Retinal Connectomics: A Review.

The retina is an ideal model for understanding the fundamental rules for how neural networks are constructed. The compact neural networks of the retina perform all of the initial processing of visual information before transmission to higher visual centers in the brain. The field of retinal connectomics uses high-resolution electron microscopy datasets to map the intricate organization of these networks and further our understanding of how these computations are performed by revealing the fundamental topologies and allowable networks behind retinal computations. In this article, we review some of the notable advances that retinal connectomics has provided in our understanding of the specific cells and the organization of their connectivities within the retina, as well as how these are shaped in development and break down in disease. Using these anatomical maps to inform modeling has been, and will continue to be, instrumental in understanding how the retina processes visual signals.

Deprescribing electronic case reviews for older veterans at risk for falls: Effects on drug burden and falls.

BACKGROUND: Falls are the most common medication-related safety event in older adults. Deprescribing fall risk-increasing drugs (FRIDs) may mitigate fall risk. This study assesses the effects of an innovative deprescribing program in reducing FRID burden and falls-related acute visits over 1 year. METHODS: The Falls Assessment of Medications in the Elderly (FAME) Program is a pilot deprescribing program designed to improve medication safety in Veterans aged ≥65, screening positive for high fall risk at the Durham Veterans Affairs Health Care System. Central case finding and electronic case reviews with deprescribing recommendations were completed by an interdisciplinary team, forwarded to prescribers for approval, then implemented during follow-up telephone visits by FAME team. Primary outcome was change in FRID burden calculated by modified Drug Burden Index (DBI) at 1 year and an exploratory outcome was 1-year fall-related acute visits. RESULTS: Overall, 472 patients (236 intervention cases, 236 matched controls) were included in the study. Of the 236 patients receiving a FAME deprescribing plan, 147 had recommendations approved by prescriber and patient. In the intention-to-treat analysis, the 1-year change in modified DBI was -0.15 (95% CI -0.23, -0.08) in the intervention cohort and -0.11 (-0.21, -0.00) in the matched control cohort (p = 0.47). The odds of increasing DBI by a clinically important threshold of 0.5 was significantly lower in the FAME cohort (OR 0.37, 0.21, 0.66). Fall-related acute events occurred in 6.3% of patients in the intervention group versus 11.0% in control patients over a one-year period (p = 0.10). CONCLUSIONS: The program was associated with a significantly lower odds of further increasing FRID burden at 1 year compared to matched controls. An electronic case review and telephone counseling program has the potential to reduce drug-related falls in high-risk older adults.

Laser-assisted permanent greenfield filter removal with ileocaval stent reconstruction following filter thrombosis, a case report.

Emerging literature supports removal of chronic indwelling IVC filters when they are contributing to complications for a patient and are no longer indicated. We present an interesting case of an elderly patient who had a history of DVT and underwent spinal surgery, which required cessation of his anticoagulation and placement of an IVC filter pre-operatively. Approximately 15 years later the patient presented to our institution with chronic occlusion of his IVC at the level of his filter which had never been removed, with bilateral lower extremity DVT and symptoms of phlegmasia cerulea dolens. Despite a previous unsuccessful attempt at DVT thrombectomy at an outside institution, interventional radiology was consulted, and he subsequently underwent successful laser sheath assisted removal of his 15-year-old permanent Greenfield filter with bilateral lower extremity DVT thrombectomy and venous stenting with significant improvement in his presenting symptoms. Clinical presentation, diagnostic workup, case findings, and outcomes are described.

Don't look back in anger: A cross-sectional and dyadic examination of the Dark Triad, anger, and aggression in athletes.

OBJECTIVES: The Dark Triad (psychopathy, Machiavellianism, and narcissism) has been linked to anti-social behaviour in sport, and while anti-social behaviour often involves aggression and violence, no research to date has examined the relationship between the Dark Triad and anger and aggression in athletes. The current two-sample study sought to address this gap. DESIGN: Multi-sample cross-sectional design. METHOD: Sample 1 included 224 athletes (MAGE = 23.85) and Sample 2 included 98 coach-athlete dyads (196 total; athlete MAGE = 18.15, coaches MAGE = 34.84). In both samples, facets of the Dark Triad were related to anger and aggression. RESULTS: In Sample 1, regression analyses indicated that psychopathy positively predicted both anger and aggression and Machiavellianism positively predicted aggression. In Sample 2, actor-partner interdependence models indicated a combination of dyadic relationships (i.e., both actor [coach and athlete personality predicted their own anger and aggression] and partner effects [coach and athlete personality predicted the other's anger and aggression]). In this regard, actor effects were found between psychopathy and both anger and aggression and narcissism and aggression. Coach to athlete partner effects were found for narcissism and anger and Machiavellianism and aggression. CONCLUSIONS: Overall, the findings provide evidence for personal and interpersonal relationships between the Dark Triad and anger and aggression and highlight the potential for the darker side of both athlete and coach personality to influence athlete emotions.

Resident involvement in cataract surgery at the Veterans Health Administration: complications, case complexity, and the role of experience.

PURPOSE: To characterize intraoperative complications, case complexity, and changes in complication rates with surgical experience for cataract surgeries involving residents at the Veterans Health Administration (VHA). SETTING: All VHA facilities where cataract surgery was performed. DESIGN: Multicenter, retrospective cohort study. METHODS: A retrospective review of all cataract surgeries within the VHA between July 2010 and June 2021 was conducted. Several parameters, including resident involvement, intraoperative complications, and case complexity as determined by Current Procedural Terminology codes, and use of pupil expansion or capsular support devices, were collected. Complication rates were compared between residents and attendings. RESULTS: Of 392 428 cataract surgeries completed across 108 VHA facilities, 90 504 were performed by attendings alone, while 301 924 involved a resident. Of these, 10 244 (11.3%) of attending cases were complex compared with 32 446 (10.7%) of resident cases. Pupil expansion devices were required in 8191 of attending cases (9.05%) and 31 659 (10.5%) of cases involving residents ( P < .001). Similarly, cases involving residents were more likely than attending-only cases to require a capsular support device (0.835% vs 0.586%, P < .001). Cases involving residents were more likely to have posterior capsular rupture (4.75% vs 2.58%, P < .001) and dropped nucleus (0.338% vs 0.198%, P < .001). Higher resident case volumes were associated with significantly lower complication rates for posterior capsular rupture, dropped nucleus, zonular loss, and suprachoroidal hemorrhage. CONCLUSIONS: Although residents had higher intraoperative complication rates than attendings, these rates were reduced with surgical experience. Residents were involved in a similar number of complex surgical cases as attendings.

Rev-erbα Knockout Reduces Ethanol Consumption and Preference in Male and Female Mice.

Alcohol use is a contributor in the premature deaths of approximately 3 million people annually. Among the risk factors for alcohol misuse is circadian rhythm disruption; however, this connection remains poorly understood. Inhibition of the circadian nuclear receptor REV-ERBα is known to disrupt molecular feedback loops integral to daily oscillations, and impact diurnal fluctuations in the expression of proteins required for reward-related neurotransmission. However, the role of REV-ERBα in alcohol and substance use-related phenotypes is unknown. Herein, we used a Rev-erbα knockout mouse line and ethanol two-bottle choice preference testing to show that disruption of Rev-erbα reduces ethanol preference in male and female mice. Rev-erbα null mice showed the lowest ethanol preference in a two-bottle choice test across all genotypes, whereas there were no ethanol preference differences between heterozygotes and wildtypes. In a separate experiment, alcohol-consuming wildtype C57Bl/6N mice were administered the REV-ERBα/ß inhibitor SR8278 (25 mg/kg or 50 mg/kg) for 7 days and alcohol preference was evaluated daily. No differences in alcohol preference were observed between the treatment and vehicle groups. Our data provides evidence that genetic variation in REV-ERBα may contribute to differences in alcohol drinking.

Naloxone Dispensing in Patients at Risk for Opioid Overdose After Total Knee Arthroplasty Within the Veterans Health Administration.

Background: Naloxone prescribing among patients undergoing surgery is not well described. This cohort study was designed to examine patients' risk factors for opioid overdose and their association with naloxone prescribing among veterans undergoing total knee arthroplasty (TKA) after a systemwide Overdose Education and Naloxone Distribution (OEND) initiative. Methods: A retrospective analysis of Veterans Health Administration (VHA) records was performed and consisted of 38,011 veterans undergoing primary TKA from 2013 to 2016. Patient overdose risk was determined using a validated risk index for overdose or serious opioid-induced respiratory depression (RIOSORD) based on patient diagnoses, health care utilization, and prescription drug use. Naloxone dispensing was examined from the year before surgery until 7 days after discharge. These rates were examined the year prior to implementation of a national OEND initiative (2013), the year of implementation (2014), and 2 years following implementation (2015-2016). Results: In 2013, 3.3% of patients presenting for TKA had moderate or high risk for overdose and none were prescribed naloxone. By 2016, after OEND implementation, 2.2% of patients presenting for TKA had moderate or high risk for overdose, but only 10.9% of the moderate-risk and 12.7% of the high-risk patients were prescribed naloxone. Conclusions: Patients presenting for TKA routinely have risk factors for opioid overdose and significant proportions are at moderate or high risk for overdose. Despite this, most patients at moderate and high risk do not receive perioperative naloxone. Risk mitigation strategies using validated tools such as RIOSORD may help identify surgical patients at greatest risk for opioid overdose who could benefit from OEND.

Microcins reveal natural mechanisms of bacterial manipulation to inform therapeutic development.

Microcins are an understudied and poorly characterized class of antimicrobial peptides. Despite the existence of only 15 examples, all identified from the Enterobacteriaceae, microcins display diversity in sequence, structure, target cell uptake, cytotoxic mechanism of action and target specificity. Collectively, these features describe some of the unique means nature has contrived for molecules to cross the 'impermeable' barrier of the Gram-negative bacterial outer membrane and inflict cytotoxic effects. Microcins appear to be widely dispersed among different species and in different environments, where they function in regulating microbial communities in diverse ways, including through competition. Growing evidence suggests that microcins may be adapted for therapeutic uses such as antimicrobial drugs, microbiome modulators or facilitators of peptide uptake into cells. Advancing our biological, ecological and biochemical understanding of the roles of microcins in bacterial interactions, and learning how to regulate and modify microcin activity, is essential to enable such therapeutic applications.

Development of a specialty medication clinical dashboard to improve tumor necrosis factor-α inhibitor safety and adherence monitoring.

PURPOSE: To describe the development of a pilot specialty medication clinical dashboard targeting tumor necrosis factor (TNF)-α inhibitor therapy. SUMMARY: This was a quality improvement project conducted between August 2019 and April 2020. The dashboard was designed with collaboration between clinical pharmacists and specialty providers in rheumatology, gastroenterology, and dermatology. Data was queried from the Veterans Affairs Corporate Data Warehouse. Patients with an active prescription or intravenous order for a TNF-α inhibitor were included. Dashboard flag criteria focused on TNF-α inhibitor safety and adherence monitoring. Flag results from the dashboard were characterized from data captured at a single time point. For 431 patients on TNF-α inhibitor treatment at the institution, 304 flags corresponding to 223 unique patients (51.7%) were identified on the dashboard: 3% of patients had a new infection, 9% had overdue monitoring laboratory tests, 5% had a critical laboratory result, 2% were on 2 biologic agents, 27% were overdue for a refill, 6% had an emergency department visit, and 2% had an inpatient admission. No patients were flagged for heart failure exacerbation or new malignancy. Seventeen percent of patients were prescribed high-dose etanercept or adalimumab, representing a potential annual cost savings of $302,497 if 50% of these patients had their dose successfully reduced to labeled dosing. Opportunities for pharmacist intervention utilizing the dashboard were identified and characterized through chart review of flagged patients. CONCLUSION: Pharmacists have the opportunity to improve safety and adherence for TNF-α inhibitor therapy through use of a specialty medication clinical dashboard. The dashboard should be used in conjunction with collaborative practice protocols.

Use and Toxicity of Checkpoint Inhibitors for Solid Tumor Treatment in a Veteran Population.

BACKGROUND: New immunotherapy agents have provided additional options for the treatment of a variety of malignancies, including the programmed death 1 (PD-1) protein inhibitors nivolumab and pembrolizumab. Initial dosing was based on patient weight, but subsequent studies supported fixed dosing, thereby prompting a change in US Food and Drug Administration-approved dosing. Depending on patient weight, one dosing strategy may be more cost-effective than another; thereby, a combination of dosing strategies may be beneficial for institutions. While these agents have been shown to be efficacious, they have been associated with immune-related adverse events (IrAEs). The purpose of this study was to determine the dosing strategy used and identify actual and potential cost savings, as well as to determine the incidence of hypothyroidism with PD-1 inhibitors in patients of the US Department of Veterans Affairs (VA). METHODS: This was a retrospective chart review of VA patients who received a PD-1 inhibitor for the treatment of a solid tumor between January 2015 and July 2017. Data were collected from the VA Corporate Data Warehouse through the VA Informatics and Computing Infrastructure. The dosing strategy for a PD-1 inhibitor was categorized into weight-based vs fixed-dosing where possible and used to identify actual and potential cost-savings opportunities. Thyroid laboratory values and levothyroxine prescriptions were evaluated to determine the overall incidence of the prespecified IrAEs. Descriptive statistics were used for primary and secondary outcomes. RESULTS: Nivolumab was the primary PD-1 inhibitor used for solid tumor treatment. Both nivolumab and pembrolizumab were primarily dosed based on patient weight. Nivolumab orders resulted in $8,514,300 estimated actual cost savings with $5,591,250 estimated missed cost savings identified. Of the patients who received nivolumab, 3249 patients were evaluated for thyroid dysfunction; 514 (15.8%) developed primary hypothyroidism based on laboratory values and levothyroxine prescription data. CONCLUSIONS: Utilization of a combination of both weight-based and fixed-dosing strategies for nivolumab has the potential for cost savings, thereby benefiting the health care institution. The incidence of IrAEs identified among patients who received PD-1 inhibitor within the VA health care system was similar to the incidences reported in published literature. This further supports recommendations for close IrAE monitoring and treatment.

Post-irradiation examination of optical components for advanced fission reactor instrumentation.

The use of optical instrumentation in advanced nuclear fission systems, such as molten salt reactors, liquid metal-cooled reactors, and high-temperature gas-cooled reactors, has the potential to enhance reactor safety and economic performance through in situ and online measurement of reactor conditions. Selection of suitable optical components, such as optical windows and fibers, is essential for operation of optical instrumentation in intense radioactive and thermal environments inherent to nuclear reactor systems. We present the development and performance of a self-contained and mobile post-irradiation examination system for rapid characterization of the optical properties of materials. The instrument combines linear absorption and nanosecond Z-scan modules in a compact, relocatable design. The system mobility allows for the evaluation of optical samples at the site of irradiation, minimizing the delay between extraction from the irradiation site and optical characterization. This provides nearly real-time information on the material performance under simultaneous irradiation and thermal annealing, simulating the relevant conditions for the use of those components in nuclear power systems.

Role of memantine in the prophylactic treatment of episodic migraine: A systematic review.

OBJECTIVE: The purpose of this systematic review is to assess the efficacy and safety of memantine for the prophylactic treatment of episodic migraine. BACKGROUND: Migraine is a prevalent chronic disease with significant costs to the health care system. Although various prophylactic treatment options are available, these medications have limitations based on efficacy, potential side effects, and patient preference. Memantine is an N-methyl-d-aspartate receptor antagonist used in dementia treatment that may have potential benefit for migraine prophylaxis. METHODS: A systematic search of PubMed, Embase, and CENTRAL databases was conducted to identify relevant published studies through December 2020 using the search terms: migraine disorders, migraine, headache disorders, or headache and memantine. Studies selected for the systematic review included prospective, interventional designs and evaluated memantine for prophylaxis of migraine. Animal studies, case reports, abstracts, review articles, protocols without results, and studies not written in English were excluded. Data were extracted using a standardized systematic process and included author, publication date, study design, sample size, patient characteristics, treatment regimen, clinical efficacy outcomes, and adverse drug effects. RESULTS: Four articles were identified for inclusion representing two prospective open-label studies and two randomized, double-blind trials, evaluating 183 patients on memantine overall. A reduction in number of migraine days and headache severity were shown in all four studies in the participants treated with memantine. The most common adverse effects included somnolence, sedation, and nausea, none of which were severe. CONCLUSION: The studies in this review establish that memantine has the potential for use as a treatment option for episodic migraine. Additional long-term studies using an active comparator would be useful to further elucidate its role.

N95 respirator reuse, decontamination methods, and microbial burden: A randomized controlled trial.

PURPOSE: To evaluate the effectiveness and ease of N95 respirator decontamination methods in a clinic setting and to identify the extent of microbial colonization on respirators associated with reuse. METHODS: In a prospective fashion, N95 respirators (n = 15) were randomized to a decontamination process (time, dry heat, or ultraviolet C light [UVC]) in outpatient clinics. Each respirator was re-used up to 5 separate clinic sessions. Swabs on each respirator for SARS-CoV-2, bacteria, and fungi were obtained before clinic, after clinic and post-treatment. Mask integrity was checked after each treatment (n = 68). Statistical analyses were performed to determine factors for positive samples. RESULTS: All three decontamination processes reduced bacteria counts similarly. On multivariate mixed model analysis, there were an additional 8.1 colonies of bacteria (95% CI 5.7 to 10.5; p < 0.01) on the inside compared to the outside surface of the respirators. Treatment resulted in a decrease of bacterial load by 8.6 colonies (95% CI -11.6 to -5.5; p < 0.01). Although no decontamination treatment affected the respirator filtration efficiency, heat treatments were associated with the breakdown of thermoplastic elastomer straps. Contamination with fungal and SARS-CoV-2 viral particles were minimal to non-existent. CONCLUSIONS: Time, heat and UVC all reduced bacterial load on reused N95 respirators. Fungal contamination was minimal. Heat could permanently damage some elastic straps making the respirators nonfunctional. Given its effectiveness against microbes, lack of damage to re-treated respirators and logistical ease, UVC represents an optimal decontamination method for individual N95 respirators when reuse is necessary.

Proton pump inhibitor usage reduces sustained viral response rates for veterans with HIV/HCV coinfection on ledipasvir/sofosbuvir: a real-world study from a multicentre VA cohort.

Previous studies have reported an association of proton pump inhibitor (PPI) use and decreased sustained viral response rate (SVR) in patients taking ledipasvir/sofosbuvir (LDV/SOF). The relationship between PPI usage and SVR is less clear in patients with HIV/HCV coinfection, where concomitant antiretrovirals may result in more complex drug interactions. This retrospective study evaluates the effects of acid suppression medications (PPI or H2 -receptor antagonist [H2 B]) use and SVR rates in patients with HIV/HCV or HCV and taking LDV/SOF in a large multicentre veteran cohort. Patients in the Veterans Affairs Health Care System who received LDV/SOF ± ribavirin from 10/10/2014 to 12/31/2015 were included. The odds ratios (OR) of PPI or H2 B use for SVR were adjusted for clinical factors and with inverse probability of treatment weighting for non-random treatment selection for acid suppression medication use. There were 9703 veterans included in our final analysis. After adjustment of other clinical factors, PPI use is associated with a lower SVR in the overall cohort (95.0% vs. 96.1%, OR: 0.86, 95% CI: 0.74-0.99, p = .03, number needed to harm 90.9) and HIV/HCV coinfection subgroup (93.4% vs. 96.9%, OR: 0.47, 95% CI: 0.26-0.85, p = .01, number needed to harm 28.6). This present study reveals PPI use is associated with reduced SVR after LDV/SOF treatment, with a more significant impact in the subgroup of patients with HIV/HCV coinfection. Precautions need to be taken when using PPI and LDV/SOF in this group of patients.

Effects of Acetaminophen, NSAIDs, Gabapentinoids, and Their Combinations on Postoperative Pulmonary Complications After Total Hip or Knee Arthroplasty.

OBJECTIVE: Multimodal analgesia has gained popularity in total hip arthroplasty (THA) and total knee arthroplasty (TKA), but large multicenter studies evaluating specific analgesic combinations are lacking. DESIGN: A retrospective study using the Premier Healthcare Database (2009-2014). SUBJECTS: Adults who underwent elective primary THA or TKA. METHODS: We categorized day-of-surgery analgesic exposure using eight mutually exclusive categories: acetaminophen (Ac), nonsteroidal anti-inflammatory drugs (Ns), gabapentinoids (Ga; gabapentin or pregabalin), Ac+Ns, Ac+Ga, Ns+Ga, Ac+Ns+Ga, and none of the three drugs. Multilevel models measured associations of the analgesic categories with a composite of postoperative pulmonary complications (PPCs). RESULTS: Among 863,139 patients, 75.2% received at least one of the three drugs. In multilevel models, compared with none of the three drugs, Ga use was associated with increased odds of PPCs when used alone (adjusted odds ratio [aOR] = 1.35, 95% confidence interval [CI] = 1.27 to 1.44), combined with Ac (aOR = 1.16, 95% CI = 1.08 to 1.26), or combined with Ns (aOR = 1.28, 95% CI = 1.21 to 1.34). In contrast, the Ac+Ns pair was associated with decreased odds of PPCs (OR = 0.86, 95% CI = 0.83 to 0.90) and lower opioid consumption. Ac+Ns+Ga was not associated with PPCs, whereas it was associated with the lowest opioid consumption on the day of surgery. CONCLUSIONS: Gabapentinoids, alone and in single combination with either acetaminophen or nonsteroidal anti-inflammatory drugs, were associated with higher PPCs, whereas the Ac+Ns pair was associated with fewer PPCs and an opioid-sparing effect. Ac+Ns+Ga was not associated with PPCs, whereas it was associated with the lowest opioid consumption on the day of surgery.

Impact of prophylactic oseltamivir on INR in patients on stable warfarin therapy.

Influenza prophylaxis with oseltamivir is recommended for exposed high-risk patients. Patients with many comorbidities have an increased likelihood of co-administration of oseltamivir and warfarin. Evidence of a drug interaction is conflicting in the literature and is limited to a 5-day treatment course. This study evaluates the impact of prophylactic oseltamivir on international normalized ratio (INR) in patients taking warfarin. This retrospective cohort study conducted within the Veterans Health Administration included patients on warfarin who received oseltamivir for influenza prophylaxis. The primary endpoint was change in INR from baseline to day 10 of oseltamivir treatment. Secondary endpoints included change in INR based on renal function and duration of oseltamivir prophylaxis, trend in INR, and frequency of bleeding and thrombosis events. A total of 1041 patients were included and received oseltamivir for a mean of 12.9 days. The mean post-oseltamivir INR was significantly increased compared to the pre-oseltamivir INR (2.39 to 2.52; p < 0.001). Patients with a creatinine clearance of 31-60 mL/min had a significant increase in INR (2.40 to 2.59; p < 0.01). There was an increase in INR when oseltamivir was used for 7 or 8-10 days. Of included patients, 5.1% and 1.8% had a recorded thrombosis or bleeding event, respectively. There was a significant increase in INR in patients on chronic warfarin therapy and concomitant prophylactic oseltamivir, but this change may only be clinically significant for certain patient populations. The most impact on INR was within 7-10 days of oseltamivir initiation and in patients with impaired renal function.