A single post-exposure oxime RS194B treatment rapidly reactivates acetylcholinesterase and reverses acute symptoms in macaques exposed to diethylphosphorothioate parathion and chlorpyrifos insecticides.

Millions of individuals globally suffer from inadvertent, occupational or self-harm exposures from organophosphate (OP) insecticides, significantly impacting human health. Similar to nerve agents, insecticides are neurotoxins that target and inhibit acetylcholinesterase (AChE) in central and peripheral synapses in the cholinergic nervous system. Post-exposure therapeutic countermeasures generally include administration of atropine with an oxime to reactivate the OP-inhibited AChE. However, animal model studies and recent clinical trials using insecticide-poisoned individuals have shown minimal clinical benefits of the currently approved oximes and their efficacy as antidotes has been debated. Currently used oximes either reactivate poorly, do not readily cross the blood-brain barrier (BBB), or are rapidly cleared from the circulation and must be repeatedly administered. Zwitterionic oximes of unbranched and simplified structure, for example RS194B, have been developed that efficiently cross the BBB resulting in reactivation of OP-inhibited AChE and dramatic reversal of severe clinical symptoms in mice and macaques exposed to OP insecticides or nerve agents. Thus, a single IM injection of RS194B has been shown to rapidly restore blood AChE and butyrylcholinesterase (BChE) activity, reverse cholinergic symptoms, and prevent death in macaques following lethal inhaled sarin and paraoxon exposure. The present macaque studies extend these findings and assess the ability of post-exposure RS194B treatment to counteract oral poisoning by highly toxic diethylphosphorothioate insecticides such as parathion and chlorpyrifos. These OPs require conversion by P450 in the liver of the inactive thions to the active toxic oxon forms, and once again demonstrated RS194B efficacy to reactivate and alleviate clinical symptoms within 60 mins of a single IM administration. Furthermore, when delivered orally, the Tmax of RS194B at 1-2 h was in the same range as those administered IM but were maintained in the circulation for longer periods greatly facilitating the use of RS194B as a non-invasive treatment, especially in isolated rural settings.

Improved patient-specific hyperthermia planning based on parametrized electromagnetic and thermal models for the SIGMA-30 applicator.

OBJECTIVE: To create an improved planning method for pediatric regional hyperthermia (RHT) using the SIGMA-30 applicator (SIGMA-30). MATERIALS AND METHODS: An electromagnetic model of SIGMA-30 was generated for use with the finite-difference time-domain (FDTD) method. Applying special MATLAB-based algorithms, voxel models of a pediatric patient with pelvic rhabdomyosarcoma were created from Computed-Tomography (CT) contours for use with the FDTD method and the finite-difference (FD) method capable of using either temperature-independent or temperature-dependent perfusion models for solving the Bioheat Transfer Equation (BHTE). Patient models were parametrized regarding, first, the positioning in the applicator, second, the absorbed power range and, third, different perfusion models, resulting in the so-called Parametrized Treatment Models (PTMs). A novel dedicated optimization procedure was developed based on quantitative comparison of numerical calculations against temperature and power measurements from two RHT therapies. RESULTS: Using measured data, a realistic absorbed power range in the patient model was estimated. Within this range, several FDTD and BHTE runs were performed and, applying the aforementioned optimization scheme, the best PTMs and perfusion models were identified for each therapy via a retrospective comparison with measurements in 14 temperature sensor positions: 5 in the tumor, 8 in rectum and one in bladder. CONCLUSION: A novel dedicated optimization procedure for identification of suitable patient-specific electromagnetic and thermal models, which can be used for improved patient planning, was developed and evaluated by comparison with treatment-derived measurements using SIGMA-30. The optimization procedure can be extended to other hyperthermia applicators and to other patient types, including adults.

Novel Toxicology Program to Support the Development of Inhaled VentaProst.

Currently, off-label continuous administration of inhaled epoprostenol is used to manage hemodynamics during mitral valve surgery. A toxicology program was developed to support the use of inhaled epoprostenol during mechanical ventilation as well as pre- and postsurgery via nasal prongs. To support use in patients using nasal prongs, a Good Laboratory Practice (GLP), 14-day rat, nose-only inhalation study was performed. No adverse findings were observed at ∼50× the dose rate received by patient during off-label use. To simulate up to 48 hours continuous aerosol exposure during mechanical ventilation, a GLP toxicology study was performed using anesthetized, intubated, mechanically ventilated dogs. Dogs inhaled epoprostenol at approximately 6× and 13× the dose rate reported in off-label human studies. This novel animal model required establishment of a dog intensive care unit providing sedation, multisystem support, partial parenteral nutrition, and management of the intubated mechanically ventilated dogs for the 48-hour duration of study. Aerosol was generated by a vibrating mesh nebulizer with novel methods required to determine dose and particle size in-vitro. Continuous pH 10.5 epoprostenol was anticipated to be associated with lung injury; however, no adverse findings were observed. As no toxicity at pH 10.5 was observed with a formulation that required refrigeration, a room temperature stable formulation at pH 12 was evaluated in the same ventilated dog model. Again, there were no adverse findings. In conclusion, current toxicology findings support the evaluation of inhaled epoprostenol at pH 12 in surgical patients with pulmonary hypertension for up to 48 hours continuous exposure.

Repeated dose inhalation developmental toxicity study in rats exposed to cellulose insulation with boric acid additive.

Cellulose insulation (CI), a common building material, is a mixture of cellulose fibers and borates. Borates are approximately 20% of the product weight and act as a flame retardant. Given possible exposure to workers and consumers, an inhalation toxicity study was conducted following Organization for Economic Co-operation and Development (OECD) 414 for Prenatal Development Toxicity to evaluate if CI is a developmental toxicant. Pregnant female rats were exposed by nose-only inhalation to CI aerosols containing 20% boric acid for six h/day, from gestational day (GD) 6-19, and fetuses were evaluated for developmental parameters. Respirable CI was produced by grinding to produce respirable particles (MMAD 2.7-2.9 µm, geometric standard deviations (GSD) 1.9-2.6), which were then aerosolized. Target air concentrations were 15, 90, and 270 mg CI/m3. Controls were exposed to air only. Slight body weight reductions (average decrease <7% vs. control) were observed in male and female GD 20 fetuses in the mid and high dose groups. No embryo/fetal developmental toxicity or alterations in any other measured variable were reported at any dose. The no observed adverse effect level (NOAEL) for developmental outcomes was 270 mg/m3.

Chronic wound repair and healing in older adults: current status and future research.

The incidence of chronic wounds is increased among older adults, and the impact of chronic wounds on quality of life is particularly profound in this population. It is well established that wound healing slows with age. However, the basic biology underlying chronic wounds and the influence of age-associated changes on wound healing are poorly understood. Most studies have used in vitro approaches and various animal models, but observed changes translate poorly to human healing conditions. The impact of age and accompanying multi-morbidity on the effectiveness of existing and emerging treatment approaches for chronic wounds is also unknown, and older adults tend to be excluded from randomized clinical trials. Poorly defined outcomes and variables, lack of standardization in data collection, and variations in the definition, measurement, and treatment of wounds also hamper clinical studies. The Association of Specialty Professors, in conjunction with the National Institute on Aging and the Wound Healing Society, held a workshop, summarized in this paper, to explore the current state of knowledge and research challenges, engage investigators across disciplines, and identify key research questions to guide future study of age-associated changes in chronic wound healing.

Patient involvement in outcome measures for psoriatic arthritis.

Psoriatic arthritis (PsA) is a heterogeneous inflammatory arthritis with a varied clinical phenotype. There has been considerable international collaboration over recent years to develop and prioritise appropriate disease domains and outcome measures to capture all aspects of this complex disease. It has been recognised that patient-reported measures and physician assessments are complementary and, when used together, allow an improved reflection of disease burden. Taking this concept one step further, the experience in rheumatoid arthritis has demonstrated benefits of incorporating the patient perspective in the development of outcome measures. We report a systematic review demonstrating (1) that there has been little incorporation of the patient perspective in the development of outcome measures and domains in PsA, (2) the proceedings from the preliminary patient involvement in outcome measures for PsA (PIOMPSA) meetings, and (3) a proposed roadmap for improving patient involvement.

Plan B and the German Catholic bishops.

Germany's Catholic bishops recently ruled that levonorgestrel emergency contraception (EC) was acceptable for prevention of pregnancy in the case of rape. The ruling represents a significant change in Catholic doctrine that has been opposed to most forms of birth control. In their ruling the bishops cited a lack of evidence that levonorgestrel EC acts as an abortifacient. This case serves as a reminder of the need for bioethics to be based on current scientific literature as well as articles of faith and morals.

Ambulatory Behavior Assessment Using Deep Learning.

This work leverages a custom implementation of a deep neural network-based object detection algorithm to detect people and a set of assistive devices relevant to clinical environments. The object detections form the basis for the quantification of different ambulatory activities and related behaviors. Using features extracted from detected people and objects as input to machine learning models, we quantify how a person ambulates and the mode of ambulation being used.Clinical relevance- This system provides the data required for clinicians and hospitalized patients to work together in the creation, monitoring, and adjustment of ambulatory goals.

Use of Real Time Clinical Video Telehealth to Home by primary care providers within the Veterans Health Administration during the first wave of the COVID-19 pandemic: variability across VA stations and with time.

Objective: Determine the extent to which use of Clinical Video Telehealth to Home (VT2H) for primary care licensed independent practitioner visits (PCLIPVs) varied over time and across the Veterans Health Administration (VA) during the first 18 months of the COVID pandemic, and if there was an association between VT2H usage and VA station characteristics. Materials and Methods: All outpatient encounters (n = 12 143 456) for Veterans (n = 4 373 638) that had VA PCLIPVs during the period of observation were categorized as conducted by VT2H, in-person, or telephone. The change over time in the percentage of total PCLIPVs conducted by VT2H was plotted and associations between VA station characteristics and VT2H usage were analyzed using simple statistics and negative binomial regression. Results: Between March 2020 and mid-August 2020, VT2H visits increased from <2% to 13% of all VA PCLIPVs. However, VT2H usage varied substantively by VA station and declined system-wide to <9% of PCLIPVs by July 2021. VA stations that serve a greater proportion of rural Veterans were found less likely to use VT2H. Discussion: The VA was successful in increasing the use of VT2H for PCLIPVs during the first phase of the COVID pandemic. However, VT2H usage varied by VA station and over time. Beyond rurality, it is unknown what station characteristics may be responsible for the variance in VT2H use. Conclusion: Future investigation is warranted to identify the unique practices employed by VA stations that were most successful in using VT2H for PCLIPVs and whether they can be effectively disseminated to other stations.

The impact of solvents on the toxicity of the banned parathion insecticide.

The aerial crop dusting and spraying of fields with the phosphorothioate insecticide parathion in the late 1900s, significantly improved crop yields but resulted in high levels of occupational toxicity in handlers and agricultural workers, as well as cases of intentional self-harm poisoning, culminating in its banning in many western countries by early 2000s. However because of the low solubility and volatility of parathion, most available products were formulated using organic solvents e.g. xylene, to increase the efficacy of the aerosols and dusts. In the present study, the toxicity of parathion was assessed when formulated in an aqueous solvents (ethanol/PBS (1:9)), and delivered to macaques as an aerosol. Doses of 780 µg/kg and 1.56 mg/kg were delivered one day apart, using a modified nebulizer calculated to result in lung deposition of ∼480 µg/kg with a similar or larger amount being swallowed; these doses being similar to the estimated lethal oral dose 286ug/kg - 1.43 mg/kg of formulated parathion in humans. Surprisingly, this dose (a combined amount of ∼14 mg) caused only low AChE inhibition and moderate BChE inhibition with no clinical symptoms, indicating that the use of organic solvents may have previously played a critical role in the severity of parathion toxicity following inhalation exposure. In addition, unlike constitutively toxic OPs, which are highly toxic when inhaled, these results are consistent with the idea that phosphorothioate insecticides appear to be more intoxicating following oral than inhalation exposure. However, this still remains uncertain because the presence of organic solvents in the ingested parathion studies was not always known.

Reversal of SSRI-associated apathy syndrome by discontinuation of therapy.

OBJECTIVE: To report 6 cases of selective serotonin reuptake inhibitor (SSRI)-associated apathy syndrome. CASE SUMMARIES: In all 6 cases, the patient reported loss of motivation while being treated with an SSRI. Loss of motivation was of new onset and temporally associated with the use of the SSRI. A trial of discontinuation of the SSRI was performed in all 6 patients and 2 were started on bupropion while cross-tapering from the SSRI. During the treatment trials, depression and apathy were monitored in all patients. Each case was assessed using the Apathy Evaluation Scale, Clinician version (AES-C), and by evaluating how the patient responded to discontinuation of the SSRI. DISCUSSION: Scores on the AES-C improved significantly in all 6 cases after the SSRI was discontinued. Improvement was also seen in the motivation, novelty, and persistence subdomain scores of the AES-C. A pretreatment AES-C score was available only in the first case. Based on the Naranjo probability scale, there was a probable cause of apathy syndrome with SSRI therapy in the first case and a possible association in the rest of the cases. CONCLUSIONS: In some patients SSRIs may cause an apathy syndrome that can be reversed through discontinuation of the agent. When evaluating patients being treated with an SSRI, clinicians should have a high degree of suspicion and specifically inquire for this iatrogenic form of apathy syndrome.

Toxicologic evaluation of tungsten: 28-day inhalation study of tungsten blue oxide in rats.

The toxicity and toxicokinetics of tungsten blue oxide (TBO) were examined. TBO is an intermediate in the production of tungsten powder, and has shown the potential to cause cellular damage in in vitro studies. However, in vivo evidence seems to indicate a lack of adverse effects. The present study was undertaken to address the dearth of longer-term inhalation toxicity studies of tungsten oxides by investigating the biological responses induced by TBO when administered via nose-only inhalation to rats at levels of 0.08, 0.325, and 0.65 mg TBO/L of air for 6 h/day for 28 consecutive days, followed by a 14-day recovery period. Inhaled TBO was absorbed systemically and blood levels of tungsten increased as inhaled concentration increased. Among the tissues analyzed for tungsten levels, lung, femur and kidney showed increased levels, with lung at least an order of magnitude greater than kidney or femur. By exposure day 14, tungsten concentration in tissues had reached steady-state. Increased lung weight was noted for both terminal and recovery animals and was attributed to deposition of TBO in the lungs, inducing a macrophage influx. Microscopic evaluation of tissues revealed a dose-related increase in alveolar pigmented macrophages, alveolar foreign material and individual alveolar foamy macrophages in lung. After a recovery period there was a slight reduction in the incidence and severity of histopathological findings. Based on the absence of other adverse effects, the increased lung weights and the microscopic findings were interpreted as nonadverse response to exposure and were not considered a specific reaction to TBO.

Rapid conversion of Tai Chi classes from face-to-face to virtual during the COVID-19 pandemic: A quality improvement project.

PURPOSE: The purpose of this quality improvement project was to examine the feasibility of rapidly converting a Tai Chi program for older Veterans from face-to-face to virtual classes. METHODS: Eighteen Veterans attending our face-to-face Tai Chi course were invited to transition to virtual classes. Feasibility was defined as the ability of program staff and participants to successfully connect and complete the initial and subsequent classes by VA Video Connect (VVC) with little to no technical difficulties, participant ability to participate in the course without safety concerns, and favorable feedback from participants and program staff. RESULTS: Nine of 18 Veterans agreed to transition to the virtual program and attended a median (interquartile range) of 11 (4-15) classes; they were younger (62.7 + 11.5 vs. 70.5 + 7.0 years, p < .05) and more likely to have the knowledge and equipment needed to participate (78% vs. 0%, p < .01) than nonparticipants. Tai Chi instructors and participating Veterans reported being able to connect to and complete the classes virtually with only minimal technical problems. No adverse events were reported. Feedback from the instructors and Veterans was positive and included comments on ease of use and enjoyability. CONCLUSION: Results suggest that virtual Tai Chi classes via VVC are feasible for some older Veterans.

An outpatient Tai Chi program: Effects on veterans' functional outcomes.

PURPOSE: To evaluate the effectiveness of an evidence-based 12-week Tai Chi course designed to improve balance and physical function in a population of older veterans. METHODS: Community dwelling veterans of all ages with gait and balance problems were invited to participate in the Tai Chi program. Participants completed the Berg Balance Scale (BBS), the Timed Up and Go (TUG) test, and the Falls Efficacy Scale-International (FES-I) at baseline and again at the end of the program. Descriptive statistics were used to summarize study participants' characteristics. The change from baseline to the end of the 12-week program was calculated for each of the three primary outcome variables (BBS, TUG, FES-I). RESULTS: Twenty-two veterans, aged 58 years and above, with perceived gait and/or balance issues were enrolled in the program with completion by 11 veterans. Veterans who completed their final assessments showed the BBS, improved significantly (p = 0.004) from baseline to the 12-week assessment. The TUG scores improved by a median of 1.3 s (p = 0.022). There was not a significant change in the FES-I. CONCLUSIONS: Preliminary findings provide evidence of the effectiveness of a 12-week Tai Chi program to improve functional outcomes for older veterans with mild to moderate gait and balance problems.

Selective serotonin reuptake inhibitors-associated apathy syndrome: A cross sectional study.

Selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, are associated with loss of motivation, anergy, and lack of curiosity often referred collectively as apathy. However, this association has not been systematically assessed using a specific rating scale for measuring apathy syndrome. Our objective was to study the association between SSRI use and apathy syndrome.We conducted a retrospective chart review of 125 patients enrolled in an outpatient psychiatry clinic. The prevalence of apathy syndrome and its clinical significance (based on standardized assessment) were compared between patients treated and not treated with SSRIs. Apathy was assessed using the Apathy Evaluation Scale-clinician version with a score ranging 18-72 with higher score for worse apathy. A score of greater than 30 is considered clinically significant apathy.Among 119 patients, the mean apathy scores were significantly higher in those treated with SSRIs compared to those not treated with SSRIs (42.5 ±â€Š9.2 vs 31.3 ±â€Š6, P < .0001). The SSRI group also had a significantly higher percentage of patients with clinically significant apathy (92% vs 61%, P < .0001). Use of all SSRIs was associated with the presence of apathy. Apathy was seen in all mental health diagnostic categories with highest Apathy evaluation scale-clinician version scores in those with dementia.SSRI use may be associated with higher rates of apathy syndrome. Clinicians should specifically inquire about iatrogenic apathy syndrome when evaluating patients on an SSRI if there is suspicion of loss of motivation. Limitations of this study included retrospective nature of this study, and that majority of the sample was males. Prospective studies are needed to elucidate information regarding the prevalence, etiology, and treatment response for SSRI-associated apathy syndrome.

Subject Identification Using a Depth Camera for Patient Ambulation Monitoring.

Our work identifies subjects based on their height and the distance between their joints. Using a depth sensing camera, we obtained the position of a person's joints in 3D space relative to each other. The distances between adjacent joints and height of a subject's head are used to create a vector of eight features for an individual to use for identification. Using modified KNN, full and partial feature sets were used to identify subjects. Additionally, our classifier can be utilized to assess ambulation (such as walking's velocity and distance) of subject, when identified.

Critical care resource use, cost, and mortality associated with firearm-related injuries in US children's hospitals.

BACKGROUND/PURPOSE: To assess trends and resource use attributable to firearm-related injuries in US pediatric intensive care units (PICUs). METHODS: Retrospective data from Pediatric Health Information Systems (PHIS) database from 2004 to 2017. RESULTS: Of 5,984,938 admissions to 28 children's hospitals, 3707 were for firearm injuries. A total of 1088 of 3707 hospitalizations (29.9%) required PICU admission. Median PICU length of stay was 2 days (IQR, 1-6 days), and the median cost for PICU patients was $37,569.31 (IQR, $19,243.83-$77,856.32). Use of mechanical ventilation (674/1088 admissions [61.9%]), surgical procedures (744/1088 admissions [68.3%]), blood transfusions (429/1088 admissions [39.9%]), and intracranial pressure monitoring devices (30/1088 admissions [2.8%]) increased in PICU patients. Computed tomography showed an overall increase (197/287 [68.6%] to 138/177 [78%], P = .037) from 2004 to 2007 to 2016-2017. Mortality among PICU patients (140/1058 [13.23%]) attributable to firearm-related injuries increased insignificantly (34/285 (11.93%] to 25/172 [14.53%], P = .746). CONCLUSIONS: Using PHIS data, we found a significant increase in median cost per hospitalization and an increase in critical care resource use, including the frequency of invasive mechanical ventilatory assistance, neuromonitoring, operations performed, and transfusion of blood products. Further research is needed to continue to characterize the burden of pediatric critical firearm injury. TYPE OF STUDY: Retrospective cohort study. LEVEL OF EVIDENCE: Level III.

Increasing the availability of Tai Chi to veterans through a training of trainers course.

PURPOSE: The purpose of this nurse-led project was to increase the number of interprofessional Tai Chi instructors for veterans through a 5-week (32 hours) training of trainers (ToT) course led by a Tai Chi master trainer. METHODS: This project was designed to evaluate the effectiveness of using the ToT model to increase the availability of Tai Chi to veterans. To understand how well the ToT course met learners' needs, a two-phase course evaluation was conducted. RESULTS: Fifteen interprofessional employees enrolled in and completed the course. Most learners were white (67%) females (67%) with a median age of 50 years. All agreed that the training provided the skills, materials, and confidence to lead Tai Chi classes. Most (93%) indicated experiencing positive health benefits from the training and none experienced any negative effects. The 3-month follow-up evaluation indicated that 10 (67%) were teaching veterans in individual or group classes with two others assisting. Twelve instructors taught more than 150 veterans. CONCLUSIONS: Overall, learners evaluated this ToT course positively and indicated their needs were met and felt prepared to teach Tai Chi despite being inexperienced. The course was a success with 80% of new instructors teaching or coteaching Tai Chi to veterans.

An Interdisciplinary Approach to Educating Medical Students About Dementia Assessment and Treatment Planning.

BACKGROUND: Many general practitioners consider dementia care beyond their clinical domain and feel that dementia assessment and treatment should be addressed by specialists, such as geriatricians, geriatric psychiatrists, or neurologists. An urgent need exists to educate all medical trainees in dementia care, regardless of their specialization interests. OBSERVATIONS: We developed a multicomponent, experiential, brief curriculum using team-based learning to expose senior medical students who rotated through the US Department of Veterans Affairs Memory Disorders Clinic at the Central Arkansas Veterans Healthcare System in Little Rock to an interdisciplinary assessment of dementia. The curriculum included didactics, clinical experience, and team-based learning. In pre- and postevaluation, students rated their perception of the role of interdisciplinary team members in assessing and managing dementia, their personal abilities to assess cognition, behavioral problems, caregiver burden, and their perception of the impact of behavioral problems on dementia care. CONCLUSIONS: Dementia knowledge gaps were prevalent in this cohort of senior medical students. Providing interdisciplinary geriatric educational experience improved students perception of their ability to assess for dementia and their recognition of the roles of interdisciplinary team members. Plans are in place to continue and expand the program to other complex geriatric syndromes.

Muscle expression of genes associated with inflammation, growth, and remodeling is strongly correlated in older adults with resistance training outcomes.

A group (n = 8) of healthy older (68 +/- 6 yr) adults participated in a 36-session progressive resistance exercise training program targeting the thigh muscles to determine the relationship between muscle gene expression and gains in muscle size and strength. Biopsies were obtained from the vastus lateralis at baseline 72 h after an acute bout of exercise and 72 h after completion of the training program. Training increased thigh muscle size (7%) and strength for the three exercises performed: knee extension (30%) and curl (28%) and leg press (20%). We quantified 18 transcripts encoding factors that function in inflammation, growth, and muscle remodeling that were demonstrated previously to be regulated by aging and acute exercise. The gain in extension strength and muscle size showed a high number of significant correlations with gene expression. These gains were most strongly correlated (P < or = 0.003, R > or = 0.89) with the baseline mRNA levels for insulin-like growth factor-1, matrix metalloproteinase-2 and its inhibitor TIMP1, and ciliary neurotrophic factor. Moreover, strength gains were inversely correlated with the change in these mRNA levels after training (P < or = 0.002 and R < or = -0.90). Changes in gene expression after acute exercise were not associated with training outcomes. These results suggest that higher baseline expression for key genes in muscle conveys an adaptive advantage for certain older adults. Individuals with lower baseline expression of these genes show less adaptation to exercise despite increased gene expression in response to training. These genes hold promise as useful predictors of training outcomes that could be used to design more effective exercise regimens for maintaining muscle function in older adults.