium manufacturing workers in jobs for which expert ratings of job-level physical and psychological demand and control were obtained during the 2 years following rating obtainment, multivariate mixed effects models were used to estimate relative risk (RR) of minor injury and minor MSD, serious injury and MSD, minor MSD only and serious MSD only by tertile of demand and control, adjusting for physical demand as well as other recognised risk factors. RESULTS: Compared with workers in jobs rated as having low psychological demand, workers in jobs with high psychological demand had 49% greater risk of serious injury and serious MSD requiring medical treatment, work restrictions or lost work time (RR=1.49; 95% CI 1.10 to 2.01). Workers in jobs rated as having low control displayed increased risk for minor injury and minor MSD (RR=1.45; 95% CI 1.12 to 1.87) compared with those in jobs rated as having high control. CONCLUSIONS: Using expert ratings of job-level exposures, this study provides evidence that psychological job demand and job control contribute independently to injury and MSD risk in a blue-collar manufacturing cohort, and emphasises the importance of monitoring psychosocial workplace exposures in addition to physical workplace exposures to promote worker health and safety.