Does Escalating Violence and Associated Fear of Crime Worsen Psychological Well-Being in Community Dwellers Living in a Rural Setting? Results From the Atahualpa Project Cohort.

BACKGROUND: Escalating street violence and criminal homicides have an adverse impact on psychological well-being. However, these consequences have been difficult to evaluate. Using a recently validated scale, we aimed to assess the impact of fear of crime on the psychological status of middle-aged and older adults living in a rural setting afflicted by endemic violence. METHODS: Participants were selected from Atahualpa residents included in previous studies targeting psychological distress in the population. A validated scale was used to objectively quantify fear of crime in participants. Differences in symptoms of depression and anxiety between baseline and follow-up were used as distinct dependent variables and the continuous score of the fear of crime scale was used as the independent variable. Linear regression models were fitted to assess the association between the exposure and the outcomes, after adjusting for relevant confounders. RESULTS: A total of 653 participants (mean age = 53.2 ± 11.5 years; 57% women) completed the requested tests. We found a 13% increase in symptoms of depression and anxiety during the peak of violence in the village compared with previous years. Linear regression models showed a significant association between the total score on the fear of crime questionnaire and worsening symptoms of depression (ß = .24; 95% CI = 0.14-0.35) and anxiety (ß = .31; 95% CI = 0.24-0.37), after adjustment for relevant confounders. CONCLUSIONS: This study shows a significant aggravating effect of fear of crime on pre-existing symptoms of depression and anxiety and a deleterious effect of these conditions on overall well-being.

Exercises for the prevention of non-specific low back pain.

OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the effects of exercise alone or exercise plus education compared with inactive control or education alone to prevent non-specific LBP.

Analysis of the airflow features and ventilation efficiency of an Ultra-Clean-Air operating theatre by qDNS simulations and experimental validation.

Ultra-Clean-Air (UCA) operating theatres aim to minimise surgical instrument contamination and wound infection through high flow rates of ultra-clean air, reducing the presence of Microbe Carrying Particles (MCPs). This study investigates the airflow patterns and ventilation characteristics of a UCA operating theatre (OT) under standard ventilation system operating conditions, considering both empty and partially occupied scenarios. Utilising a precise computational model, quasi-Direct Numerical Simulations (qDNS) were conducted to delineate flow velocity profiles, energy spectra, distributions of turbulent kinetic energy, energy dissipation rate, local Kolmogorov scales, and pressure-based coherent structures. These results were also complemented by a tracer gas decay analysis following ASHRAE standard guidelines. Simulations showed that contrary to the intended laminar regime, the OT's geometry inherently fosters a predominantly turbulent airflow, sustained until evacuation through the exhaust vents, and facilitating recirculation zones irrespective of occupancy level. Notably, the occupied scenario demonstrated superior ventilation efficiency, a phenomenon attributed to enhanced kinetic energy induced by the additional obstructions. The findings underscore the critical role of UCA-OT design in mitigating MCP dissemination, highlighting the potential to augment the design to optimise airflow across a broader theatre spectrum, thereby diminishing recirculation zones and consequently reducing the propensity for Surgical Site Infections (SSIs). The study advocates for design refinements to harness the turbulent dynamics beneficially, steering towards a safer surgical environment.

Lysosomal acid lipase A modulates leukemia stem cell response to venetoclax/tyrosine kinase inhibitor combination therapy in blast phase chronic myeloid leukemia.

The treatment of blast phase chronic myeloid leukemia (bpCML) remains a challenge due at least in part to drug resistance of leukemia stem cells (LSCs). Recent clinical evidence suggests that the BCL-2 inhibitor venetoclax in combination with ABL-targeting tyrosine kinase inhibitors (TKIs) can eradicate bpCML LSCs. In this report, we employed preclinical models of bpCML to investigate the efficacy and underlying mechanism of LSC-targeting with venetoclax/TKI combinations. Transcriptional analysis of LSCs exposed to venetoclax and dasatinib revealed upregulation of genes involved in lysosomal biology, in particular lysosomal acid lipase A (LIPA), a regulator of free fatty acids. Metabolomic analysis confirmed increased levels of free fatty acids in response to venetoclax/dasatinib. Pre-treatment of leukemia cells with bafilomycin, a specific lysosome inhibitor, or genetic perturbation of LIPA, resulted in increased sensitivity of leukemia cells toward venetoclax/dasatinib, implicating LIPA in treatment resistance. Importantly, venetoclax/dasatinib treatment does not affect normal stem cell function, suggestive of a leukemia-specific response. These results demonstrate that venetoclax/dasatinib is an LSCselective regimen in bpCML and that disrupting LIPA and fatty acid transport enhances venetoclax/dasatinib response in targeting LSCs, providing a rationale for exploring lysosomal disruption as an adjunct therapeutic strategy to prolong disease remission.

DiTA: helping you search for evidence of diagnostic test accuracy in physical therapy.

BACKGROUND: Physical therapists use diagnostic tests in a variety of settings. Choosing the best diagnostic test to apply in a particular situation can be difficult. The choice of diagnostic test should be informed, at least in part, by evidence of test accuracy. Finding evidence of diagnostic test accuracy has, until recently, been challenging. Ideally, there would exist a database that comprehensively indexes evidence on diagnostic tests relevant to physical therapy practice, is free to access, and is easy to use. OBJECTIVE: This Masterclass will describe the DiTA (Diagnostic Test Accuracy) database (dita.org.au) including its development and search interface, and provide advice on how to search and retrieve records. DISCUSSION: DiTA indexes more than 2400 primary studies and systematic reviews of diagnostic test accuracy relevant to physical therapy practice. Users can search DiTA using text fields and dropdown lists to find evidence of diagnostic test accuracy. The database is freely accessible on the internet. Since its launch, DiTA has been accessed from almost every country in the world, the largest number of searches having been conducted from Brazil.

The importance of international collaborations in science and structural biology.

The Acta Cryst. F - Structural Biology Communications Editors explain how important international collaborations are in science and structural biology.

Oncologic Outcomes of Interventions to Decrease Allograft Ischemia-Reperfusion Injury within Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma: A Systematic Review.

Ischemia-reperfusion injury (IRI) during liver transplantation has been implicated in the recurrence of hepatocellular carcinoma (HCC). This systematic review aimed to evaluate interventions to reduce IRI during liver transplantation for HCC and their impact on oncologic outcomes. A comprehensive literature search retrieved four retrospective studies involving 938 HCC patients, utilising interventions such as post-operative prostaglandin administration, hypothermic machine perfusion, and normothermic machine perfusion. Overall, treated patients exhibited reduced post-operative hepatocellular injury and inflammation and significantly enhanced recurrence-free survival. Despite these promising results, the impact of these interventions on overall survival remains unclear. This underscores the imperative for further prospective research to comprehensively understand the efficacy of these interventions in HCC patients undergoing transplantation. The findings highlight the potential benefits of these strategies while emphasising the need for continued investigation into their overall impact.

Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

Efficacy of Alum-Adjuvanted Peptide and Carbohydrate Conjugate Vaccine Candidates against Group A Streptococcus Pharyngeal Infection in a Non-Human Primate Model.

Vaccine development against group A Streptococcus (GAS) has gained traction in the last decade, fuelled by recognition of the significant worldwide burden of the disease. Several vaccine candidates are currently being evaluated in preclinical and early clinical studies. Here, we investigate two conjugate vaccine candidates that have shown promise in mouse models of infection. Two antigens, the J8 peptide from the conserved C-terminal end of the M protein, and the group A carbohydrate lacking N-acetylglucosamine side chain (ΔGAC) were each conjugated to arginine deiminase (ADI), an anchorless surface protein from GAS. Both conjugate vaccine candidates combined with alum adjuvant were tested in a non-human primate (NHP) model of pharyngeal infection. High antibody titres were detected against J8 and ADI antigens, while high background antibody titres in NHP sera hindered accurate quantification of ΔGAC-specific antibodies. The severity of pharyngitis and tonsillitis signs, as well as the level of GAS colonisation, showed no significant differences in NHPs immunised with either conjugate vaccine candidate compared to NHPs in the negative control group.

The Relationship Between Disc Herniation Morphology and Patient-Reported Outcomes after Microdiscectomy.

OBJECTIVE: Determine if herniation morphology based on the Michigan State University Classification is associated with differences in (1) patient-reported outcome measures (or (2) surgical outcomes after a microdiscectomy. METHODS: Adult patients undergoing single-level microdiscectomy between 2014 and 2021 were identified. Demographics and surgical characteristics were collected through a query search and manual chart review. The Michigan State University classification, which assesses disc herniation laterality (zone A was central, zone B/C was lateral) and degree of extrusion into the central canal (grade 1 was up to 50% of the distance to the intra-facet line, grade >1 was beyond this line), was identified on preoperative MRIs. patient-reported outcome measures were collected at preoperative, 3-month, and 1-year postoperative time points. RESULTS: Of 233 patients, 84 had zone A versus 149 zone B/C herniations while 76 had grade 1 disc extrusion and 157 had >1 grade. There was no difference in surgical outcomes between groups (P > 0.05). Patients with extrusion grade >1 were found to have lower Physical Component Score at baseline. On bivariate and multivariable logistic regression analysis, extrusion grade >1 was a significant independent predictor of greater improvement in Physical Component Score at three months (estimate = 7.957; CI: 4.443-11.471, P < 0.001), but not at 1 year. CONCLUSIONS: Although all patients were found to improve after microdiscectomy, patients with disc herniations extending further posteriorly reported lower preoperative physical function but experienced significantly greater improvement three months after surgery. However, improvement in Visual Analog Scale Leg and back, ODI, and MCS at three and twelve months was unrelated to laterality or depth of disc herniation.

On the association between dietary oily fish intake and bone mineral density in frequent fish consumers of Amerindian ancestry. The three villages study.

Reports addressing the effects of oily fish intake on bone health are inconsistent. This study shows that consumption of ≥ 5.2 oily fish servings/week (728 g) is associated with lower prevalence of osteopenia/osteoporosis in elderly women of Amerindian ancestry. Results suggest a beneficial effect of oily fish intake in this population. OBJECTIVES: Oily fish is a major dietary source of omega-3 polyunsaturated fatty acids and other nutrients that may have a positive effect on bone health. However, this association is inconsistent and seems to be more evident in certain ethnic groups. We aimed to assess the association between oily fish intake and bone mineral density (BMD) in frequent fish consumers of Amerindian ancestry living in rural Ecuador. METHODS: This study included 399 individuals aged ≥ 60 years living in three neighboring rural villages of coastal Ecuador. Dietary oily fish intake was quantified systematically using validated surveys and BMD was determined by dual-energy x-ray absorptiometry. Ordinal logistic regression models, adjusted for demographics and cardiovascular risk factors, were fitted to assess the independent association between oily fish intake and bone health. RESULTS: Participants had a mean age of 68.8 ± 6.8 years, and 58% were women. The mean intake of oily fish was 8.5 ± 4.7 servings/week, with 308 (77%) reporting high fish intake (≥ 5.2 servings/week [728 g]). Ninety-four (24%) participants had normal BMD T-scores, 149 (37%) had osteopenia, and 156 (39%) had osteoporosis. Ordinal logistic regression models showed no association between high fish intake and bone health in the total population. When men and women were analyzed separately, the association became significant for women only in both unadjusted (OR: 2.52; 95% C.I.: 1.22 - 5.23) and fully-adjusted models (OR: 2.23; 95% C.I.: 1.03 - 4.81). CONCLUSION: Consumption of ≥ 5.2 oily fish servings/week is associated with lower prevalence of osteopenia and osteoporosis in elderly women of Amerindian ancestry.

Radiology Reports Do Not Accurately Portray the Severity of Cervical Neural Foraminal Stenosis.

STUDY DESIGN: Retrospective study. OBJECTIVE: (1) To compare cervical magnetic resonance imaging (MRI) radiology reports to a validated grading system for cervical foraminal stenosis (FS) and (2) to evaluate whether the severity of cervical neural FS on MRI correlates to motor weakness or patient-reported outcomes. BACKGROUND: Radiology reports of cervical spine MRI are often reviewed to assess the degree of neural FS. However, research looking at the association between these reports and objective MRI findings, as well as clinical symptoms, is lacking. PATIENTS AND METHODS: We retrospectively identified all adult patients undergoing primary 1 or 2-level anterior cervical discectomy and fusion at a single academic center for an indication of cervical radiculopathy. Preoperative MRI was assessed for neural FS severity using the grading system described by Kim and colleagues for each level of fusion, as well as adjacent levels. Neural FS severity was recorded from diagnostic radiologist MRI reports. Motor weakness was defined as an examination grade <4/5 on the final preoperative encounter. Regression analysis was conducted to evaluate whether the degree of FS by either classification was related to patient-reported outcome measure severity. RESULTS: A total of 283 patients were included in the study, and 998 total levels were assessed. There were significant differences between the MRI grading system and the assessment by radio-logists ( P < 0.001). In levels with moderate stenosis, 28.9% were classified as having no stenosis by radiology. In levels with severe stenosis, 29.7% were classified as having mild-moderate stenosis or less. Motor weakness was found similarly often in levels of moderate or severe stenosis (6.9% and 9.2%, respectively). On regression analysis, no associations were found between baseline patient-reported outcome measures and stenosis severity assessed by radiologists or MRI grading systems. CONCLUSION: Radiology reports on the severity of cervical neural FS are not consistent with a validated MRI grading system. These radiology reports underestimated the severity of neural foraminal compression and may be inappropriate when used for clinical decision-making. LEVEL OF EVIDENCE: Level III.

A Longitudinal Evaluation of Coronavirus Disease 2019 and Its Effects on Spinal Decompressions With or Without Fusion.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: The objectives were to (1) compare the safety of spine surgery before and after the emergence of coronavirus disease 2019 (COVID-19) and (2) determine whether patients with a history of COVID-19 were at increased risk of adverse events. SUMMARY AND BACKGROUND DATA: The COVID-19 pandemic had a tremendous impact on several health care services. In spine surgery, elective cases were canceled and patients received delayed care due to the uncertainty of disease transmission and surgical outcomes. As new coronavirus variants arise, health care systems require guidance on how to provide optimal patient care to all those in need of our services. PATIENTS AND METHODS: A retrospective review of patients undergoing spine surgery between January 1, 2019 and June 30, 2021 was performed. Patients were split into pre-COVID or post-COVID cohorts based on local government guidelines. Inpatient complications, 90-day readmission, and 90-day mortality were compared between groups. Secondary analysis included multiple logistic regression to determine independent predictors of each outcome. RESULTS: A total of 2976 patients were included for analysis with 1701 patients designated as pre-COVID and 1275 as post-COVID. The pre-COVID cohort had fewer patients undergoing revision surgery (16.8% vs 21.9%, P < 0.001) and a lower home discharge rate (84.5% vs 88.2%, P = 0.008). Inpatient complication (9.9% vs 9.2%, P = 0.562), inpatient mortality (0.1% vs 0.2%, P = 0.193), 90-day readmission (3.4% vs 3.2%, P = 0.828), and 90-day mortality rates (0.8% vs 0.8%, P = 0.902) were similar between groups. Patients with positive COVID-19 tests before surgery had similar complication rates (7.7% vs 6.1%, P = 1.000) as those without a positive test documented. CONCLUSIONS: After the emergence of COVID-19, patients undergoing spine surgery had a greater number of medical comorbidities, but similar rates of inpatient complications, readmission, and mortality. Prior COVID-19 infection was not associated with an increased risk of postsurgical complications or mortality. LEVEL OF EVIDENCE: Level III.

The Inhibitory Effect of NSAIDs and Opioids on Spinal Fusion: An Animal Model.

STUDY DESIGN: Translational research. OBJECTIVE: To evaluate the relative effects of NSAIDs, opioids, and a combination of the two on spinal fusion inhibition in a rodent model. SUMMARY OF BACKGROUND DATA: Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are common postoperative analgesic agents. Since NSAIDs inhibit the cyclooxygenase (COX) pathway, they are seldom prescribed following spinal fusion. Opioids may be given instead, but recent evidence suggests opioids also adversely affect spinal fusion quality and success. METHODS: Eighty male Sprague-Dawley rats underwent L4-5 posterior lumbar fusion and were given one of the following analgesia regimens: saline, morphine (6 mg/kg), ketorolac (4 mg/kg), or morphine (3 mg/kg) and ketorolac (2 mg/kg). Serum samples were drawn to evaluate systemic pro-osteoblastic cytokines and vascular endothelial growth factor-A (VEGF-A) levels, which were measured through enzyme-linked immunosorbent assays (ELISA). After six weeks, the rats were sacrificed, and the operated spinal segments underwent manual palpation, microCT, and histologic analysis. RESULTS: Manual palpation scores were significantly diminished in the opioid, NSAID, and multimodal groups when compared with control ( P <0.001). MicroCT fusion scores ( P <0.001) and fusion rates (control: 75% vs . NSAID: 35% vs . opioid: 0% vs . combination: 15%, P <0.001) were significantly diminished in the treatment groups. The bone volume (BV) to tissue volume (TV) ratio (BV/TV) ( P <0.001) and bone mineral density (BMD) ( P <0.001) were all lower in the treatment groups, with the opioid and combined groups having the lowest BMD. Although statistically insignificant ( P <0.09), the concentration of VEGF-A was greater in the control group compared with opioids, NSAIDs, and the combined group. CONCLUSION: Opioids and NSAIDs, both independently and combined, inhibited spinal fusion and caused inferior bony callus. Administration of opioids resulted in the lowest rate of spinal fusion. We propose this may be due to the inhibition of VEGF-A, which limits angiogenesis to the burgeoning fusion mass.

Preoperative Oswestry Disability Index Should not be Utilized to Determine Surgical Eligibility for Patients Requiring Lumbar Fusion for Degenerative Lumbar Spine Disease.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To evaluate how preoperative Oswestry Disability Index (ODI) thresholds might affect minimal clinically important difference (MCID) achievement following lumbar fusion. SUMMARY OF BACKGROUND DATA: As payers invest in alternative payment models, some are suggesting threshold cutoffs of patient-reported outcomes (PROMs) in reimbursement approvals for orthopedic procedures. The feasibility of this has not been investigated in spine surgery. MATERIALS/METHODS: We included all adult patients undergoing one to three-level primary lumbar fusion at a single urban tertiary academic center from 2014 to 2020. ODI was collected preoperatively and one year postoperatively. We implemented theoretical threshold cutoffs at increments of 10. MCID was set at 14.3. The percent of patients meeting MCID were determined among patients "approved" or "denied" at each threshold. At each threshold, the positive predictive value (PPV) for MCID attainment was calculated. RESULTS: A total 1368 patients were included and 62.4% (N=364) achieved MCID. As the ODI thresholds increased, a greater percent of patients in each group reached the MCID. At the lowest ODI threshold, 6.58% (N=90) of patients would be denied, rising to 20.2%, 39.5%, 58.4%, 79.9%, and 91.4% at ODI thresholds of 30, 40, 50, 60, and 70, respectively. The PPV increased from 0.072 among patients with ODI>20 to 0.919 at ODI>70. The number of patients denied a clinical improvement in the denied category per patient achieving the MCID increased at each threshold (ODI>20: 1.96; ODI>30: 2.40; ODI>40: 2.75; ODI>50: 3.03; ODI>60: 3.54; ODI>70: 3.75). CONCLUSION: Patients with poorer preoperative ODI are significantly more likely to achieve MCID following lumbar spine fusion at all ODI thresholds. Setting a preoperative ODI threshold for surgical eligibility will restrict access to patients who may benefit from spine fusion despite ODI>20 demonstrating the lowest predictive value for MCID achievement. LEVEL OF EVIDENCE: 3.

Diagnostic Delay in HPV-Related Oropharyngeal Squamous Cell Carcinoma.

Introduction Human papillomavirus-related (HPV + ) oropharyngeal squamous cell carcinoma (OPSCC) is increasing in incidence and presents diagnostic challenges given its unique clinical presentation. Objective The purpose of the present study is to characterize the impact of the unique clinical presentation of HPV-related OPSCC on delays in diagnosis. Methods Retrospective review of presenting symptoms and clinical characteristics of 284 patients with OPSCC treated from 2002-2014. Delay in diagnosis was defined as the presence of any of the following: multiple non-diagnostic fine needle aspirate (FNA) biopsies; two or more courses of antibiotic therapy; surgery with incorrect preoperative diagnosis; evaluation by an otolaryngologist without further workup; or surgery without definitive postoperative diagnosis. Results p16+ tumors demonstrated a distinct clinical presentation that more commonly involved a neck mass (85.1% versus 57.3% of p16-; p < 0.001) and less frequently included odynophagia (24.6% versus 51.7% of p16-; p < 0.001). Patients who experienced diagnostic delay were more likely to have p16+ tumors (77.7% delayed versus 62.8% not delayed; p = 0.006). p16+ primary tumors were more likely to be undetectable by physical examination of the head and neck including flexible laryngoscopy (19.0% versus 6.7% of p16-; p = 0.007) and more frequently associated with nondiagnostic FNA biopsies of a cervical nodal mass (11.8% versus 3.4% of p16-, p = 0.03). Conclusions Compared with non-HPV related OPSCC, the unique clinical presentation and characteristics of HPV+ OPSCC are associated with an increased incidence of diagnostic delay. Targeted education of appropriate care providers may improve time to diagnosis and treatment.

The Impact of Biological and Social Factors on Mortality in Older Adults Living in Rural Communities.

BACKGROUND: Information on factors that increase mortality in remote settings is limited. This study aims to estimate the independent and joint role of several factors on mortality risk among older adults living in rural Ecuador. METHODS: Participants were selected from community-dwelling older adults who were included in previous studies targeting mortality risk factors in the study population. Generalized structural equation modeling (GSEM) was utilized to evaluate prior causal assumptions, to redraw causal links, and to introduce latent variables that may help to explain how the independently significant variables are associated with mortality. RESULTS: The study included 590 individuals (mean age: 67.9 ± 7.3 years; 57% women), followed for a median of 8.2 years. Mortality rate was 3.4 per 100 person-years. Prior work on separate multivariate Poisson and Cox models was used to build a tentative causal construct. A GSEM containing all variables showed that age, symptoms of depression, high social risk, high fasting glucose, a history of overt stroke, and neck circumference were directly associated with mortality. Two latent variables were introduced, 1 representing the impact of biological factors and another, the impact of social factors on mortality. The social variable significantly influenced the biological variable which carried most of the direct effect on mortality. CONCLUSIONS: Several factors contributed to mortality risk in the study population, the most significant being biological factors which are highly influenced by social factors. High social risk interact with biological variables and play an important role in mortality risk.

Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezuelan Equine Encephalitis virus within olfactory sensory neurons.

BACKGROUND: Venezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied. METHODS: We utilized an established murine model of intranasal infection with VEEV and a repository of scRNAseq data from IFN-treated OSN to assess the cellular targets and IFN signaling responses after VEEV exposure. RESULTS: We found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 h during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFNα triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFNα treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS. CONCLUSIONS: Our results demonstrate a critical and promising first evaluation of intranasal IFNα for the treatment of human encephalitic alphavirus exposures.

Interpreting Meta-Analyses: A Guide to Funnel and Forest Plots.

Meta-analyses represent the best available medical evidence. Although a powerful tool, they are not without criticisms since any bias in the original studies are then compounded when they are pooled together for the meta-analysis. Funnel plots provide a useful graphical representation of the presence of bias, and forest plots represent the heterogeneity of findings within studies included in a meta-analysis. The purpose of this review is to help readers interpret these statistical tools to better understand the findings of a meta-analysis.

Cognitive performance and all-cause mortality in community dwellers of Amerindian ancestry living in rural Ecuador: A population-based, longitudinal prospective study.

OBJECTIVE: There is limited information on mortality risk in individuals with cognitive impairment living in rural Latin America. In this study, we assess the association between cognitive impairment and all-cause mortality in adults of Amerindian ancestry living in rural Ecuador. PATIENTS AND METHODS: Middle-aged and older adults enrolled in the population-based Three Villages Study cohort were followed prospectively in order to estimate mortality risk according to their baseline cognitive performance as determined by the Montreal Cognitive Assessment (MoCA). Results were adjusted for demographics, level of education, traditional cardiovascular risk factors, symptoms of depression, severe tooth loss, and oily fish intake (factors previously associated with mortality in the study population). RESULTS: Analysis included 1022 individuals followed for an average of 7.8 ± 3.4 years. Mean MoCA score was 21.2 ± 5.4 points (median: 22 points), with 334 (32.7%) individuals showing cognitive impairment, as evidenced by a MoCA score ≤ 19 points (the cutoff for poor cognitive performance based on previous studies in the same population). A total of 150 (14.7%) individuals died during the follow-up. Crude mortality rate was 2.87 per 100 person-years (95% C.I.: 2.08 - 3.96). For individuals with normal cognition, the mortality rate was 1.21 (95% C.I.: 0.92 - 1.50) while for those with cognitive impairment the rate increased to 3.48 (95% C.I.: 2.73 - 4.23). A multivariate Cox-proportional hazards model, confirmed that individuals with cognitive impairment had a significantly higher mortality risk than those without cognitive impairment (HR: 1.52; 95% C.I.: 1.05 - 2.18). CONCLUSIONS: Cognitive impairment is associated with mortality in the study population.