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The NIA Long Life Family Study (LLFS) is a longitudinal, multicenter, multinational, population-based multigenerational family study of the genetic and nongenetic determinants of exceptional longevity and healthy aging. The Visit 1 in-person evaluation (2006-2009) recruited 4 953 individuals from 539 two-generation families, selected from the upper 1% tail of the Family Longevity Selection Score (FLoSS, which quantifies the degree of familial clustering of longevity). Demographic, anthropometric, cognitive, activities of daily living, ankle-brachial index, blood pressure, physical performance, and pulmonary function, along with serum, plasma, lymphocytes, red cells, and DNA, were collected. A Genome Wide Association Scan (GWAS) (Ilumina Omni 2.5M chip) followed by imputation was conducted. Visit 2 (2014-2017) repeated all Visit 1 protocols and added carotid ultrasonography of atherosclerotic plaque and wall thickness, additional cognitive testing, and perceived fatigability. On average, LLFS families show healthier aging profiles than reference populations, such as the Framingham Heart Study, at all age/sex groups, for many critical healthy aging phenotypes. However, participants are not uniformly protected. There is considerable heterogeneity among the pedigrees, with some showing exceptional cognition, others showing exceptional grip strength, others exceptional pulmonary function, etc. with little overlap in these families. There is strong heritability for key healthy aging phenotypes, both cross-sectionally and longitudinally, suggesting that at least some of this protection may be genetic. Little of the variance in these heritable phenotypes is explained by the common genome (GWAS + Imputation), which may indicate that rare protective variants for specific phenotypes may be running in selected families. [ABSTRACT FROM AUTHOR]

Background: Antisense peptide nucleic acids (PNAs) constitute an alternative to traditional antibiotics, by their ability to silence essential genes.Objectives: To evaluate the antibacterial effects of antisense PNA-peptide conjugates that target the gene encoding the alpha subunit (NrdA) of the Escherichia coli ribonucleotide reductase (RNR).Methods: Bacterial susceptibility of a series of NrdA-targeting PNAs was studied by MIC determination and time-kill analysis. Western-blot analysis, gene complementation and synergy with hydroxyurea were employed to determine the efficiency of NrdA-PNA antisense treatment. The effect on chromosome replication was addressed by determining the DNA synthesis rate, by flow cytometry analysis, by quantitative PCR and by fluorescence microscopy. The use of DNA repair mutants provided insight into the bactericidal action of NrdA-PNA.Results: Treatment with NrdA-PNA specifically inhibited growth of E. coli, as well as NrdA protein translation at 4 μM. Also, the DNA synthesis rate was reduced, preventing completion of chromosome replication and resulting in formation of double-stranded DNA breaks and cell death.Conclusions: These data present subunits of the NrdAB RNR as a target for future antisense microbial agents and provide insight into the bacterial physiological response to RNR-targeting antimicrobials. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes is associated with increased risks of cognitive dysfunction and brain abnormalities. The extent to which risk factor modification can mitigate these risks is unclear. We investigated the associations between incident dementia, cognitive performance, and brain abnormalities among individuals with type 2 diabetes, according to the number of risk factors on target, compared with control subjects without diabetes.Research Design and Methods: Prospective data were from UK Biobank of 87,856 individuals (n = 10,663 diabetes, n = 77,193 control subjects; baseline 2006-2010), with dementia follow-up until February 2018. Individuals with diabetes were categorized according to the number of seven selected risk factors within the guideline-recommended target range (nonsmoking; guideline-recommended levels of glycated hemoglobin, blood pressure, BMI, albuminuria, physical activity, and diet). Outcomes were incident dementia, domain-specific cognitive performance, white matter hyperintensities, and total brain volume.Results: After a mean follow-up of 9.0 years, 147 individuals (1.4%) with diabetes and 412 control subjects (0.5%) had incident dementia. Among individuals with diabetes, excess dementia risk decreased stepwise for a higher number of risk factors on target. Compared with control subjects (incidence rate per 1,000 person-years 0.62 [95% CI 0.56; 0.68]), individuals with diabetes who had five to seven risk factors on target had no significant excess dementia risk (absolute rate difference per 1,000 person-years 0.20 [-0.11; 0.52]; hazard ratio 1.32 [0.89; 1.95]). Similarly, differences in processing speed, executive function, and brain volumes were progressively smaller for a higher number of risk factors on target. These results were replicated in the Maastricht Study.Conclusions: Among individuals with diabetes, excess dementia risk, lower cognitive performance, and brain abnormalities decreased stepwise for a higher number of risk factors on target. [ABSTRACT FROM AUTHOR]

Background: The E4 allele of the APOE gene is known to be associated with cognitive impairment. However, a limited number of studies have examined the association between the E2 allele and longitudinal changes of cognitive function.Objective: To determine whether rates of cognitive change differ in carriers of the APOE E2 allele compared to other genotypes.Methods: We conducted a secondary analysis of data from two ongoing longitudinal cohort studies, the Long Life Family Study (LLFS) and New England Centenarian Study (NECS). We included participants who had APOE genotyping data, data from longitudinal administrations of the Telephone Interview for Cognitive Status (TICS), and age, sex, and education available. We assessed whether cognitive change as measured by rate of decline in TICS score differed among people with different APOE genotypes. We used a hierarchical mixed effect model with APOE genotypes, their interactions with age, and potential confounders.Results: After adjusting for sex and education, in carriers of the common E3/E3 genotype, TICS score decreased by 0.15 points per year of age. In those with the E2/E2 genotype, TICS score decreased by 0.05 points per year of age, a significantly slower rate of decline (p = 0.017). We observed no protective effect of the E2/E3 genotype on cognitive decline.Conclusion: These results suggest a protective effect of the E2/E2 genotype on a measure of global cognitive function. [ABSTRACT FROM AUTHOR]

We studied a subset of patients with autopsy-confirmed multiple system atrophy who presented a clinical picture that closely resembled either Parkinson's disease or progressive supranuclear palsy. These mimics are not captured by the current diagnostic criteria for multiple system atrophy. Among 218 autopsy-proven multiple system atrophy cases reviewed, 177 (81.2%) were clinically diagnosed and pathologically confirmed as multiple system atrophy (i.e. typical cases), while the remaining 41 (18.8%) had received an alternative clinical diagnosis, including Parkinson's disease (i.e. Parkinson's disease mimics; n = 16) and progressive supranuclear palsy (i.e. progressive supranuclear palsy mimics; n = 17). We also reviewed the clinical records of another 105 patients with pathologically confirmed Parkinson's disease or progressive supranuclear palsy, who had received a correct final clinical diagnosis (i.e. Parkinson's disease, n = 35; progressive supranuclear palsy-Richardson syndrome, n = 35; and progressive supranuclear palsy-parkinsonism, n = 35). We investigated 12 red flag features that would support a diagnosis of multiple system atrophy according to the current diagnostic criteria. Compared with typical multiple system atrophy, Parkinson's disease mimics more frequently had a good levodopa response and visual hallucinations. Vertical gaze palsy and apraxia of eyelid opening were more commonly observed in progressive supranuclear palsy mimics. Multiple logistic regression analysis revealed an increased likelihood of having multiple system atrophy [Parkinson's disease mimic versus typical Parkinson's disease, odds ratio (OR): 8.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.3] if a patient developed any one of seven selected red flag features in the first 10 years of disease. Severe autonomic dysfunction (orthostatic hypotension and/or urinary incontinence with the need for a urinary catheter) was more frequent in clinically atypical multiple system atrophy than other parkinsonian disorders (Parkinson's disease mimic versus typical Parkinson's disease, OR: 4.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 8.8). The atypical multiple system atrophy cases more frequently had autonomic dysfunction within 3 years of symptom onset than the pathologically confirmed patients with Parkinson's disease or progressive supranuclear palsy (Parkinson's disease mimic versus typical Parkinson's disease, OR: 4.7; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.7). Using all included clinical features and 21 early clinical features within 3 years of symptom onset, we developed decision tree algorithms with combinations of clinical pointers to differentiate clinically atypical cases of multiple system atrophy from Parkinson's disease or progressive supranuclear palsy. [ABSTRACT FROM AUTHOR]

Introduction: Over half of all people with lower limb amputation (LLA) experience at least one fall annually. Furthermore, the majority of LLAs result from dysvascular health complications, contributing to balance deficits. However, fall-related research specific to dysvascular LLA remains limited.Objective: To characterize falls among adults with dysvascular LLA, using an existing Fall-Type Classification Framework and to describe the functional characteristics of participants across the framework categories.Design: Secondary data analysis from two randomized controlled trials.Setting: Outpatient setting.Participants: People (n = 69) 6 months to 5 years from dysvascular lower extremity amputation, who were ≥50 years of age and independently ambulatory using a prosthesis.Intervention: None.Outcome: Descriptions of self-reported falls were collected on a weekly basis for 12 weeks, and analyzed using an existing Fall-Type Classification Framework. Fall frequencies, estimated count, and estimated proportions were compared across all framework categories, with 95% confidence intervals. Functional measures (Timed Up and Go, Two Minute Walk, Five Meter Walk, and average step count) were collected, and averages for each participant who experienced a fall were calculated.Results: Thirty participants (43.5%) reported 42 falls within 12 weeks. A variety of fall types were described. Incidence of falls was highest for intrinsic destabilization sources, from incorrect weight shift patterns during transfer activities.Conclusion: Patients with dysvascular LLAs experience a variety of fall types. The high frequency of intrinsically sourced, incorrect weight-shift falls during transfer activities emphasizes the need to focus rehabilitation efforts on improving postural control in patients with dysvascular LLAs during activities such as reaching, turning, and transferring. [ABSTRACT FROM AUTHOR]

Objectives: Leptin (LEP) is a vital placental hormone that is known to affect different aspects of placental function and fetal development. The present study aimed to determine the association of placental LEP transcript abundance with maternal, placental, and newborn parameters.Subjects/methods: In this retrospective case-control study, placental samples (n = 105) were collected from small (SGA) and appropriate (AGA) for gestational age full-term singleton pregnancies (n = 44 SGA and n = 61 AGA). Placental transcript abundance of LEP was assessed by real-time quantitative PCR after normalization to a reference gene panel. LEP methylation was measured using a quantitative MethyLight assay in a subset of samples (n = 54).Results: Placental LEP transcript abundance was negatively and significantly associated with placental weight (β = -3.883, P = 0.015). This association continued to be significant in the SGA group (β = -10.332, P = 0.001), both in female (β = -15.423, P = 0.021) and male births (β = -10.029, P = 0.007). LEP transcript abundance was not associated with LEP methylation levels (Spearman's ρ = 0.148, P = 0.287).Conclusion: We conclude that placental upregulation of LEP is an integral and fetal sex-independent component of placental growth restriction, which can be potentially targeted through maternal dietary modifications to improve fetoplacental growth. [ABSTRACT FROM AUTHOR]

Background. Inappropriate empirical antibiotics promote antibiotic resistance. Antibiograms guide empirical antibiotic therapy by outlining the percentage susceptibility of each pathogen to individual antibiotics. In 2016, the Trauma Intensive Care Unit at Charlotte Maxeke Johannesburg Academic Hospital escalated empirical antibiotic therapy for nosocomial infections from piperacillin-tazobactam to imipenem plus amikacin. Objectives. This study assessed the impact of escalation in empirical antimicrobial treatment on organism prevalence and resistance profile. Methods. A retrospective analysis of bacterial and fungal microscopy, culture and susceptibility reports from the laboratory information system of the National Health Laboratory Services, from 1 January 2015 to 31 December 2015 and 1 January 2017 to 31 December 2017, was conducted. Data were de-duplicated according to standard guidelines. Fisher's exact test was used to determine p-values. Results. Organism prevalence shifted between the years, with a 2.7% increase in streptococci (p=0.0199), 1.7% increase in Candida auris (p=0.0031) and 4.6% and 4.4% reduction in Acinetobacter baumannii (p=0.0508) and Pseudomonas aeruginosa (p=0.0196), respectively. Similarly, there was a change in the resistance profile, with a 28.9% reduction in multi-drug resistant (MDR) A. baumannii (p=0.0001), 60.4% reduction in MDR P aeruginosa (p=0.0001) and a 6.5% increase in carbapenem-resistant Enterobacterales (p=0.007). The predominant specimen type differed between the years, with significantly more pus, tissue and fluid samples and fewer respiratory samples sent for investigation in 2017 than 2015. Conclusion. Escalation in the use of empirical antibiotics showed a change in organism prevalence and an improvement in the susceptibility profile of MDR non-fermenters. [ABSTRACT FROM AUTHOR]

Background: Lower-limb amputation (LLA) due to non-traumatic vascular etiology is linked to extremely low physical activity and high disability.Objective: To test the feasibility of a biobehavioral intervention designed to promote physical activity.Design: A randomized, single-blind feasibility trial with a crossover design.Setting: Veterans Administration Medical Center.Participants: Military veterans (age: 65.7 [7.8] years; mean [standard deviation]) with nontraumatic lower-limb amputation (LLA), randomized to two groups: GROUP1 (n = 16) and GROUP2 (n = 15). Both groups had similar baseline amputation characteristics (level of amputation and time since amputation).Interventions: Twelve weekly, 30-minute telehealth sessions of physical activity behavior-change intervention, with GROUP1 participating in weeks 1-12 and GROUP2 in weeks 13-24. GROUP1 noncontact phase in weeks 13-24 and GROUP2 attention control telehealth phase in weeks 1-12.Main Outcome Measures: Feasibility (participant retention, dose goal attainment, intervention acceptability [Intrinsic Motivation Inventory [IMI] Interest and Enjoyment scale], safety) and signal of efficacy (free-living physical activity [accelerometer-based average daily step count], Late Life Function and Disability Index - Disability Scale [LLFDI-DS]).Results: Participant retention rate was high (90%), with three participants lost to follow-up during the intervention period. Dose goal attainment was low, with only 10% of participants achieving an a priori walking dose goal. Intervention was rated as acceptable, with mean IMI Interest and Enjoyment score (5.8) statistically higher than the null value of 5.0 (P = .002). There were no between-group differences in adverse event rates (falls: P = .19, lower extremity wounds: P = .60). There was no signal of efficacy for change in average daily step count (d = -0.15) or LLFDI-DS (d = -0.22 and 0.17 for frequency and limitations scales, respectively).Conclusions: Telehealth delivered biobehavioral intervention resulted in acceptable participant retention, low dose goal attainment, high participant acceptability, and low safety risk, while having no signal of efficacy (physical activity, disability) for people with nontraumatic LLA. [ABSTRACT FROM AUTHOR]

Importance: Nonoperative management with antibiotics alone has the potential to treat uncomplicated pediatric appendicitis with fewer disability days than surgery.Objective: To determine the success rate of nonoperative management and compare differences in treatment-related disability, satisfaction, health-related quality of life, and complications between nonoperative management and surgery in children with uncomplicated appendicitis.Design, Setting, and Participants: Multi-institutional nonrandomized controlled intervention study of 1068 children aged 7 through 17 years with uncomplicated appendicitis treated at 10 tertiary children's hospitals across 7 US states between May 2015 and October 2018 with 1-year follow-up through October 2019. Of the 1209 eligible patients approached, 1068 enrolled in the study.Interventions: Patient and family selection of nonoperative management with antibiotics alone (nonoperative group, n = 370) or urgent (≤12 hours of admission) laparoscopic appendectomy (surgery group, n = 698).Main Outcomes and Measures: The 2 primary outcomes assessed at 1 year were disability days, defined as the total number of days the child was not able to participate in all of his/her normal activities secondary to appendicitis-related care (expected difference, 5 days), and success rate of nonoperative management, defined as the proportion of patients initially managed nonoperatively who did not undergo appendectomy by 1 year (lowest acceptable success rate, ≥70%). Inverse probability of treatment weighting (IPTW) was used to adjust for differences between treatment groups for all outcome assessments.Results: Among 1068 patients who were enrolled (median age, 12.4 years; 38% girls), 370 (35%) chose nonoperative management and 698 (65%) chose surgery. A total of 806 (75%) had complete follow-up: 284 (77%) in the nonoperative group; 522 (75%) in the surgery group. Patients in the nonoperative group were more often younger (median age, 12.3 years vs 12.5 years), Black (9.6% vs 4.9%) or other race (14.6% vs 8.7%), had caregivers with a bachelor's degree (29.8% vs 23.5%), and underwent diagnostic ultrasound (79.7% vs 74.5%). After IPTW, the success rate of nonoperative management at 1 year was 67.1% (96% CI, 61.5%-72.31%; P = .86). Nonoperative management was associated with significantly fewer patient disability days at 1 year than did surgery (adjusted mean, 6.6 vs 10.9 days; mean difference, -4.3 days (99% CI, -6.17 to -2.43; P < .001). Of 16 other prespecified secondary end points, 10 showed no significant difference.Conclusion and Relevance: Among children with uncomplicated appendicitis, an initial nonoperative management strategy with antibiotics alone had a success rate of 67.1% and, compared with urgent surgery, was associated with statistically significantly fewer disability days at 1 year. However, there was substantial loss to follow-up, the comparison with the prespecified threshold for an acceptable success rate of nonoperative management was not statistically significant, and the hypothesized difference in disability days was not met.Trial Registration: ClinicalTrials.gov Identifier: NCT02271932. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes has been associated with depression. However, the underlying pathophysiological mechanisms remain unknown. Cerebral small vessel disease, a consequence of diabetes, may lead to depression. Therefore, we evaluated whether cerebral small vessel disease mediates the association between type 2 diabetes and higher depressive symptoms.Research Design and Methods: We used longitudinal data from the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, with examinations from 2002 to 2006 and 5 years later. Type 2 diabetes was defined as self-reported history of type 2 diabetes, use of blood glucose-lowering drugs, or fasting blood glucose level ≥7.0 mmol/L. Cerebral small vessel disease load was quantified in a composite score based on MRI-defined presence of high white matter hyperintensity volume, low total brain parenchyma volume, and subcortical infarcts, cerebral microbleeds, and large perivascular spaces. The 5-year change in the 15-item Geriatric Depression Scale score (GDS-15) was measured between baseline and follow-up.Results: Included were 2,135 individuals without dementia and baseline depression (baseline age 74.5 [SD 4.6] years, 1,245 women [58.3%], and 197 [9.2%] with diabetes). The GDS-15 score increased 0.4 (SD 1.6) points over time. Baseline diabetes was associated with a greater increase in the GDS-15 score (β = 0.337; 95% CI 0.094; 0.579), adjusted for age, sex, education, and cardiovascular risk factors. Baseline cerebral small vessel disease and change of cerebral small vessel disease statistically significantly mediated a part of this association.Conclusions: Type 2 diabetes is associated with a greater increase in depressive symptoms score over 5 years, and cerebral small vessel disease partly explains this association. [ABSTRACT FROM AUTHOR]

Recent post-mortem studies reported 22-37% of patients with multiple system atrophy can develop cognitive impairment. With the aim of identifying associations between cognitive impairment including memory impairment and α-synuclein pathology, 148 consecutive patients with pathologically proven multiple system atrophy were reviewed. Among them, 118 (79.7%) were reported to have had normal cognition in life, whereas the remaining 30 (20.3%) developed cognitive impairment. Twelve of them had pure frontal-subcortical dysfunction, defined as the presence of executive dysfunction, impaired processing speed, personality change, disinhibition or stereotypy; six had pure memory impairment; and 12 had both types of impairment. Semi-quantitative analysis of neuronal cytoplasmic inclusions in the hippocampus and parahippocampus revealed a disease duration-related increase in neuronal cytoplasmic inclusions in the dentate gyrus and cornu ammonis regions 1 and 2 of patients with normal cognition. In contrast, such a correlation with disease duration was not found in patients with cognitive impairment. Compared to the patients with normal cognition, patients with memory impairment (pure memory impairment: n = 6; memory impairment + frontal-subcortical dysfunction: n = 12) had more neuronal cytoplasmic inclusions in the dentate gyrus, cornu ammonis regions 1-4 and entorhinal cortex. In the multiple system atrophy mixed pathological subgroup, which equally affects the striatonigral and olivopontocerebellar systems, patients with the same combination of memory impairment developed more neuronal inclusions in the dentate gyrus, cornu ammonis regions 1, 2 and 4, and the subiculum compared to patients with normal cognition. Using patients with normal cognition (n = 18), frontal-subcortical dysfunction (n = 12) and memory impairment + frontal-subcortical dysfunction (n = 18), we further investigated whether neuronal or glial cytoplasmic inclusions in the prefrontal, temporal and cingulate cortices or the underlying white matter might affect cognitive impairment in patients with multiple system atrophy. We also examined topographic correlates of frontal-subcortical dysfunction with other clinical symptoms. Although no differences in neuronal or glial cytoplasmic inclusions were identified between the groups in the regions examined, frontal release signs were found more commonly when patients developed frontal-subcortical dysfunction, indicating the involvement of the frontal-subcortical circuit in the pathogenesis of frontal-subcortical dysfunction. Here, investigating cognitive impairment in the largest number of pathologically proven multiple system atrophy cases described to date, we provide evidence that neuronal cytoplasmic inclusion burden in the hippocampus and parahippocampus is associated with the occurrence of memory impairment in multiple system atrophy. Further investigation is necessary to identify the underlying pathological basis of frontal-subcortical dysfunction in multiple system atrophy. [ABSTRACT FROM AUTHOR]

Objectives: Adequate vitamin B12 is a requisite during pregnancy and its deficiency is linked with increased risk for adverse outcomes, likely mediated by impaired placental angiogenesis. Thus, we aimed to test associations of maternal vitamin B12 status with the placental expression of angiogenesis-associated genes ENG, VEGF, and FLT.Subjects/methods: In this retrospective case-control study, placental and maternal trimester 1 blood samples (n = 104) were collected from small for gestational age (SGA) and appropriate for gestational age (AGA) full-term singleton pregnancies. Maternal trimester 1 vitamin B12 status was measured. Placentae and neonates were weighed at birth. Realtime quantitative PCR was performed to assess placental transcript abundance of ENG, VEGF, and FLT normalized to a panel of reference genes. Associations of placental transcript abundance of the genes with maternal trimester 1 vitamin B12 status were evaluated.Results: Placental ENG transcript abundance associated negatively with maternal trimester 1 vitamin B12 status (β = -0.461, P = 0.017, n = 104). This association was specific to the female births (β = -0.590, P = 0.014, n = 60). Placental VEGF transcript levels were negatively associated with maternal trimester 1 vitamin B12 status only in the female births (β = -1.995, P = 0.029). Placental FLT transcript levels were not associated with maternal trimester 1 vitamin B12 status.Conclusion: Maternal trimester 1 vitamin B12 status was associated negatively with placental ENG and VEGF expression predominantly in the female births. Therefore, we hypothesize that the placenta adapts to low maternal vitamin B12 status by up-regulating angiogenic pathways in a gender-specific manner. [ABSTRACT FROM AUTHOR]

Impulsive compulsive behaviours in Parkinson's disease have been linked to increased dopaminergic release in the ventral striatum and excessive stimulation of dopamine D3 receptors. Thirty-one patients with impulsive compulsive behaviours and Parkinson's disease who donated their brains to the Queen Square Brain Bank for Neurological Disorders were assessed for α-synuclein neuropathological load and tyrosine hydroxylase levels in the nucleus accumbens, dorsal putamen and caudate using immunohistochemistry. Dopamine D2 and dopamine D3 receptors protein levels in the nucleus accumbens, frontal cortex and putamen were determined using western blotting. Results were compared to 29 Parkinson's disease cases without impulsive compulsive behaviours matched by age, sex, disease duration, age at Parkinson's disease onset and disease duration. The majority of patients with impulsive compulsive behaviours had dopamine dysregulation syndrome. Patients with Parkinson's disease and impulsive compulsive behaviours had lower α-synuclein load and dopamine D3 receptor levels in the nucleus accumbens. No differences were seen between groups in the other brain areas and in the analysis of tyrosine hydroxylase and dopamine D2 receptor levels. Lower α-synuclein load in the nucleus accumbens of individuals with Parkinson's disease and impulsive compulsive behaviours was confirmed on western blotting. Downregulation of the dopamine D3 receptor levels may have occurred either as a consequence of the degenerative process or of a pre-morbid trait. The lower levels of α-synuclein may have contributed to an excessive stimulation of the ventral striatum resulting in impulsive compulsive behaviours. [ABSTRACT FROM AUTHOR]

Background: Although community engagement has been promoted as a strategy for health systems strengthening, there is need for more evidence for effectiveness of this approach. We describe an operations research (OR) Study and assessment of one form of community engagement, the development and implementation of a participatory community-based health information system (PCBHIS), in slum communities in Freetown, Sierra Leone.Methods: A child survival project was implemented in 10 slum communities, which were then randomly allocated to intervention (PCBHIS) and comparison areas. In the 5 PCBHIS communities, the findings from monthly reports submitted by community health workers (CHWs) and verbal autopsy findings for deaths of children who died before reaching 5 years of age, were processed and shared at bimonthly meetings in each community. These meetings, called Community Health Data Review (CHDR) meetings, were attended by community leaders, including members of the Ward Development Committee (WDC) and Health Management Committee (HMC), by the CHW Peer Supervisors, and by representatives of the Peripheral Health Unit. Following a review of the information, attendees proposed actions to strengthen community-based health services in their community. These meetings were held over a period of 20 months from July 2015 to March 2017. At baseline and endline, knowledge, practice and coverage (KPC) surveys measured household health-related behaviors and care-seeking behaviors. The capacity of HMCs and WDCs to engage with the local health system was also measured at baseline and endline. Reports of CHW household contact and assessments of CHW quality were obtained in the endline KPC household survey, and household contacts measured in monthly submitted reports were also tabulated.Results: The self-assessment scores of WDCs' capacity to fulfil their roles improved more in the intervention than in the comparison area for all six components, but for only 1 of the 6 was the improvement statistically significant (monthly and quarterly meetings in which Peer Supervisor and/or CHW supervision was an agenda item). The scores for the HMCs improved less in the intervention area than in the comparison area for all six components, but none of these differences were statistically significant. Topics of discussion in CHDRs focused primarily on CHW functionality. All three indicators of CHW functioning (as measured by reports submitted from CHWs) improved more in the intervention area relative to the comparison area, with 2 out of 3 measures of improvement reaching statistical significance. Five of 7 household behaviors judged to be amenable to promotion by CHWs improved more in the intervention area than in the comparison area, and 2 out of the 5 were statistically significant (feeding colostrum and appropriate infant and young child feeding). Four of the 6 care-seeking behaviors judged to be amenable to promotion by CHWs improved more in the intervention area than in the comparison area, and 1 was statistically significant (treatment of diarrhea with ORS and zinc). None of the findings that favored the comparison area were statistically significant.Conclusions: This study was implemented in challenging circumstances. The OR Study intervention was delayed because of interruptions in finalizing the national CHW policy, two separate cholera epidemics, and the Ebola epidemic lasting more than 2 years. Weaknesses in the CHW intervention severely limited the extent to which the PCBHIS could be used to observe trends in mortality and morbidity. Nonetheless, the positive results achieved in the area of functionality of the CHW intervention and community structure capacity are encouraging. Results suggest there is value in further methodologically rigorous investigations into improving community-based health system functioning through a similar approach to community engagement. [ABSTRACT FROM AUTHOR]

Background: Although dantrolene effectively treats malignant hyperthermia (MH), discrepant recommendations exist concerning dantrolene availability. Whereas Malignant Hyperthermia Association of the United States guidelines state dantrolene must be available within 10 min of the decision to treat MH wherever volatile anesthetics or succinylcholine are administered, a Society for Ambulatory Anesthesia protocol permits Class B ambulatory facilities to stock succinylcholine for airway rescue without dantrolene. The authors investigated (1) succinylcholine use rates, including for airway rescue, in anesthetizing/sedating locations; (2) whether succinylcholine without volatile anesthetics triggers MH warranting dantrolene; and (3) the relationship between dantrolene administration and MH morbidity/mortality.Methods: The authors performed focused analyses of the Multicenter Perioperative Outcomes Group (2005 through 2016), North American MH Registry (2013 through 2016), and Anesthesia Closed Claims Project (1970 through 2014) databases, as well as a systematic literature review (1987 through 2017). The authors used difficult mask ventilation (grades III and IV) as a surrogate for airway rescue. MH experts judged dantrolene treatment. For MH morbidity/mortality analyses, the authors included U.S. and Canadian cases that were fulminant or scored 20 or higher on the clinical grading scale and in which volatile anesthetics or succinylcholine were given.Results: Among 6,368,356 queried outcomes cases, 246,904 (3.9%) received succinylcholine without volatile agents. Succinylcholine was used in 46% (n = 710) of grade IV mask ventilation cases (median dose, 100 mg, 1.2 mg/kg). Succinylcholine without volatile anesthetics triggered 24 MH cases, 13 requiring dantrolene. Among 310 anesthetic-triggered MH cases, morbidity was 20 to 37%. Treatment delay increased complications every 10 min, reaching 100% with a 50-min delay. Overall mortality was 1 to 10%; 15 U.S. patients died, including 4 after anesthetics in freestanding facilities.Conclusions: Providers use succinylcholine commonly, including during difficult mask ventilation. Succinylcholine administered without volatile anesthetics may trigger MH events requiring dantrolene. Delayed dantrolene treatment increases the likelihood of MH complications. The data reported herein support stocking dantrolene wherever succinylcholine or volatile anesthetics may be used. [ABSTRACT FROM AUTHOR]

Importance: There is consistent evidence of the association between ideal cardiovascular health and lower incident cardiovascular disease (CVD); however, most studies used a single measure of cardiovascular health.Objective: To examine how cardiovascular health changes over time and whether these changes are associated with incident CVD.Design, Setting, and Participants: Prospective cohort study in a UK general community (Whitehall II), with examinations of cardiovascular health from 1985/1988 (baseline) and every 5 years thereafter until 2015/2016 and follow-up for incident CVD until March 2017.Exposures: Using the 7 metrics of the American Heart Association (nonsmoking; and ideal levels of body mass index, physical activity, diet, blood pressure, fasting blood glucose, and total cholesterol), participants with 0 to 2, 3 to 4, and 5 to 7 ideal metrics were categorized as having low, moderate, and high cardiovascular health. Change in cardiovascular health over 10 years between 1985/1988 and 1997/1999 was considered.Main Outcome and Measure: Incident CVD (coronary heart disease and stroke).Results: The study population included 9256 participants without prior CVD (mean [SD] age at baseline, 44.8 [6.0] years; 2941 [32%] women), of whom 6326 had data about cardiovascular health change. Over a median follow-up of 18.9 years after 1997/1999, 1114 incident CVD events occurred. In multivariable analysis and compared with individuals with persistently low cardiovascular health (consistently low group, 13.5% of participants; CVD incident rate per 1000 person-years, 9.6 [95% CI, 8.4-10.9]), there was no significant association with CVD risk in the low to moderate group (6.8% of participants; absolute rate difference per 1000 person-years, -1.9 [95% CI, -3.9 to 0.1]; HR, 0.84 [95% CI, 0.66-1.08]), the low to high group, (0.3% of participants; absolute rate difference per 1000 person-years, -7.7 [95% CI, -11.5 to -3.9]; HR, 0.19 [95% CI, 0.03-1.35]), and the moderate to low group (18.0% of participants; absolute rate difference per 1000 person-years, -1.3 [95% CI, -3.0 to 0.3]; HR, 0.96 [95% CI, 0.80-1.15]). A lower CVD risk was observed in the consistently moderate group (38.9% of participants; absolute rate difference per 1000 person-years, -4.2 [95% CI, -5.5 to -2.8]; HR, 0.62 [95% CI, 0.53-0.74]), the moderate to high group (5.8% of participants; absolute rate difference per 1000 person-years, -6.4 [95% CI, -8.0 to -4.7]; HR, 0.39 [95% CI, 0.27-0.56]), the high to low group (1.9% of participants; absolute rate difference per 1000 person-years, -5.3 [95% CI, -7.8 to -2.8]; HR, 0.49 [95% CI, 0.29-0.83]), the high to moderate group (9.3% of participants; absolute rate difference per 1000 person-years, -4.5 [95% CI, -6.2 to -2.9]; HR, 0.66 [95% CI, 0.51-0.85]), and the consistently high group (5.5% of participants; absolute rate difference per 1000 person-years, -5.6 [95% CI, -7.4 to -3.9]; HR, 0.57 [95% CI, 0.40-0.80]).Conclusions and Relevance: Among a group of participants without CVD who received follow-up over a median 18.9 years, there was no consistent relationship between direction of change in category of a composite metric of cardiovascular health and risk of CVD. [ABSTRACT FROM AUTHOR]

During postnatal refractive development, an emmetropization mechanism uses refractive error to modulate the growth rate of the eye. Hyperopia (image focused behind the retina) produces what has been described as "GO" signaling that increases growth. Myopia (image focused in front of the retina) produces "STOP" signaling that slows growth. The interaction between GO and STOP conditions is non-linear; brief daily exposure to STOP counteracts long periods of GO. In young tree shrews, long-wavelength (red) light, presented 14 h per day, also appears to produce STOP signals. We asked if red light also shows temporal non-linearity; does brief exposure slow the normal decrease in hyperopia in infant animals? At 11 days after eye opening (DVE), infant tree shrews (n = 5/group) began 13 days of daily treatment (red LEDs, 624 ± 10 or 636 ± 10 nm half peak intensity bandwidth) at durations of 0 h (normal animals, n = 7) or 1, 2, 4, or 7 h. Following each daily red period, colony lighting resumed. A 14 h red group had no colony lights. Refractive state was measured daily; ocular component dimensions at the end of the 13-day red-light period. Even 1 h of red light exposure produced some hyperopia. The average hyperopic shift from normal rose exponentially with duration (time constant 2.5 h). Vitreous chamber depth decreased non-linearly with duration (time constant, 3.3 h). After red treatment was discontinued, refractions in colony lighting recovered toward normal; the initial rate was linearly related to the amount of hyperopia. The red light may produce STOP signaling similar to myopic refractive error. [ABSTRACT FROM AUTHOR]

Background/objectives: Vitamin B12 deficiency during pregnancy has been associated with increased risk of adverse perinatal outcomes. However, few studies have investigated the burden and determinants of vitamin B12 status in young infants. This study was conducted to determine the associations between maternal and infant vitamin B12 status.Subjects/methods: Pregnant women participating in a vitamin B12 supplementation trial in Bangalore, India, were randomized to receive vitamin B12 (50 μg) or placebo supplementation daily during pregnancy through 6 weeks postpartum. All women received 60 mg of iron and 500 μg of folic acid daily during pregnancy, as per standard of care. This prospective analysis was conducted to determine the associations between maternal vitamin B12 biomarkers (that is, plasma vitamin B12, methylmalonic acid (MMA) and tHcy) during each trimester with infant vitamin B12 status (n=77) at 6 weeks of age.Results: At baseline (⩽14 weeks of gestation), 51% of mothers were vitamin B12 deficient (vitamin B12<150 pmol/l) and 43% had impaired vitamin B12 status (vitamin B12<150 pmol/l and MMA>0.26 μmol/l); 44% of infants were vitamin B12 deficient at 6 weeks of age. After adjusting for vitamin B12 supplementation, higher vitamin B12 concentrations in each trimester were associated with increased infant vitamin B12 concentrations and lower risk of vitamin B12 deficiency in infants (P<0.05). After adjusting for vitamin B12 supplementation, infants born to women with vitamin B12 deficiency had a twofold greater risk of vitamin B12 deficiency (P<0.01). Higher maternal folate concentrations also predicted lower risk of vitamin B12 deficiency in infants (P<0.05). Impaired maternal vitamin B12 status, which combined both circulating and functional biomarkers, was the single best predictor of infant vitamin B12 status.Conclusions: Impaired maternal vitamin B12 status throughout pregnancy predicted higher risk of vitamin B12 deficiency in infants, after adjusting for vitamin B12 supplementation. Future interventions are needed to improve vitamin B12 status periconceptionally, and to ensure optimal vitamin B12 status and health outcomes in pregnant women and their children. [ABSTRACT FROM AUTHOR]

Aims: Left bundle branch block (LBBB) is induced in approximately one-third of all transcatheter aortic valve implantation (TAVI) procedures. We investigated electrophysiological remodelling in patients with TAVI-induced LBBB.Methods and Results: This retrospective study comprises 107 patients with initially narrow QRS complex of whom 40 did not and 67 did develop persistent LBBB after TAVI. 12-lead electrocardiograms (ECGs) taken before TAVI, within 24 hours ('acute'), and 1-12 months after TAVI ('chronic') were used to reconstruct vectorcardiograms. From these vectorcardiograms, QRS and T-wave area were calculated as comprehensive indices of depolarization and repolarization abnormalities, respectively. TAVI-induced LBBB resulted in significant acute depolarization and repolarization changes while further repolarization changes were observed with longer lasting LBBB. The amount of long-term repolarization changes (remodelling) was highly variable between patients. The change in T-wave area between acute and chronic LBBB ranged from +57% to - 77%. After dividing the LBBB cohort into tertiles based on the change in T-wave area, only baseline QRS area was larger in the tertile with no significant change in T-wave area. During longer lasting LBBB, the spatial vector gradient (SVG) changed orientation towards the direction of the QRS-vector, indicating that later-activated regions developed shorter action potential duration.Conclusion: This study in patients with TAVI-induced LBBB shows that repolarization changes develop within months after onset of LBBB, and that these changes are highly variable between individual patients. [ABSTRACT FROM AUTHOR]

Background: Multiple novel oral anticoagulants and left atrial appendage closure devices (WATCHMAN) have been tested against dose-adjusted vitamin K antagonists in randomized controlled trials for stroke prophylaxis in non-valvular atrial fibrillation. No direct comparisons of these strategies are available from randomized controlled trials. We conducted the current analyses by combining efficacy and safety characteristics of all FDA approved stroke prophylaxis treatment strategies for patients with non-valvular atrial fibrillation. Materials and Methods: We searched SCOPUS from 1945 till October 2015 for randomized controlled trials comparing these strategies and reporting efficacy and safety outcomes. Six randomized controlled trials were identified and included in the final analyses and review. We followed PRISMA guidelines for network meta-analyses while reporting the current analyses. We collected data on ischemic stroke, major bleeding, and the composite primary safety endpoint as defined by various randomized controlled trials. Network meta-analyses were conducted using consistency and inconsistency models for efficacy and safety outcomes. Surface under the cumulative ranking curve were then utilized to cluster rank these treatments for safety and efficacy. Results: Six randomized controlled trials with 59,627 patients comparing six treatment strategies were eligible for the analyses. All prophylaxis strategies had comparable rates of ischemic stroke. Apixaban was associated with the least number of primary safety endpoint events as compared with all other treatments. In the cluster analyses assessing safety and efficacy, apixaban, edoxaban and dabigatran ranked best followed by vitamin K antagonists and rivaroxaban, whereas the WATCHMAN left atrial appendage closure device ranked last. Conclusions: Dose-adjusted vitamin K antagonists, novel oral anticoagulants, and the WATCHMAN left atrial appendage closure devices are equally efficacious for ischemic stroke prevention but these treatments have different safety profiles. More randomized controlled trials are needed to directly compare these strategies. [ABSTRACT FROM AUTHOR]

Objective. The purpose of this study was to perform a comparative analysis of the contralateral oblique (CLO) view and the lateral view for lumbar interlaminar epidural access. Design. After the epidural space was accessed, fluoroscopic images at eight different angles (anteroposterior view, multiple CLO, and lateral view) were prospectively obtained. Visualization and location of needle tip relative to bony landmarks were analyzed. The epidural location of the needle was subsequently confirmed by contrast injection and analysis in multiple views. Results. Visualization of the needle tip and the relevant radiologic landmarks was superior in the CLO view. The needle tip location in the epidural space was most consistent at a CLO angle of 45°. Conclusion. This study shows that the CLO view for lumbar interlaminar epidural access offers clear advantages over the lateral view on many clinically important grounds: the needle tip visualization is better, the important radiological landmarks are better visualized, and the needle tip when placed in the epidural space presents a more precise relationship to these landmarks. All of these differences were highly significant. Thus, when using this view, the needle may be directly placed in very close vicinity to the epidural space and true loss of resistance expected soon thereafter. In addition, this view provides the ability to plot the cranio-caudad needle trajectory. The combination of these factors is likely to improve the ease and efficiency of epidural access. The crisp visualization of the final moments of epidural access could also translate to improved safety and accuracy. In light of this, it is suggested that a CLO view at 45° be considered the preferred view for gauging needle depth during interlaminar lumbar epidural access. [ABSTRACT FROM AUTHOR]

Purpose: Some labouring women with neuraxial labour analgesia experience severe upper back pain, typically between the scapulae. This pain may complicate management of neuraxial analgesia/anesthesia, and it may also have important implications for the mode of delivery. This case series describes the clinical course and management of three patients who developed interscapular pain associated with neuraxial labour analgesia.Principal Findings: Neuraxial labour analgesia was initiated in all patients with a combined spinal-epidural technique and maintained via patient-controlled epidural analgesia. Two patients were nulliparous. One patient experienced interscapular pain during initiation of epidural anesthesia for Cesarean delivery after 19 hr of maintenance of labour analgesia with local anesthetic/opioid solution. The other two patients experienced interscapular pain during routine maintenance of epidural labour analgesia. In two patients, the epidural space was identified using loss of resistance to air. Another patient recalled experiencing interscapular pain with her prior labour epidural. Management of these patients included decreasing the epidural infusion rate, increasing the concentration of local anesthetic in the epidural infusion solution, administration of epidural opioids, and replacement of the epidural catheter. All patients eventually experienced relief of their interscapular pain.Conclusions: While little is understood about the etiology of this unique anesthetic complication, it may have important clinical consequences, including inadequate analgesia, inability to provide timely epidural anesthesia, and an increased risk of Cesarean delivery. Future work should characterize at-risk patients, delineate effective treatment strategies, and identify any associated long-term consequences. [ABSTRACT FROM AUTHOR]

This study investigated the impact of state nursing home staffing standards on nurse staffing levels for the year 2011. Specifically, the study attempted to measure state staffing standards at facility level (i.e., nurse staffing levels that each individual nursing home must retain by its state staffing standards) and analyzed the policy impact. The study findings indicated that state staffing standards for the categories of registered nurse, licensed nurse, or total nurse are positively related to registered nurse, licensed nurse, or total nurse staffing levels, respectively. Nursing homes more actively responded to licensed staffing requirements than total staffing requirements. However, nursing homes did not increase their staffing levels as much as those required by state staffing standards. It is possibly because the quality-oriented inspection allows flexibility in nursing homes' control of nurse staffing levels. [ABSTRACT FROM AUTHOR]

Background: Treatment for symptomatic peripheral artery disease includes lower extremity bypass surgery (LEB) and peripheral endovascular interventions (PVIs); however, limited comparative effectiveness data exist between the 2 therapies. We assessed the safety and effectiveness of LEB and PVI in patients with symptomatic claudication and critical limb ischemia.Methods and Results: In a community-based clinical registry at 2 large integrated healthcare delivery systems, we compared 883 patients undergoing PVI and 975 patients undergoing LEB between January 1, 2005 and December 31, 2011. Rates of target lesion revascularization were greater for PVI than for LEB in patients presenting with claudication (12.3±2.7% and 19.0±3.5% at 1 and 3 years versus 5.2±2.4% and 8.3±3.1%, log-rank P<0.001) and critical limb ischemia (19.1±4.8% and 31.6±6.3% at 1 and 3 years versus 10.8±2.5% and 16.0±3.2%, log-rank P<0.001). However, in comparison with PVI, LEB was associated with increased rates of complications up to 30 days following the procedure (37.1% versus 11.9%, P<0.001). There were no differences in amputation rates between the 2 groups. Findings remained consistent in sensitivity analyses by using propensity methods to account for treatment selection.Conclusions: In patients with symptomatic peripheral artery disease, in comparison with LEB, PVI was associated with fewer 30-day procedural complications, higher revascularization rates at 1 and 3 years, and no difference in subsequent amputations. [ABSTRACT FROM AUTHOR]

Concreteness—the psycholinguistic property of referring to a perceptible entity—enhances processing speed, comprehension, and memory. These represent selective filters for cognition likely to influence language evolution in competitive language environments. Taking a culturomics approach, we use multiple language corpora representing more than 350 billion words combined with concreteness norms for over 40,000 English words and demonstrate a systematic rise in concrete language in American English over the last 200 years, both within and across word classes (nouns, verbs, and prepositions). Comparisons between new and old concreteness norms indicate this is not explained by semantic bleaching, but we find some evidence that the rise is related to changes in population demographics and may be associated with increasing numbers of second language learners or attention economics in response to crowding in the language market. We also examine the influence of gender and literacy. In sum, we demonstrate evolution in the psycholinguistic structure of American English, with a well-established impact on cognitive processing, which is likely to permeate modern language use. [ABSTRACT FROM AUTHOR]

Background/Purpose Compared with trans-femoral percutaneous coronary intervention (TFI), trans-radial PCI (TRI) has a lower risk of bleeding, access site complications and hospital costs, and is preferred by patients. However, TRI accounts for a minority of PCIs in the US, and there is currently little research that explores why. Methods/Material We conducted a national survey in February 2013 to assess perceptions of TRI vs. TFI, and barriers to TRI adoption and implementation among interventional cardiologists employed by the US Veterans Health Administration (VHA), and linked these data to site-level TRI annual rates for 2013. Results We received 78 completed surveys (32% response rate). Respondents at sites that perform few or no TRIs identified increased radiation exposure as the greatest barrier while at sites that perform a high percentage of TRIs respondents identified the steep learning curve as the greatest barrier. Majorities of survey respondents at all sites rated TRI as superior on 5 of 7 criteria, including patient comfort and bleeding complications, but rated TFI as superior on procedure time and procedure success. Conclusions Even interventional cardiologists at sites that perform few or any TRIs recognized the superiority of TRI for patient comfort and safety, but rated it inferior to TFI on procedure time and technical results. Interventional cardiologists at high-TRI labs rated TRI as equivalent on procedure time and technical results. Efforts to increase TRI adoption and implementation may be more successful if they emphasize that procedure times and technical results depend on achieving proficiency. [ABSTRACT FROM AUTHOR]

The current mountain pine beetle (MPB; Dendroctonusponderosae) outbreak in the southern Rocky Mountains has impacted ~750 000 ha of forest. Weather and habitat heterogeneity influence forest insect population dynamics at multiple spatial and temporal scales. Comparison of forest insect population dynamics in two principal host species may elucidate the relative contribution of weather and landscape factors in initiating and driving extensive outbreaks. To investigate potential drivers of the current MPB outbreak, we compared broadscale spatiotemporal patterns of MPB activity in lodgepole pine (Pinus contorta) and ponderosa pine (Pinus ponderosa) from 1996 to 2010 in Colorado and southern Wyoming with regional weather fluctuations, and then tracked the annual meso-scale progression of the epidemic in lodgepole pine with respect to weather, topographic, previous MPB activity, and forest stand attributes. MPB activity in lodgepole pine compared to ponderosa pine showed higher magnitude and extent of spatial synchrony. Warm temperatures and low annual precipitation favorable to beetle populations showed high regional synchrony across areas of both pine species, suggesting that habitat interacts with weather in synchronizing MPB populations. Cluster analysis of time series patterns identified multiple, disjunct locations of incipient MPB activity (epicenters) in lodgepole pine, which overlapped an earlier 1980s MPB outbreak, and suggests a regional trigger (drought) across this homogenous forest type. Negative departures from mean annual precipitation played a key role in subsequent spread of MPB outbreak. Development of the outbreak was also associated with lower elevations, greater dominance by lodgepole pine, stands of larger tree size, and stands with higher percentage canopy cover. After epidemic levels of MPB activity were attained, MPB activity was less strongly associated with stand and weather variables. These results emphasize the importance of considering differences in patterns of MPB dynamics for different host pine species even under similar regional-scale weather variation and the nonstationarity of outbreak dynamics over time. [ABSTRACT FROM AUTHOR]

To explore African American mothers' and daughters' practices and influences related to vaginal douching. Design and Sample: Our overall study used a sequential mixed-method design with 3 phases. Phase 1, the focus of this report, used grounded theory methods and in-depth, semistructured individual interviews. Two generations of African American girls and women: 24 girls (“daughters”) aged 14–18 and 17 women (“mothers” or “mother figures”) aged 22–43, recruited from 1 adolescent health clinic in Baltimore, MD. Measures: In-depth interviews were taped and transcribed and data analysis used the constant comparison method. Results: Daughters were much less likely to douche or to have been exposed to douching information than mothers. Many mothers and daughters were influenced by health care providers and/or family members to not initiate, to decrease, or to stop douching. Women who currently douche often do so because of the perception of improved smell and cleanliness around menstruation and sexual intercourse. Conclusions: These data indicate that although some women continue to believe that vaginal douching has therapeutic value, others have been influenced to stop or not start douching by family and health care providers. Health care providers should continue efforts to educate patients on the risks of vaginal douching. [ABSTRACT FROM AUTHOR]

Discusses the genetic basis of human aging and longevity. Manifestations of longevity genes; Categories of longevity genes; Value of understanding the genetic basis of aging and longevity.

In addition to heartburn and regurgitation, cough is a frequent nonspecific complaint of patients with gastroesophageal reflux disease. The incidence of alternative etiologies for patients with chronic cough who are undergoing antireflux surgery is not known. To determine this, and the response of chronic cough to fundoplication, we performed a retrospective review of 129 patients with proven gastroesophageal reflux referred for surgical therapy. Chronic cough was present in 37 (29%) preoperatively. No differences were found in age, sex, or preoperative manometric findings between those with and without chronic cough. Patients with cough had a higher number of lower esophageal reflux events on preoperative 24-hour pH testing, and were more likely to have persistent dysphagia after surgery. Fifty-nine percent of patients with cough had an alternative etiology for cough, compared to 36% of those without cough. Of the common alternative etiologies, only a history of postnasal drip occurred more frequently in those with cough. Complete resolution of cough occurred in 24 patients (64%), with another 10 (27%) reporting significant improvement. The average cough score improved significantly regardless of which coexisting etiology the patients may have had. Additionally, heartburn and regurgitation were improved in 94% of all patients. (J Gastrointest Surg 2002;6:17–21.) [Copyright &y& Elsevier]

Soy consumption has been associated with a lower incidence of breast cancer in Southeast Asia. Among the phytochemicals in soy, genistein has been suggested to be chemopreventive. Because genistein is an estrogen-receptor (ER) agonist, the chemopreventive mechanism has been attributed to its ability to compete with estrogen for receptor binding. In this study, we used an ER-positive cell line to investigate the effects of different genistein concentrations on the apoptotic response. The threshold concentration at which a significant number of cells underwent apoptosis was titrated to be 25 micromol/L. At or above this concentration, c-jun N-terminus kinase was activated and Bax and Bcl-2 expression were both elevated. The elevated Bcl-2 protein might neutralize the proapoptotic effect of Bax. Therefore, the mechanism of genistein-induced apoptosis at this concentration might rely largely on the stress pathway rather than the pathway mediated by the Bcl-2 family of proteins. [ABSTRACT FROM AUTHOR]

Local immobilization is a good model for studying disuse-induced bone loss and to appreciate the effects of drugs, especially preventive action of antiresorptive therapy. In fact, increased osteoclastic activity is the main point of such a bone loss. The effect of salmon calcitonin was investigated on immobilization-induced osteoporosis in the sheep. Twenty-four nonovariectomized, adult, female, Welsh mountain sheep were submitted, by an external fixator procedure, to hock joint immobilization from the tibia to the the metatarsus for 12 weeks. The sheep were randomized into two groups receiving either an injection of placebo or salmon calcitonin (100 IU) three times per week, for 12 weeks. Histomorphometric analysis was performed on pre- and posttherapeutic transiliac bone biopsies, and on immobilized (left) and nonimmobilized calcanei removed after sacrifice. Results showed a 29% significant decrease of cancellous bone volume in the placebo group due to a significant reduced trabecular thickness when we compared immobilized versus nonimmobilized calcaneus. This structural adaptation appeared to be the consequence of an overall increased bone turnover. In the calcitonin group, same changes were observed, with a 23% reduction of bone mass in the immobilized calcaneus. By comparing calcitonin with placebo groups in both left and right calcanei, no difference was found. On the other hand, a significant increase of mineralization parameters in the iliac crest was only observed in the calcitonin group. In conclusion, salmon calcitonin, at a dose of 100 IU/day three times a week, was ineffective in preventing local disuse osteoporosis in this sheep model. [ABSTRACT FROM AUTHOR]

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Sexually transmitted disease (STD) in rural Bangladesh is currently a topic of great concern. To date, little information is available in the literature regarding its prevalence. It is now known, however, that the current level of STD awareness among the rural population with regard to modes of transmission and means of prevention is inadequate. In 1994, the MCH-FP Extension Project (Rural) of ICDDR, B surveyed 8674 married women of reproductive age (MWRA) in 4 rural thanas to examine their awareness of STDs. The association between socio-demographic and programmatic factors (variables which affect STD information availability) and awareness of STDs was examined by both bivariate and multivariate analyses. Seven focus group discussions were conducted among groups of government health and family planning workers and paramedics to assess their knowledge of STDs and attitudes about their prevention. Only 12% of the original group had even a basic understanding about STDs and how to protect themselves from them. Twenty-five per cent of the women surveyed had ever heard of either syphilis or gonorrhoea. Of these women, less than half could mention specific mechanisms involved in the transmission of these diseases. Seven per cent reported that syphilis and gonorrhoea are transmitted through sexual intercourse. Thirteen per cent reported that the infections are transmitted from spouses to their partners. Four per cent reported that STDs can be spread by having multiple sexual partners. The results of logistic regression analysis indicate that awareness of STDs was higher among relatively older women than among younger women. Awareness of STDs was most strongly and positively associated with the education of both the women and their husbands. Awareness of STDs was also found to be higher among women who were more socially mobile (e.g. those who frequent cinemas or mothers' clubs). The findings of focus group discussions indicate that family planning and health care service providers have a moderate level of STD awareness. Modes of transmission and means of prevention, however, were areas of weakness. It will, therefore, be necessary, whether to prevent a potential STD epidemic or to combat current STD prevalence, to implement culturally acceptable and affordable means of disseminating knowledge in rural areas of Bangladesh. Training of health care providers will be an essential first step. [ABSTRACT FROM AUTHOR]

High precision in the manual control of needles and biopsy probes in medical treatment requires high skill and dexterity levels. In anaesthesia, force sensation is an important feedback mechanism, and the practitioner needs to refresh or develop skills to improve on the interpretation of needle progress towards the target site. This paper describes an experimental tactile force simulator for uniaxial needle action for which the force resisting progress of the needle is derived from measured data. As an example, the approach taken to develop the simulation of the insertion of epidural needles is described. Adaptation to other procedures would be possible by adopting new reference models based on appropriate measured force data. [ABSTRACT FROM AUTHOR]

Background: Estimates for the incidence of difficult intubation in the obstetric population vary widely, although previous studies reporting rates of difficult intubation in obstetrics are older and limited by smaller samples. The goals of this study were to provide a contemporary estimate of the frequency of difficult and failed intubation in women undergoing general anesthesia for cesarean delivery and to elucidate risk factors for difficult intubation in women undergoing general anesthesia for cesarean delivery.Methods: This is a multicenter, retrospective cohort study utilizing the Multicenter Perioperative Outcomes Group database. The study population included women aged 15 to 44 yr undergoing general anesthesia for cesarean delivery between 2004 and 2019 at 1 of 45 medical centers. Coprimary outcomes included the frequencies of difficult and failed intubation. Difficult intubation was defined as Cormack-Lehane view of 3 or greater, three or more intubation attempts, rescue fiberoptic intubation, rescue supraglottic airway, or surgical airway. Failed intubation was defined as any attempt at intubation without successful endotracheal tube placement. The rates of difficult and failed intubation were assessed. Several patient demographic, anatomical, and obstetric factors were evaluated for potential associations with difficult intubation.Results: This study identified 14,748 cases of cesarean delivery performed under general anesthesia. There were 295 cases of difficult intubation, with a frequency of 1:49 (95% CI, 1:55 to 1:44; n = 14,531). There were 18 cases of failed intubation, with a frequency of 1:808 (95% CI, 1:1,276 to 1:511; n = 14,537). Factors with the highest point estimates for the odds of difficult intubation included increased body mass index, Mallampati score III or IV, small hyoid-to-mentum distance, limited jaw protrusion, limited mouth opening, and cervical spine limitations.Conclusions: In this large, multicenter, contemporary study of more than 14,000 general anesthetics for cesarean delivery, an overall risk of difficult intubation of 1:49 and a risk of failed intubation of 1:808 were observed. Most risk factors for difficult intubation were nonobstetric in nature. These data demonstrate that difficult intubation in obstetrics remains an ongoing concern.Editor’s Perspective: [ABSTRACT FROM AUTHOR]

Focuses on a study which examined whether there is an increase in phosphatidylserine in the lipid bilayer of erythrocyte and platelet cell membranes in type 1 diabetics. Subjects; Discussion of results; Significance of the study.

In infant tree shrews, exposure to narrow-band long-wavelength (red) light, that stimulates long-wavelength sensitive cones almost exclusively, slows axial elongation and produces hyperopia. We asked if red light produces hyperopia in juvenile and adolescent animals, ages when plus lenses are ineffective. Animals were raised in fluorescent colony lighting (100-300 lux) until they began 13days of red-light treatment at 11 (n=5, "infant"), 35 (n=5, "juvenile") or 95 (n=5, "adolescent") days of visual experience (DVE). LEDs provided 527-749 lux on the cage floor. To control for the higher red illuminance, a fluorescent control group (n=5) of juvenile (35 DVE) animals was exposed to ∼975 lux. Refractions were measured daily; ocular component dimensions at the start and end of treatment and end of recovery in colony lighting. These groups were compared with normals (n=7). In red light, the refractive state of both juvenile and adolescent animals became significantly (P<0.05) hyperopic: juvenile 3.9±1.0 diopters (D, mean±SEM) vs. normal 0.8±0.1D; adolescent 1.6±0.2D vs. normal 0.4±0.1D. The fluorescent control group refractions (0.6±0.3D) were normal. In red-treated juveniles the vitreous chamber was significantly smaller than normal (P<0.05): juvenile 2.67±0.03mmvs. normal 2.75±0.02mm. The choroid was also significantly thicker: juvenile 77±4μmvs. normal 57±3μm (P<0.05). Although plus lenses do not restrain eye growth in juvenile tree shrews, the red light-induced slowed growth and hyperopia in juvenile and adolescent tree shrews demonstrates that the emmetropization mechanism is still capable of restraining eye growth at these ages. [ABSTRACT FROM AUTHOR]

Objectives: With a continual shortage of geriatricians, adult-gerontology primary care nurse practitioners have assumed a greater role in the delivery of outpatient care for older adults. Given the long duration of physician training, the high cost of medical school, and the lower salaries compared with subspecialists, the financial advantage of a career as a geriatrician as opposed to a nurse practitioner is uncertain. This study compares the estimated career earnings of a geriatrician and an adult-gerontology primary care nurse practitioner.Methods: We used a synthetic model of estimated net earnings during a 43-year career span for a 22-year old person embarking on a career as a geriatrician versus a career as an adult-gerontology primary care nurse practitioner. We estimated annual net income and net retirement savings using different annual compound rates and calculated the financial impact of forgiving medical student loans, shortening the duration of physician training, and reinstituting the practice pathway for geriatric medicine certification.Results: Career net incomes for the geriatrician did not match the nurse practitioner until almost age 40. At 65 years of age, the difference between the geriatrician and nurse practitioner was 30.6%. A higher annual compound rate was associated with an even smaller percentage difference. Combining all three health policy interventions lowered the break-even age to 28 and more than doubled the difference in career earnings.Conclusions: Small estimated differences in net career earnings exist between geriatricians and adult-gerontology primary care nurse practitioners. Health policy interventions had a dramatic positive effect on geriatricians' lifetime net earnings in calculated estimates. [ABSTRACT FROM AUTHOR]

Background: In patients undergoing percutaneous coronary intervention (PCI), drug-eluting stents (DES) reduce repeat revascularizations compared with bare-metal stents (BMS), but their effects on death and myocardial infarction (MI) are mixed. Few studies have focused on patients with end-stage renal disease.Objectives: This study compared mortality and cardiovascular morbidity during percutaneous coronary intervention with DES and with BMS in dialysis patients.Methods: We identified 36,117 dialysis patients from the USRDS (United States Renal Data System) who had coronary stenting in the United States between April 23, 2003, and December 31, 2010, and examined the association of DES versus BMS with 1-year outcomes: death; death or MI; and death, MI, or repeat revascularization. We also conducted a temporal analysis by dividing the study period into 3 DES eras: Transitional (April 23, 2003, to June 30, 2004); Liberal (July 1, 2004, to December 31, 2006); and Selective (January 1, 2007, to December 31, 2010).Results: One-year event rates were high, with 38 deaths; 55 death or MI events; and 71 death, MI, or repeat revascularization events per 100 person-years. DES, compared with BMS, were associated with a significant 18% lower risk of death; 16% lower risk of death or MI; and 13% lower risk of death, MI, or repeat revascularization. DES use varied, from 56% in the Transitional era to 85% in the Liberal era and 62% in the Selective era. DES outcomes in the Liberal era were significantly better than in the Transitional Era, but not significantly better than in the Selective Era.Conclusions: DES for percutaneous coronary intervention appears to be safe for use in U.S. dialysis patients and is associated with lower rates of death, MI, and repeat revascularization. [ABSTRACT FROM AUTHOR]

Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis. [ABSTRACT FROM AUTHOR]

Background: The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP).Methods: In stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets.Findings: Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead single nucleotide polymorphism rs2242367, p=7·5 × 10-10, hazard ratio 1·42 [95% CI 1·22-1·67]). rs2242367 was associated with survival in the individuals added in stage two (n=238; p=0·049, 1·22 [1·00-1·48]) and in the pooled analysis of both stages (n=1239; p=1·3 × 10-10, 1·37 [1·25-1·51]). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs), LINC02555 and AC079630.4, in whole blood. Although we did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed a posterior probability of hypothesis 4 of 0·77, suggesting colocalisation due to a single shared causal variant.Interpretation: Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association might be through a lncRNA-regulated effect on LRRK2 expression because LINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 has been associated with sporadic and familial forms of Parkinson's disease, and our finding suggests a genetic overlap with PSP. Further functional studies will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP and related tauopathies.Funding: PSP Association, CBD Solutions, Medical Research Council (UK). [ABSTRACT FROM AUTHOR]

Background: Thrombocytopenia has been considered a relative or even absolute contraindication to neuraxial techniques due to the risk of epidural hematoma. There is limited literature to estimate the risk of epidural hematoma in thrombocytopenic parturients. The authors reviewed a large perioperative database and performed a systematic review to further define the risk of epidural hematoma requiring surgical decompression in this population.Methods: The authors performed a retrospective cohort study using the Multicenter Perioperative Outcomes Group database to identify thrombocytopenic parturients who received a neuraxial technique and to estimate the risk of epidural hematoma. Patients were stratified by platelet count, and those requiring surgical decompression were identified. A systematic review was performed, and risk estimates were combined with those from the existing literature.Results: A total of 573 parturients with a platelet count less than 100,000 mm who received a neuraxial technique across 14 institutions were identified in the Multicenter Perioperative Outcomes Group database, and a total of 1,524 parturients were identified after combining the data from the systematic review. No cases of epidural hematoma requiring surgical decompression were observed. The upper bound of the 95% CI for the risk of epidural hematoma for a platelet count of 0 to 49,000 mm is 11%, for 50,000 to 69,000 mm is 3%, and for 70,000 to 100,000 mm is 0.2%.Conclusions: The number of thrombocytopenic parturients in the literature who received neuraxial techniques without complication has been significantly increased. The risk of epidural hematoma associated with neuraxial techniques in parturients at a platelet count less than 70,000 mm remains poorly defined due to limited observations. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to compared the use and effectiveness of bleeding avoidance strategies (BAS) by sex. Background: Women have higher rates of bleeding following percutaneous coronary intervention (PCI). Methods: Among 570,777 men (67.5%) and women (32.5%) who underwent PCI in the National Cardiovascular Data Registry''s CathPCI Registry between July 1, 2009 and March 31, 2011, in-hospital bleeding rates and the use of BAS (vascular closure devices, bivalirudin, radial approach, and their combinations) were assessed. The relative risk of bleeding for each BAS compared with no BAS was determined in women and men using multivariable logistic regressions adjusted for clinical characteristics and the propensity for receiving BAS. Finally, the absolute risk differences in bleeding associated with BAS were compared. Results: Overall, the use of any BAS differed slightly between women and men (75.4% vs. 75.7%, p = 0.01). When BAS was not used, women had significantly higher rates of bleeding than men (12.5% vs. 6.2%, p < 0.01). Both sexes had similar adjusted risk reductions of bleeding when any BAS was used (women, odds ratio: 0.60, 95% confidence interval [CI]: 0.57 to 0.63; men, odds ratio: 0.62, 95% CI: 0.59 to 0.65). Women and men had lower absolute bleeding risks with BAS; however, these absolute risk differences were greater in women (6.3% vs. 3.2%, p < 0.01). Conclusions: Women continue to have almost twice the rate of bleeding following PCI. The use of any BAS was associated with a similarly lower risk of bleeding for men and women; however, the absolute risk differences were substantially higher in women. These data underscore the importance of applying effective strategies to limit post-PCI bleeding, especially in women. [Copyright &y& Elsevier]

Abstract: Results are presented from a study designed to evaluate the impact upon urban area transport and dispersion (T&D) modeling accuracy by coupling a microscale computational fluid dynamics (CFD) model with a mesoscale numerical weather prediction (NWP) model. The CFD model taking part in the evaluation was the CFD-Urban model while the NWP model was the Weather Research and Forecasting (WRF) model. The following two different approaches of supplying initial and boundary conditions to drive CFD-Urban were evaluated by comparing the resulting tracer gas transport fields to field data: (i) using observation obtained from a single sounding site during the URBAN 2000 field experiment and (ii) using WRF output in quasi-steady mode. The WRF and the CFD-Urban model results were evaluated against data obtained from the Intensive Observation Period (IOP) 10 during the URBAN 2000 field experiment. It was found that the CFD-Urban T&D prediction was significantly improved when using wind fields produced by downscaling WRF output as initial and boundary conditions. One key reason for such success is that the turning of lower boundary layer wind and pressure gradient are well represented in the time-varying three-dimensional WRF fields. [Copyright &y& Elsevier]

Background: Microgravity has been thought to induce osteoporosis because of reduced weight-bearing. However, up to now, few data have been available about its precise nature and timecourse.Methods: We measured bone mineral density (BMD) at the distal radius and tibia in 15 cosmonauts of the Russian MIR space station who sojourned in space either 1 (n=two), 2 (two), or 6 months (11). After recovery periods of similar duration to the space missions, BMD was measured for the 2-month and 6-month crews.Findings: Neither cancellous nor cortical bone of the radius was significantly changed at any of the timepoints. On the contrary, in the weight-bearing tibial site, cancellous BMD loss was already present after the first month and deteriorated with mission duration. In tibial cortices, bone loss was noted after a 2-month flight. In the 6-month group, cortical bone loss was less pronounced than that for cancellous bone. In some individuals, tibial deterioration was great. Actual BMD did not depend on preceding cumulative periods spent in space. During recovery, tibial bone loss persisted, suggesting that the time needed to recover is longer than the mission duration.Interpretation: In space, despite physical training, bone loss is an adaptive process that can become pathological after recovery on Earth. Striking interindividual variations in bone responses seem to suggest a need for adequate crew preselection. Targeted treatment or prevention strategies would be useful, not only for space purposes, but also for the increasing number of osteoporotic patients on Earth. [ABSTRACT FROM AUTHOR]

Objective: To demonstrate the feasibility of studying exosomes directly from peritoneal fluid, we isolated exosomes from endometriosis patient samples and from controls, and characterized their cargo.Design: Case-control experimental study.Setting: Academic clinical center.Patient (s): Women with and without endometriosis who underwent laparoscopic surgery (n = 28 in total).Intervention (s): None.Main Outcome Measure (s): Concentration of exosomes within peritoneal fluid and protein content of the isolated exosomes.Result (s): Peritoneal fluid samples were pooled according to the cycle phase and disease stage to form six experimental groups, from which the exosomes were isolated. Exosomes were successfully isolated from peritoneal fluid in all the study groups. The concentration varied with cycle phase and disease stage. Proteomic analysis showed specific proteins in the exosomes derived from endometriosis patients that were absent in the controls. Five proteins were found exclusively in the endometriosis groups: PRDX1, H2A type 2-C, ANXA2, ITIH4, and the tubulin α-chain.Conclusion (s): Exosomes are present in peritoneal fluid. The characterization of endometriosis-specific exosomes opens up new avenues for the diagnosis and investigation of endometriosis. [ABSTRACT FROM AUTHOR]