Factors associated with a history of critical wandering among Medic-Alert subscribers.

BACKGROUND: Critical wandering occurs when an individual living with dementia leaves a location and is unaware of place or time. Critical wandering incidents are expected to increase with the growing prevalence of persons living with dementia worldwide. We investigated the association between demographic, psychopathological, and environmental factors and a history of critical wandering among Medic-Alert subscribers, both with and without dementia. METHODS: Our retrospective study included data of 25,785 Canadian Medic-Alert subscribers who were aged 40 years or older. We used multivariable logistic regression analysis to examine the associations between a history of critical wandering and dementia status as psychopathological independent variable, controlled by demographic (age, ethnic background, sex at birth, Canadian languages spoken) and environmental (living arrangement, population density) factors. RESULTS: The overall study sample comprised of mainly older adults (77.4%). Medic-Alert subscribers who were older, male sex at birth, living with dementia, of a minority ethnic group and who did not have proficiency in an official Canadian language had a higher likelihood of a history of critical wandering. Residing in an urban environment, in an institution or with a family member, were environmental factors associated with a higher likelihood of a history of critical wandering. CONCLUSIONS: People living with dementia experience a higher likelihood of a history of critical wandering compared to those without dementia. Medic-Alert and similar organizations can develop algorithms based on the associated factors that can be used to flag risks of critical wandering. This can inform preventative strategies at the individual and community levels.

Admixture mapping analysis reveals differential genetic ancestry associated with Chagas disease susceptibility in the Colombian population.

Chagas disease is an infection caused by the parasite Trypanosoma cruzi, endemic in Latino America. Leveraging the three-way admixture between Native American (AMR), European (EUR) and African (AFR) populations in Latin Americans, we aimed to better understand the genetic basis of Chagas disease by performing an admixture mapping study in a Colombian population. A two-stage study was conducted, and subjects were classified as seropositive and seronegative for T. cruzi. In stage 1, global and local ancestries were estimated using reference data from the 1000 Genomes Project (1KGP), and local ancestry associations were performed by logistic regression models. The AMR ancestry showed a protective association with Chagas disease within the major histocompatibility complex region [Odds ratio (OR) = 0.74, 95% confidence interval (CI) = 0.66-0.83, lowest P-value = 4.53 × 10-8]. The fine mapping assessment on imputed genotypes combining data from stage 1 and 2 from an independent Colombian cohort, revealed nominally associated variants in high linkage disequilibrium with the top signal (rs2032134, OR = 0.93, 95% CI = 0.90-0.97, P-value = 3.54 × 10-4) in the previously associated locus. To assess ancestry-specific adaptive signals, a selective sweep scan in an AMR reference population from 1KGP together with an in silico functional analysis highlighted the Tripartite Motif family and the human leukocyte antigen genes, with crucial role in the immune response against pathogens. Furthermore, these analyses emphasized the macrophages, neutrophils and eosinophils, as key players in the defense against T. cruzi. This first admixture mapping study in Chagas disease provided novel insights underlying the host immune response in the pathogenesis of this neglected disease.

Evaluation of a whole-exome sequencing pipeline and benchmarking of causal germline variant prioritizers.

Most causal variants of Mendelian diseases are exonic. Whole-exome sequencing (WES) has become the diagnostic gold standard, but causative variant prioritization constitutes a bottleneck. Here we assessed an in-house sample-to-sequence pipeline and benchmarked free prioritization tools for germline causal variants from WES data. WES of 61 unselected patients with a known genetic disease cause was obtained. Variant prioritizations were performed by diverse tools and recorded to obtain a diagnostic yield when the causal variant was present in the first, fifth, and 10th top rankings. A fraction of causal variants was not captured by WES (8.2%) or did not pass the quality control criteria (13.1%). Most of the applications inspected were unavailable or had technical limitations, leaving nine tools for complete evaluation. Exomiser performed best in the top first rankings, while LIRICAL led in the top fifth rankings. Based on the more conservative top 10th rankings, Xrare had the highest diagnostic yield, followed by a three-way tie among Exomiser, LIRICAL, and PhenIX, then followed by AMELIE, TAPES, Phen-Gen,  AIVar, and VarNote-PAT. Xrare, Exomiser, LIRICAL, and PhenIX are the most efficient options for variant prioritization in real patient WES data.

Administration of BDNF in the ventral tegmental area produces a switch from a nicotine-non-dependent D1R-mediated motivational state to a nicotine-dependent-like D2R-mediated motivational state.

Brain-derived neurotrophic factor (BDNF) has been implicated in the transition from a non-dependent motivational state to a drug-dependent and drug-withdrawn motivational state. Chronic nicotine can increase BDNF in the rodent brain and is associated with smoking severity in humans; however, it is unknown whether this increased BDNF is linked functionally to the switch from a nicotine-non-dependent to a nicotine-dependent state. We used a place conditioning paradigm to measure the conditioned responses to nicotine, showing that a dose of acute nicotine that non-dependent male mice find aversive is found rewarding in chronic nicotine-treated mice experiencing withdrawal. A single BDNF injection in the ventral tegmental area (in the absence of chronic nicotine treatment) caused mice to behave as if they were nicotine dependent and in withdrawal, switching the neurobiological substrate mediating the conditioned motivational effects from dopamine D1 receptors to D2 receptors. Quantification of gene expression of BDNF and its receptor, tropomyosin-receptor-kinase B (TrkB), revealed an increase in TrkB mRNA but not BDNF mRNA in the VTA in nicotine-dependent and nicotine-withdrawn mice. These results suggest that BDNF signalling in the VTA is a critical neurobiological substrate for the transition to nicotine dependence. The modulation of BDNF signalling may be a promising new pharmacological avenue for the treatment of addictive behaviour.

NanoCLUST: a species-level analysis of 16S rRNA nanopore sequencing data.

SUMMARY: NanoCLUST is an analysis pipeline for the classification of amplicon-based full-length 16S rRNA nanopore reads. It is characterized by an unsupervised read clustering step, based on Uniform Manifold Approximation and Projection (UMAP), followed by the construction of a polished read and subsequent Blast classification. Here, we demonstrate that NanoCLUST performs better than other state-of-the-art software in the characterization of two commercial mock communities, enabling accurate bacterial identification and abundance profile estimation at species-level resolution. AVAILABILITY AND IMPLEMENTATION: Source code, test data and documentation of NanoCLUST are freely available at https://github.com/genomicsITER/NanoCLUST under MIT License. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Improvement in the Thermostability of a Recombinant ß-Glucosidase Immobilized in Zeolite under Different Conditions.

ß-Glucosidase is part of the cellulases and is responsible for degrading cellobiose into glucose, a compound that can be used to produce biofuels. However, the use of the free enzyme makes the process more expensive. Enzyme immobilization improves catalytic characteristics and supports, such as zeolites, which have physical-chemical characteristics and ion exchange capacity that have a promising application in the biotechnological industry. This research aimed to immobilize by adsorption a recombinant ß-glucosidase from Trichoderma reesei, obtained in Escherichia coli BL21 (DE3), in a commercial zeolite. A Box Behnken statistical design was applied to find the optimal immobilization parameters, the stability against pH and temperature was determined, and the immobilized enzyme was characterized by SEM. The highest enzymatic activity was determined with 100 mg of zeolite at 35 °C and 175 min. Compared to the free enzyme, the immobilized recombinant ß-glucosidase presented greater activity from pH 2 to 4 and greater thermostability. The kinetic parameters were calculated, and a lower KM value was obtained for the immobilized enzyme compared to the free enzyme. The obtained immobilization parameters by a simple adsorption method and the significant operational stability indicate promising applications in different fields.

Data silos undermine efforts to characterize, predict, and mitigate dementia-related missing person incidents.

It is estimated that up to 60% of people living with dementia go missing at least once during the course of their disease. Databases on missing incidents involving people living with dementia are managed in silos with minimal or incomplete data. A national strategy for the collection of data on missing incidents of people living with dementia would optimize time and resources spent on police and search and rescue and enhance chances of saving lives of those who go missing. Such a strategy would be a first step toward developing strategies to prevent future missing person incidents among this population. The objectives of this manuscript are to: (1) describe the issues and challenges related to the lack of integrated data on people living with dementia at risk of going missing, and (2) propose directions to create a national database.

Ageing, technology, and health: Advancing the concepts of autonomy and independence.

The global pandemic expedited the adoption of AgeTech solutions that aim to help older adults maintain their autonomy and independence. This article examines the negative impact of the Western worldview of autonomy and independence on older adults. Negative impact can manifest as ageism and may be compounded by intersections of identities with race, gender, and culture. We propose an inclusive framework for health leaders, one that is not binary or categorical, but instead, on a continuum: (1) relational autonomy which assumes that relationships form one's identity; therefore, no one is autonomous to the exclusion of others, and (2) interdependence which proposes that one's lifestyle choice is supported by interreliance with aspects of one's environment. We examine two examples of AgeTech from the perspective of relational autonomy and interdependence and discuss how health leaders can use this inclusive framework to ensure that their services do not discriminate against older adults.

Endonasal resection of orbital cavernous venous malformations with septal preservation.

PURPOSE: Multiple surgical approaches have been described to maximize visualization and accessibility for resection while minimizing morbidity in the patient with orbital intraconal tumors. Transnasal endoscopic approaches have become increasingly standard in select orbital cavernous venous malformations but often require a partial septectomy. The purpose of this manuscript is to communicate a septal preserving modified transseptal approach. METHODS: A 37-year old male was found to have an inferomedial intraconal orbital mass, measuring up to 2.6 cm on magnetic resonance imaging. Binarial transseptal access with septal preservation was obtained with a Killian incision on the right and a small incision in the midseptum on the left. RESULTS: Successful tumor delivery through the nasal cavity resulted in orbital relaxation. Postoperative evaluation of the septum demonstrated an intact septum with nearly no evidence of septal trauma from surgical manipulation. CONCLUSION: This technique is easily performed and affords adequate visualization and freedom of movement as traditional binarial transseptal approaches without the disadvantages of partial septal loss such as increased crusting, olfactory disturbance, and loss of nasoseptal flaps.

Admixture mapping of asthma in southwestern Europeans with North African ancestry influences.

The prevalence of asthma symptoms in Canary Islanders, a southwestern European population from Spain, is almost three times higher than the country average. Because the genetic risks identified so far explain <5% of asthma heritability, here we aimed to discover new asthma loci by completing the first admixture mapping study in Canary Islanders leveraging their distinctive genetic makeup, where significant northwest African influences coexist in the European genetic diversity landscape. A 2-stage study was conducted in 1,491 unrelated individuals self-declaring having a Canary Islands origin for the 4 grandparents. Local ancestry estimates were obtained for the shared positions with reference data from putative ancestral populations from Europe, North Africa, and sub-Saharan Africa. Case-control deviations in local ancestry were tested for each ancestry separately using logistic regressions adjusted for principal components, followed by fine-mapping analyses based on imputed genotypes and analyses of the likely deleterious exonic variants. The admixture mapping analysis of asthma detected that local North African ancestry in a locus spanning 365 kb of chromosome 16q23.3 was associated with asthma risk at study-wide significance [lowest P = 1.12 × 10-4; odds ratio (OR) = 2.05; 95% confidence interval (CI) = 1.41-3.00]. Fine-mapping studies identified a variant associated with asthma, and results were replicated in independent samples (rs3852738, OR = 1.34; 95% CI = 1.13-1.59, P = 7.58 × 10-4). Whole exome sequencing data from a subset of individuals revealed an enrichment of likely deleterious variants among asthma cases in 16q23.3, particularly in the phospholipase Cγ2 (PLCG2) gene (P = 3.67 × 10-4). By completing the first mapping study of asthma in admixed populations from Europe, our results revealed a new plausible asthma locus.

Opioid Taper Is Associated with Subsequent Termination of Care: a Retrospective Cohort Study.

BACKGROUND: Opioid tapering is increasingly utilized by providers to decrease risks of chronic opioid therapy, but it is unknown whether tapering is associated with termination of care. OBJECTIVE: To determine whether patients taking chronic opioid therapy who experienced opioid tapers were at greater risk of subsequently terminating their care compared with those who were continued on their doses. DESIGN: Retrospective cohort study of patients in a large, urban health system between 2008 and 2012 with 2 years of follow-up. PARTICIPANTS: Adult patients prescribed a stable baseline dose of chronic opioid therapy of at least 25 morphine milligram equivalents per day during a baseline year. MAIN MEASURES: An opioid taper during an exposure year, defined as a reduction in the average daily dose of at least 30% from the baseline dose in both of the two 6-month periods in the year following the baseline year. Opioid dose continuation was defined as any increase in dose, no change in dose, or any decrease up to 30% compared with baseline dose in the exposure year. The primary outcome was termination of care, defined as no outpatient encounters in the health system, in the year following the exposure year. KEY RESULTS: Of 1624 patients on chronic opioid therapy, 207 (15.5%) experienced an opioid taper and 78 (4.8%) experienced termination of care. Compared with opioid dose continuation, opioid taper was significantly associated with termination of care (AOR 4.3 [95% CI 2.2-8.5]). CONCLUSIONS: Opioid taper is associated with subsequent termination of care. These findings invite caution and demonstrate the need to fully understand the risks and benefits of opioid tapers.

Access to α-Aminophosphonic Acid Derivatives and Phosphonopeptides by [Rh(P-OP)]-Catalyzed Stereoselective Hydrogenation.

The hydrogenation of N-substituted vinylphosphonates using rhodium complexes derived from P-OP ligands L1, ent-L1, or (R,R)-Me-DuPHOS as catalysts has been successfully accomplished, achieving very high levels of stereoselectivity (up to 99% ee or de). The described synthetic strategy allowed for the efficient preparation of α-aminophosphonic acid derivatives and phosphonopeptides, which are valuable building blocks for the preparation of biologically relevant molecules.

Opioid Use During the Six Months After an Emergency Department Visit for Acute Pain: A Prospective Cohort Study.

STUDY OBJECTIVE: Despite the frequent use of opioids to treat acute pain, the long-term risks and analgesic benefits of an opioid prescription for an individual emergency department (ED) patient with acute pain are still poorly understood and inadequately quantified. Our objective was to determine the frequency of recurrent or persistent opioid use during the 6 months after the ED visit METHODS: This was a prospective, observational cohort study of opioid-naive patients presenting to 2 EDs for acute pain who were prescribed an opioid at discharge. Patients were followed by telephone 6 months after the ED visit. Additionally, we reviewed the statewide prescription monitoring program database. Outcomes included frequency of recurrent and persistent opioid use and frequency of persistent moderate or severe pain 6 months after the ED visit. Persistent opioid use was defined as filling greater than or equal to 6 prescriptions during the 6-month study period. RESULTS: During 9 months beginning in November 2017, 733 patients were approached for participation. Four hundred eighty-four met inclusion criteria and consented to participate. Four hundred ten patients (85%) provided 6-month telephone data. The prescription monitoring database was reviewed for all 484 patients (100%). Most patients (317/484, 66%; 95% confidence interval 61% to 70%) filled only the initial prescription they received in the ED. One in 5 patients (102/484, 21%; 95% confidence interval 18% to 25%) filled at least 2 prescriptions within the 6-month period. Five patients (1%; 95% confidence interval 0% to 2%) met criteria for persistent opioid use. Of these 5 patients, all but 1 reported moderate or severe pain in the affected body part 6 months later. CONCLUSION: Although 1 in 5 opioid-naive ED patients who received an opioid prescription for acute pain on ED discharge filled at least 2 opioid prescriptions in 6 months, only 1% had persistent opioid use. These patients with persistent opioid use were likely to report moderate or severe pain 6 months after the ED visit.

Medical Record Documentation About Opioid Tapering: Examining Benefit-to-Harm Framework and Patient Engagement.

OBJECTIVE: Guidelines recommend that clinicians make decisions about opioid tapering for patients with chronic pain using a benefit-to-harm framework and engaging patients. Studies have not examined clinician documentation about opioid tapering using this framework. DESIGN AND SETTING: Thematic and content analysis of clinician documentation about opioid tapering in patients' medical records in a large academic health system. METHODS: Medical records were reviewed for patients aged 18 or older, without cancer, who were prescribed stable doses of long-term opioid therapy between 10/2015 and 10/2016 then experienced an opioid taper (dose reduction ≥30%) between 10/2016 and 10/2017. Inductive thematic analysis of clinician documentation within six months of taper initiation was conducted to understand rationale for taper, and deductive content analysis was conducted to determine the frequencies of a priori elements of a benefit-to-harm framework. RESULTS: Thematic analysis of 39 patients' records revealed 1) documented rationale for tapering prominently cited potential harms of continuing opioids, rather than observed harms or lack of benefits; 2) patient engagement was variable and disagreement with tapering was prominent. Content analysis found no patients' records with explicit mention of benefit-to-harm assessments. Benefits of continuing opioids were mentioned in 56% of patients' records, observed harms were mentioned in 28%, and potential harms were mentioned in 90%. CONCLUSIONS: In this study, documentation of opioid tapering focused on potential harms of continuing opioids, indicated variable patient engagement, and lacked a complete benefit-to-harm framework. Future initiatives should develop standardized ways of incorporating a benefit-to-harm framework and patient engagement into clinician decisions and documentation about opioid tapering.

Effect of fermentation time and acid casein concentration as nitrogen source on microbial rennet production.

We evaluated the effects of fermentation time and acid casein content on the microbial rennet obtained by solid-state fermentation using wheat bran as the carbon source. The experiments used two fermentation times (72 and 96 h), while acid casein content was 1.5, 2.0, 2.5, and 3.0 g. Rennet strength from eight enzymatic extracts was measured using pasteurized whole milk. Rennet strength of samples from 72 h of fermentation showed an increase when acid casein content increased. The rennet strength increased at 96 h of fermentation with increasing amount of casein (up to 2.5 g), and then decreased with the largest addition (3.0 g) of casein. Coagulation time for the sample with highest rennet strength was 420 s.

Evaluation of cerebral oxygen perfusion during shoulder arthroplasty performed in the semi-beach chair position.

BACKGROUND: The beach chair position is commonly used when performing shoulder arthroplasty. However, this position has been associated with hypotension, potentially leading to cerebral hypoperfusion, which may cause neurologic injury. In addition, shoulder arthroplasty cases are associated with longer operative times, posing a potentially greater risk of cerebral hypoperfusion. We aim to evaluate the risk of cerebral desaturation events (CDEs) during the course of total shoulder arthroplasty. METHODS: Twenty-six patients undergoing shoulder arthroplasties were monitored for changes in cerebral perfusion. Seven specific time-points during the procedure were labeled for comparison of events: baseline, beach chair, incision, humeral broaching, glenoid reaming, glenoid component implantation, and humeral component implantation. Cerebral oxygen perfusion was measured using near-infrared spectroscopy. A CDE was described as a decrease of oxygen saturation greater than 20%. RESULTS: Nineteeen of 25 subjects experienced a CDE. 42% of these patients experienced CDEs during semi-beach chair positioning. Patients experienced the largest oxygen saturation drop during semi-beach chair positioning. Transition from baseline to semi-beach chair was the only event to have a statistically significant decrease in cerebral perfusion (8%, P < .05). There was a statistically significant percentage change in mean oxygen saturation in the semi-beach chair interval (10%, P < .01) and the semi-beach chair to incision interval (7%, P < .01). CONCLUSIONS: Most patients experienced an intraoperative CDE, with greatest incidence during semi-beach chair positioning. The largest decline in cerebral oxygen saturation occurred during semi-beach chair positioning. Implant implantation was not associated with decrease in cerebral oximetry.

Consideration in Microvascular Reconstruction during Times of Social Crises: Perspectives on Resource Utilization.

Reconstruction of head and neck surgical defects can be a complicated, costly process. While the era of cost-effective medicine has begun to broadly question the necessity of high-cost care, times of extraordinary sociomedical demand bring increased scrutiny to even routine costs and resource utilization. Within this context, we reviewed the advantages, drawbacks, and financial costs of both regional and free flap reconstructions, namely the decreased costs and hospital resource utilization that may be associated with reconstruction using regional flaps. Although beset by reports of partial necrosis in certain regional flaps-particularly the submental island, cervicofacial advancement, and supraclavicular artery island flaps-many reports have demonstrated complication and flap failure rates equivalent to those of free flaps. Additionally, regional flaps have been associated with decreased costs for hospital stay, most notably in cases of postoperative complications. In cases necessitating free flap reconstruction, cost-savings strategies such as bypassing postoperative intensive care unit admissions have been shown to provide satisfactory, safe outcomes. As the head and neck surgeon continues to adapt to the medical pressures of a global pandemic, resource-sparing approaches to oncologic care will persist in their newfound importance.

NanoDJ: a Dockerized Jupyter notebook for interactive Oxford Nanopore MinION sequence manipulation and genome assembly.

BACKGROUND: The Oxford Nanopore Technologies (ONT) MinION portable sequencer makes it possible to use cutting-edge genomic technologies in the field and the academic classroom. RESULTS: We present NanoDJ, a Jupyter notebook integration of tools for simplified manipulation and assembly of DNA sequences produced by ONT devices. It integrates basecalling, read trimming and quality control, simulation and plotting routines with a variety of widely used aligners and assemblers, including procedures for hybrid assembly. CONCLUSIONS: With the use of Jupyter-facilitated access to self-explanatory contents of applications and the interactive visualization of results, as well as by its distribution into a Docker software container, NanoDJ is aimed to simplify and make more reproducible ONT DNA sequence analysis. The NanoDJ package code, documentation and installation instructions are freely available at https://github.com/genomicsITER/NanoDJ .

Health reform in Mexico: governance and potential outcomes.

Adopting key mechanisms to restructure public policy in developing countries is a crucial political task. The strengthening of infrastructure of health services, care quality, monitoring and population health; all might contribute to assuring the functionality of a national system for health monitoring and care. Over the last decades, the Mexican government has launched wide-ranging political reforms aiming to overcome socioeconomic and environmental problems, namely health, education, finances, energy and pension. The proposed (but yet not implemented) health reform in Mexico during E. Peña Nieto's administration (2012-2018) pretended an adjustment in Article 4 of the Mexican Constitution to compact medical care and reduce the State's responsibility to a provision of minimum health packages for the population. Here we use a simple analytical model to describe and interprete the concepts of context, process, actors and content and the outcome of three of the most important resulting components of this intended reform i.e. universality, basic packages, and 'outsourcing'. In light of the start of the Mexico's new federal administration, we argue that, if not properly defined by all actors, the implementation of such structural health reform in Mexico would precipitate a model of private/public association exacerbating a crisis of political representation, human rights, justice and governance.

Race and Gender Are Associated with Opioid Dose Reduction Among Patients on Chronic Opioid Therapy.

OBJECTIVE: Among patients with chronic pain, risk of opioid use is elevated with high opioid dose or concurrent benzodiazepine use. This study examined whether these clinical factors, or sociodemographic factors of race and gender, are associated with opioid dose reduction. DESIGN AND SETTING: A retrospective cohort study of outpatients prescribed chronic opioid therapy between 2007 and 2012 within a large, academic health care system in Bronx, New York, using electronic medical record data. Included patients were prescribed a stable dose of chronic opioid therapy over a one-year "baseline period" and did not have cancer. METHODS: The primary outcome was opioid dose reduction (≥30% reduction from baseline) within two years. Multivariable logistic regression tested the associations of two clinical variables (baseline daily opioid dose and concurrent benzodiazepine prescription) and two sociodemographic variables (race/ethnicity and gender) with opioid dose reduction. RESULTS: Of 1,097 patients, 463 (42.2%) had opioid dose reduction. High opioid dose (≥100 morphine-milligram equivalents [MME]) was associated with lower odds of opioid dose reduction compared with an opioid dose <100 MME (adjusted odds ratio [AOR] = 0.69, 95% confidence interval [CI] = 0.54-0.89). Concurrent benzodiazepine prescription was not associated with opioid dose reduction. Black (vs white) race and female (vs male) gender were associated with greater odds of opioid dose reduction (AOR = 1.82, 95% CI = 1.22-2.70; and AOR = 1.43, 95% CI = 1.11-1.83, respectively). CONCLUSIONS: Black race and female gender were associated with greater odds of opioid dose reduction, whereas clinical factors of high opioid dose and concurrent benzodiazepine prescription were not. Efforts to reduce opioid dose should target patients based on clinical factors and address potential biases in clinical decision-making.