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Background Older adults presenting to the emergency department (ED) represent a highly vulnerable patient population with complex conditions and multiple comorbidities. The introduction of a Geriatric and Palliative (GAP)-ED partnership may be an effective strategy to avoid unneeded admissions and improve outcomes for this population. Objectives The primary objective was to decrease 30-day revisit and hospitalization rates in this population through identifying patients that could be safely sent home with connection to community resources. Secondary outcomes included achieving high patient and family satisfaction scores assessed through follow-up interviews. Methods The GAP-ED intervention included the placement of a Specialist in the ED to coordinate care for older adults presenting to the ED who were likely to be discharged home. Independent t-tests and chi-squared tests were used to assess for changes in outcomes between the intervention group and a blocked matched historical usual-care group. Results There was no significant difference in 30-day ED revisits between the two groups, but there was a statistically significant reduction in hospital admissions from these 30-day revisits. Patient and family satisfaction with the presence of the GAP-ED Specialist was high. Conclusion The implementation of a GAP-ED partnership and use of a GAP-ED Specialist is an effective means of reducing hospitalization in older adults revisiting the ED.

Eukaryotic cells are subdivided into membrane-bound compartments specialized in different cellular functions and requiring dedicated sets of proteins. Although cells developed compartment-specific mechanisms for protein quality control, chaperones and ubiquitin are generally required for maintaining cellular proteostasis. Proteotoxic stress is signalled from one compartment into another to adjust the cellular stress response. Moreover, transport of misfolded proteins between different compartments can buffer local defects in protein quality control. Mitochondria are special organelles in that they possess an own expression, folding and proteolytic machinery, of bacterial origin, which do not have ubiquitin. Nevertheless, the importance of extensive cross-talk between mitochondria and other subcellular compartments is increasingly clear. Here, we will present local quality control mechanisms and discuss how cellular proteostasis is affected by the interplay between mitochondria and the ubiquitin proteasome system.

Purpose While generally reducing morbidity and mortality, TASER® electrical weapons have risks associated with their usage, including burn injuries and head and cervical trauma associated with uncontrolled falls. The primary non-fatal complications appear to be significant eye injury but no analysis of the mechanisms or suggested treatments has been published. Methods We used a biomechanical model to predict the risk of eye injury as a function of distance from the weapon muzzle to the eye. We compared our model results to recently published epidemiological findings. We also describe the typical presentation and suggest treatment options. Results The globe rupture model predicted that a globe rupture can be expected (50% risk) when the eye is within 6 m of the muzzle and decreases rapidly beyond that. This critical distance is 9 m for lens and retinal damage which is approximately the range of the most common probe cartridges. Beyond 9 m, hyphema is expected along with a perforation by the dart portion of the probe. Our prediction of globe rupture out to 6 m (out of a typical range of 9 m) is consistent with the published risk of enucleation or unilateral blindness being 69 ± 18%, with an eye penetration. Conclusions Significant eye injury is expected from a penetration by an electrical weapon probe at close range. The risk decreases rapidly at extended distances from the muzzle. Not all penetrating globe injuries from electrical weapon probes will result in blindness.

Background Acquired thrombophilia is a potential sequela of malignancy, chronic inflammation, and conditions characterized by severe protein deficiency (for example, nephrotic syndrome, protein-losing enteropathy). As such, venous thrombosis is often a feature, and occasionally a presenting sign, of systemic disease. Ménétrier’s disease is a rare hyperplastic gastropathy that may lead to gastrointestinal protein loss and hypoalbuminemia. To date, reports of venous thrombosis associated with Ménétrier’s disease are exceedingly scarce. Case presentation We report the case of a 40-year-old white man who presented with unprovoked deep venous thrombosis, pulmonary embolism, and renal vein thrombosis. Upon receiving therapeutic anticoagulation, he developed severe gastrointestinal bleeding, and endoscopic evaluation led to a diagnosis of Ménétrier’s disease. A laboratory workup revealed deficiency of protein C, protein S, and antithrombin III, as well as markedly elevated levels of factor VIII. He was determined to have an acquired thrombophilia as a direct result of Ménétrier’s disease. Conclusions This case describes an acquired thrombophilic state in a patient with Ménétrier’s disease and profound hypoalbuminemia. Although this association is rarely described, we discuss the probable mechanisms leading to our patient’s thrombosis. Specifically, we posit that his gastrointestinal protein loss led to a deficiency of several anticoagulant proteins and a compensatory elevation in factor VIII, as occurs in nephrotic syndrome and inflammatory bowel disease. Of note, this patient’s recurrent venous thrombosis was the initial clinical sign of his gastrointestinal pathology.

The US Food and Drug Administration (FDA) has approved multiple systemic vascular endothelial growth factor (VEGF) inhibitors since 2004 to treat various malignancies. Inhibition of the VEGF signaling pathway can result in impairment of vascular wall integrity through medial degeneration and endothelial dysfunction, potentially resulting in arterial (including aortic) aneurysm/dissection. We performed a postmarketing review to evaluate arterial aneurysm/dissection as a potential safety risk for patients with cancer treated with VEGF inhibitors. We searched the FDA Adverse Event Reporting System (FAERS) database and literature for reports of arterial (including aortic) aneurysm/dissection with VEGF inhibitors currently approved by the FDA for a cancer indication. We identified 240 cases of arterial aneurysm/dissection associated with VEGF inhibitors. The median time to onset of an arterial aneurysm/dissection event from the initiation of a VEGF inhibitor was 94 days (range 1–1955 days). Notably, 22% (53/240) of cases reported fatal outcomes related to arterial aneurysm/dissection. We determined the drug–event association as probable in 15 cases that lacked relevant confounding factors for arterial aneurysm/dissection, which is supported by unremarkable computed tomography (CT) findings prior to starting VEGF inhibitor therapy, despite nondrug-associated background arterial aneurysm/dissection generally demonstrating preexisting arterial abnormalities. FAERS and literature case-level evidence suggests that VEGF inhibitors may have contributed to arterial aneurysm/dissection, as a class effect, based on short onset relative to natural history of disease and biologic plausibility. Cardiovascular and oncology healthcare professionals should be aware of this rare, but life-threatening safety risk associated with VEGF inhibitors.

Background: Vaccination coverages need to be constantly maintained and improved with the implementation of vaccination strategies. This paper describes the development of an evidence-based tool to guide their planning and evaluation.Methods: A scoping review was performed in MEDLINE and institutional websites to search for similar available tools. A first version of the tool was developed considering review results and a four-step method used for the control and continuous improvement of processes and products, namely the Deming cycle. A panel of eight experts was then involved in a Delphi study for the finalization of the tool that was eventually discussed in a face-to-face meeting.Results: The scoping review found only one document and the first version of the tool was composed of 30 items. After the Delphi first round, 11 additional items were suggested and 5 original items amended. After the Delphi second round 41 items were eventually included. During the face-to-face meeting, 7 items were recognized as requisites for setting vaccination strategies, whereas 17 as relevant ones.Conclusions: Current public health challenges impose the need for evidence-based tools to organize effective vaccination strategies. Our tool is a first proposal which aims to reflect this focus.

Mitochondrial respiratory chain complexes associate in supercomplexes, but the physiological role of these assemblies remains controversial. Recent studies in EMBO Reports reveal that supercomplexes promote metabolic fitness. Berndtsson et al (2020) demonstrate that supercomplex formation enhances electron transport by reducing the distance for diffusion of cytochrome c between cytochrome bc1 complex and cytochrome c oxidase and thereby increases competitive fitness in yeast. Similarly, Garcia-Poyatos et al (2020) report that zebrafish lacking the supercomplex assembly factor SCAF1 display a reduced growth and decreased female fertility.

Summary Background Between March and December, 2020, more than 20 000 laboratory-confirmed cases of SARS-CoV-2 infection were reported in Zambia. However, the number of SARS-CoV-2 infections is likely to be higher than the confirmed case counts because many infected people have mild or no symptoms, and limitations exist with regard to testing capacity and surveillance systems in Zambia. We aimed to estimate SARS-CoV-2 prevalence in six districts of Zambia in July, 2020, using a population-based household survey. Methods Between July 4 and July 27, 2020, we did a cross-sectional cluster-sample survey of households in six districts of Zambia. Within each district, 16 standardised enumeration areas were randomly selected as primary sampling units using probability proportional to size. 20 households from each standardised enumeration area were selected using simple random sampling. All members of selected households were eligible to participate. Consenting participants completed a questionnaire and were tested for SARS-CoV-2 infection using real-time PCR (rtPCR) and anti-SARS-CoV-2 antibodies using ELISA. Prevalence estimates, adjusted for the survey design, were calculated for each diagnostic test separately, and combined. We applied the prevalence estimates to census population projections for each district to derive the estimated number of SARS-CoV-2 infections. Findings Overall, 4258 people from 1866 households participated in the study. The median age of participants was 18·2 years (IQR 7·7–31·4) and 50·6% of participants were female. SARS-CoV-2 prevalence for the combined measure was 10·6% (95% CI 7·3–13·9). The rtPCR-positive prevalence was 7·6% (4·7–10·6) and ELISA-positive prevalence was 2·1% (1·1–3·1). An estimated 454 708 SARS-CoV-2 infections (95% CI 312 705–596 713) occurred in the six districts between March and July, 2020, compared with 4917 laboratory-confirmed cases reported in official statistics from the Zambia National Public Health Institute. Interpretation The estimated number of SARS-CoV-2 infections was much higher than the number of reported cases in six districts in Zambia. The high rtPCR-positive SARS-CoV-2 prevalence was consistent with observed community transmission during the study period. The low ELISA-positive SARS-CoV-2 prevalence might be associated with mitigation measures instituted after initial cases were reported in March, 2020. Zambia should monitor patterns of SARS-CoV-2 prevalence and promote measures that can reduce transmission. Funding US Centers for Disease Control and Prevention.

Respiratory and pulmonary diseases are among the leading causes of death globally. Despite tremendous advancements, there are no effective pharmacological therapies capable of curing diseases such as COPD (chronic obstructive pulmonary disease), ARDS (acute respiratory distress syndrome), and COVID-19. Novel and innovative therapies such as advanced therapy medicinal products (ATMPs) are still in early development. However, they have exhibited significant potential preclinically and clinically. There are several longitudinal studies published, primarily focusing on the use of cell therapies for respiratory diseases due to their anti-inflammatory and reparative properties, thereby hinting that they have the capability of reducing mortality and improving the quality of life for patients. The primary objective of this paper is to set out a state of the art review on the use of aerosolized MSCs and their potential to treat these incurable diseases. This review will examine selected respiratory and pulmonary diseases, present an overview of the therapeutic potential of cell therapy and finally provide insight into potential routes of administration, with a focus on aerosol-mediated ATMP delivery.

Summary The formation of insoluble inclusions in the cytosol and nucleus is associated with impaired protein homeostasis and is a hallmark of several neurodegenerative diseases. Due to the absence of the autophagic machinery, nuclear protein aggregates require a solubilization step preceding degradation by the 26S proteasome. Using yeast, we identify a nuclear protein quality control pathway required for the clearance of protein aggregates. The nuclear J-domain protein Apj1 supports protein disaggregation together with Hsp70 but independent of the canonical disaggregase Hsp104. Disaggregation mediated by Apj1/Hsp70 promotes turnover rather than refolding. A loss of Apj1 activity uncouples disaggregation from proteasomal turnover, resulting in accumulation of toxic soluble protein species. Endogenous substrates of the Apj1/Hsp70 pathway include both nuclear and cytoplasmic proteins, which aggregate inside the nucleus upon proteotoxic stress. These findings demonstrate the coordinated activity of the Apj1/Hsp70 disaggregation system with the 26S proteasome in facilitating the clearance of toxic inclusions inside the nucleus., Graphical Abstract, Highlights • Nuclear Hsp40 Apj1 mediates proteolytic clearance of intra-nuclear protein inclusions • Apj1 supports Hsp104-independent disaggregation in vitro and in vivo • Apj1 competes with Hsp104 in disaggregation, supporting turnover instead of refolding • Inside the nucleus, Apj1 functions in quality control of nuclear and cytoplasmic proteins, den Brave et al. show that the Hsp40 chaperone Apj1 promotes Hsp70-dependent disaggregation of intra-nuclear protein aggregates. This Hsp104-independent disaggregation activity promotes proteolytic turnover and competes with substrate refolding. Co-ordinated disaggregation with turnover protects against potential toxicity of solubilized proteins.

Mitochondria are essential organelles important for energy production, proliferation, and cell death. Biogenesis, homeostasis, and degradation of this organelle are tightly controlled to match cellular needs and counteract chronic stress conditions. Despite providing their own DNA, the vast majority of mitochondrial proteins are encoded in the nucleus, synthesized by cytosolic ribosomes, and subsequently imported into different mitochondrial compartments. The integrity of the mitochondrial proteome is permanently challenged by defects in folding, transport, and turnover of mitochondrial proteins. Therefore, damaged proteins are constantly sequestered from the outer mitochondrial membrane and targeted for proteasomal degradation in the cytosol via mitochondrial-associated degradation (MAD). Recent studies identified specialized quality control mechanisms important to decrease mislocalized proteins, which affect the mitochondrial import machinery. Interestingly, central factors of these ubiquitin-dependent pathways are shared with the ER-associated degradation (ERAD) machinery, indicating close collaboration between both tubular organelles. Here, we summarize recently described cellular stress response mechanisms, which are triggered by defects in mitochondrial protein import and quality control. Moreover, we discuss how ubiquitin-dependent degradation is integrated with cytosolic stress responses, particularly focused on the crosstalk between MAD and ERAD.

Activation of the PI3K–AKT signaling cascade is a common critical event during malignant transformation. In this study, we used thyroid gland epithelial cells and a series of genetically engineered mouse strains as model systems to demonstrate that, although necessary, AKT activation is not sufficient for PI3K-driven transformation. Instead, transformation requires the activity of the PDK1-regulated AGC family of protein kinases. In particular, SGK1 was found to be essential for proliferation and survival of thyroid cancer cells harboring PI3K-activating mutations. Notably, cotargeting SGK1 and AKT resulted in significantly higher growth suppression than inhibiting either PI3K or AKT alone. Overall, these findings underscore the clinical relevance of AKT-independent pathways in tumors driven by genetic lesions targeting the PI3K cascade. Cancer Res; 77(24); 6914–26. ©2017 AACR.

Highly infectious diseases can spread rapidly across borders through travel or trade, and international coordination is essential to a prompt and efficient response by public health laboratories. Therefore, developing strategies to identify priorities for a rational allocation of resources for research and surveillance has been the focus of a large body of research in recent years. This paper describes the activities and the strategy used by a European-wide consortium funded by the European Commission, named EMERGE (Efficient response to highly dangerous and emerging pathogens at EU level), for the selection of high-threat pathogens with cross-border potential that will become the focus of its preparedness activities. The approach used is based on an objective scoring system, a close collaboration with other networks dealing with highly infection diseases, and a diagnostic gaps analysis. The result is a tool that is simple, objective and adaptable, which will be used periodically to re-evaluate activities and priorities, representing a step forward towards a better response to infectious disease emergencies.

The FDA has approved three androgen receptor inhibitors—enzalutamide, apalutamide, and darolutamide—for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). These approvals were all based on randomized, double blind, placebo-controlled trials demonstrating large improvements in metastasis-free survival (MFS) and internally consistent evidence of benefit seen across secondary endpoints. In this article, we summarize the FDA regulatory history of MFS and we describe the design, conduct, and results of the three pivotal trials supporting these important treatment options for patients with nmCRPC.

American Indians face pervasive trauma exposure, collective histories of communal suffering, and elevated risk for depression and posttraumatic stress disorder. In addition to socioeconomic barriers, access to culturally responsive treatment is limited, which may compromise treatment engagement. The Iwankapiya study piloted the Historical Trauma and Unresolved Grief Intervention (HTUG), combined with Group Interpersonal Psychotherapy (IPT), to reduce symptoms of depression and related trauma and grief. The study hypothesized that HTUG + IPT would lead to greater group engagement and decreased depression and related symptoms compared with IPT-Only. American Indian adults (n = 52) were randomized into one of two 12-session interventions, HTUG + IPT or IPT-Only, at two tribal sites: one Northern Plains reservation (n = 26) and one Southwest urban clinic (n = 26). Standardized measures assessed depression, posttraumatic stress disorder, grief, trauma, and substance use. Data were collected at screening, baseline, end of intervention, and 8 weeks postintervention; depression and group engagement measures were also collected at Weeks 4 and 8 of the intervention. Depression scores significantly decreased for both treatments, but there were no significant differences in depression between the two groups: IPT-Only (30.2 ± 6.4 at baseline to 16.7 ± 12.1 at follow-up) and HTUG + IPT (30.2 ± 8.1 at baseline to 19.9 ± 8.8 at follow-up). However, HTUG + IPT participants demonstrated significantly greater group engagement. Postintervention, clinicians expressed preference for HTUG + IPT based upon qualitative observations of greater perceived gains among participants. Given the degree of trauma exposure in tribal communities, these findings in a relatively small sample suggest HTUG should be further examined in context of treatment engagement. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Objective A 12-lead electrocardiogram (ECG) is the standard of care for chest pain patients. However, 12-lead ECGs have difficulty detecting ischemia of the right ventricle or posterior wall of the heart. New technology exists to mathematically synthesize these leads from a 12-lead ECG; however, this technology has not been evaluated in the emergency department (ED). We assessed the level of agreement between synthesized 18-lead ECGs and actual 18-lead ECGs in identifying ST elevations, ST depressions, and T wave inversions in ED patients. Methods Actual 12- and 18-lead ECGs were acquired and synthesized 18-lead ECGs were produced based on waveforms from 12-lead ECGs. A blinded cardiologist interpreted the actual and synthesized 18-lead ECGs to identify the presence of abnormalities. Using actual 18-lead ECGs as the reference, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and kappa of synthesized 18-lead ECGs in identifying abnormalities were determined. Results Data from 295 patients were analyzed. There was 100% agreement between synthesized 18-lead ECGs and actual 18-lead ECGs in identifying ST elevations and ST depressions (sensitivity, specificity, PPV, and NPV of 100%, and kappa of 1.00). Synthesized 18-lead ECGs had 95% sensitivity, 80% specificity, 97% PPV, and 70% NPV in identifying T wave inversions, when compared with actual 18-lead ECGs (kappa: 0.70). Conclusion Synthesized 18-lead ECGs demonstrated 100% agreement with actual 18-lead ECGs in the identification of ST elevations and ST depressions and good agreement in the identification of T wave inversions in a sample of patients ED patients with complaints suspicious of cardiac origin.

Mitochondrial fusion requires a conformational change in α4 of the GTPase domain, followed by AAA-ATPase regulation, thus revealing striking mechanistic similarities between small and large GTPases., Mitochondria are essential organelles whose function is upheld by their dynamic nature. This plasticity is mediated by large dynamin-related GTPases, called mitofusins in the case of fusion between two mitochondrial outer membranes. Fusion requires ubiquitylation, attached to K398 in the yeast mitofusin Fzo1, occurring in atypical and conserved forms. Here, modelling located ubiquitylation to α4 of the GTPase domain, a critical helix in Ras-mediated events. Structure-driven analysis revealed a dual role of K398. First, it is required for GTP-dependent dynamic changes of α4. Indeed, mutations designed to restore the conformational switch, in the absence of K398, rescued wild-type-like ubiquitylation on Fzo1 and allowed fusion. Second, K398 is needed for Fzo1 recognition by the pro-fusion factors Cdc48 and Ubp2. Finally, the atypical ubiquitylation pattern is stringently required bilaterally on both involved mitochondria. In contrast, exchange of the conserved pattern with conventional ubiquitin chains was not sufficient for fusion. In sum, α4 lysines from both small and large GTPases could generally have an electrostatic function for membrane interaction, followed by posttranslational modifications, thus driving membrane fusion events.

PURPOSE To assess the relationship among tumor response rate, overall survival, and the development of related adverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients with urothelial cancer treated with anti–programmed death protein 1 or ligand 1 (anti–PD-1/L1) antibodies. PATIENTS AND METHODS We examined seven trials in 1,747 patients with metastatic or locally advanced urothelial cancer that led to approval of an anti–PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy, and two enrolled patients who were cisplatin ineligible. The data sets were searched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined by the investigator. ImAEs were defined as AESIs treated with topical or systemic corticosteroids. RESULTS In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti–PD-1/L1 antibody, whereas a related imAE occurred in 28% and 12% of patients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overall survival was seen in patients with related AESIs compared with those with no related AESIs (hazard ratio, 0.45; 95% CI, 0.39 to 0.52). Fifty-seven percent of responding patients with a related AESI reported the AESI before documentation of response. CONCLUSION Patients who responded to treatment with an anti–PD-1/L1 antibody were more likely to report a related AESI or related imAE. This relationship did not seem to be due to the increased duration of exposure in responding patients. Systemic corticosteroid use did not appear to affect the duration of response.

Background Long-term sustainability of successful improvement initiatives remains a pragmatic challenge with limited literature guidance. A chronic obstructive pulmonary disease (COPD) care bundle was developed and implemented to mitigate care-delivery failures and unmet patient needs at University of Cincinnati Medical Center that led to a 35% reduction in 30-day all-cause readmissions. Here, two-year outcomes and the method of achieving sustainability are presented. Methods After implementation of the COPD care bundle, 30-day all-cause readmissions reduced from 22.7% to 14.7%. In 2016 the project transitioned from implementation to the sustainability phase. A four-member sustainability team was formed (pulmonologist, hospitalist, respiratory therapist, and pharmacist) with clearly defined roles for monitoring and facilitating sustainability actions. The process of bundle delivery was purposefully designed for higher reliability. Staff education and daily operations were updated to incorporate the new process. Outcome (readmission rate) and process (bundle adherence) measures were monitored monthly. Any significant drop (special cause variation) would be reviewed by the team and further action taken, if needed. The National Health Service sustainability model was used, with adjustments made to meet our contextual needs. Results The 30-day all-cause readmission rate remained the same as during the initial implementation phase (14.9%). Adherence to COPD care bundle components was 87.7%. During the two-year period, three occasions triggered a team discussion and detailed review. Conclusion Sustainability requires a purposefully designed, resilient process; standard work; engagement of the team and leadership; and a monitoring system of key process and outcome measures. Application of sustainability models should be adjusted for specific contextual needs.

Background Mitosis is a process of cell division resulting in two genetically equivalent daughter cells. Excessive proliferation of cells due to mitosis is the hallmark in pre cancer and cancer. Aims This study was conducted to count the number of mitotic figures in normal oral mucosa, oral epithelial dysplasia and squamous cell carcinoma in both Hematoxylin and Eosin (H&E) and Crystal Violet stained sections. Also the overall number of mitotic figures with both stains were compared along with the evaluation of staining efficacy of both the stains. Methods and material The present study was conducted on 20 specimens each of the three categories. These were further divided into two groups for staining with H&E and with 1% Crystal Violet respectively. Images were captured and analyzed using image analysis software Dewinter Biowizard 4.1. Results Comparison of mitotic figure count in three categories in sections stained with both stains showed statistically significant difference (p Conclusion Number of mitotic figures progressively increase with the advancement of the pathology. Use of 1% Crystal Violet provides better appreciation of mitotic figures and can be employed as a selective stain in routine histopathology.

Although there is literature concentrating on cross-cultural approaches to academic and community partnerships with Native communities, few address the process and experiences of American Indian women leading federally funded and culturally grounded behavioral health intervention research in Native communities. This paper summarizes relevant literature on community-engaged research with Native communities, examines traditional roles and modern challenges for American Indian women, describes the culturally grounded collaborative process for the authors' behavioral health intervention development with Native communities, and considers emergent themes from our own research experiences navigating competing demands from mainstream and Native communities. It concludes with recommendations for supporting and enhancing resilience.

Background: The quality of antenatal care (ANC) a woman receives during pregnancy is crucial to both the child and the mother’s life. It has been established that providing high-quality ANC can save lives and has a positive impact on postnatal health care services. However, the quality of ANC in Zambia requires attention as maternal and neonatal mortality rates are still unacceptably high with Lusaka district not being left out of the problem. Methods: Using a cross-sectional study design, the main aim of this study was to determine the demand side factors associated with high-quality antenatal care among pregnant women in Lusaka. It also estimated the proportion of women who received high-quality ANC during their last antenatal visit. Multifactorial logistic regression model was fitted in STATA version 13 to predict the demographic, socio and economic factors that influence the quality of ANC. Results: It was established that only 47.1% of pregnant women received high-quality ANC while 52.9% received low quality. Six key ANC interventions were considered, among which urine (36.7%) and blood (46.8%) testing were the least received basic components of ANC. After adjusting for the effect of other factors, women with secondary education had higher odds of receiving high-quality ANC than women with primary level of education (OR = 1.98; 95% CI: 1.24 to 3.14). Women staying with their husband/partners had lesser odds of receiving high quality ANC compared to those that were not staying with their partners (OR = 0.47; 95% CI: 0.28 to 0.79). Conclusion: The quality of antenatal care received by pregnant women in Lusaka is low. Continued efforts to improve the delivery of basic ANC services such as blood and urine testing is required to improve the quality of healthcare services provided by medical personnel at all levels.

Introduction: Human electronic control with the Conducted Electrical Weapon (CEW) has gained widespread acceptance as the preferred law enforcement force option technology due to its dramatic injury and fatal shooting reduction. However, with bulky or baggy clothing, a CEW probe may fail to make direct skin contact and thus arcing is critical to complete the circuit. The goal of the study was to evaluate the ability of modern CEWs to deliver their pulse charges across typical required arcing distances.Methods: Popular TASER® CEW models X26E (openloop output), and the X2 and X26P (with closed-loop outputs) were activated using a cartridge connected to a custom polymer air-gap fixture. For each model 5 units were tested. The raw and normalized charge delivery were evaluated according to ANSI-CPLSO-17.Results: All 5 units of each model satisfied ANSICPLSO-17 even at maximum arcing length. The X26P CEW had the greatest arcing gap capability.Conclusions: The stabilized closed-loop charge output feedback of modern electrical weapons (X2 and X26P CEWs) provides a significantly improved output consistency under arcing conditions. With arc lengths of 10–20 mm per probe, the X2 CEW normalized output charge exceeds that of some units of the older higher output X26E CEW model.

Cdc48/p97, a ubiquitin-selective chaperone, orchestrates the function of E3 ligases and deubiquitylases (DUBs). Here, we identify a new function of Cdc48 in ubiquitin-dependent regulation of mitochondrial dynamics. The DUBs Ubp12 and Ubp2 exert opposing effects on mitochondrial fusion and cleave different ubiquitin chains on the mitofusin Fzo1. We demonstrate that Cdc48 integrates the activities of these two DUBs, which are themselves ubiquitylated. First, Cdc48 promotes proteolysis of Ubp12, stabilizing pro-fusion ubiquitylation on Fzo1. Second, loss of Ubp12 stabilizes Ubp2 and thereby facilitates removal of ubiquitin chains on Fzo1 inhibiting fusion. Thus, Cdc48 synergistically regulates the ubiquitylation status of Fzo1, allowing to control the balance between activation or repression of mitochondrial fusion. In conclusion, we unravel a new cascade of ubiquitylation events, comprising Cdc48 and two DUBs, fine-tuning the fusogenic activity of Fzo1., eLife digest Mitochondria are little compartments within a cell that produce the energy needed for most biological processes. Each cell possesses several mitochondria, which can fuse together and then break again into smaller units. This fusion process is essential for cellular health. Two proteins in the cell have a major role in controlling mitochondrial fusion: Ubp12 and Ubp2. Ubp12 prevents fusion, while Ubp2 activates it. These molecules carry out their roles by acting on a third protein called mitofusin, which is a key gatekeeper of the fusion mechanism. Cells often ‘tag’ proteins with small molecules called ubiquitin to change the protein’s role and how it interacts with other cellular structures. Depending on how they are ‘tagged’, mitofusins can exist in two forms. One type of tagging means that the protein then promotes fusion of the mitochondria; the other leads to the mitofusin being destroyed by the cell. It is still unclear how Ubp12, Ubp2 and the different forms of mitofusins interact with each other to finely control mitochondrial fusion. Here, Simões, Schuster et al. clarify these interactions in yeast and show how these proteins are themselves regulated. Ubp2 promotes fusion by attaching to the mitofusin that is labeled to be destroyed, and removing this tag: the mitofusin will then not be degraded, and can promote fusion. Ubp12 prevents fusion through two mechanisms. First, it can remove the ‘pro-fusion’ tag on the mitofusin that prompts mitochondrial fusion. Second, Simões, Schuster et al. now show that Ubp12 also inhibits Ubp2 and its fusion-promoting activity. In turn, the experiments reveal that a master protein called Cdc48 can control the entire Ubp12-Ubp2-mitofusin pathway. Cdc48 directly represses Ubp12 and therefore its anti-fusion activity. This inhibition also leaves Ubp2 free to stimulate fusion through its action on mitofusin. The molecules involved in controlling mitochondrial fusion in yeast are very similar to the ones in people. In humans, improper regulation of mitofusins causes an incurable disease of the nerves and the brain called Charcot-Marie-Tooth 2A. Understanding how the fusion of mitochondria is controlled can lead to new drug discoveries.

Modification by the ubiquitin-like protein SUMO affects hundreds of cellular substrate proteins and regulates a wide variety of physiological processes. While the SUMO system appears to predominantly target nuclear proteins and, to a lesser extent, cytosolic proteins, hardly anything is known about the SUMOylation of proteins targeted to membrane-enclosed organelles. Here, we identify a large set of structurally and functionally unrelated mitochondrial proteins as substrates of the SUMO pathway in yeast. We show that SUMO modification of mitochondrial proteins does not rely on mitochondrial targeting and, in fact, is strongly enhanced upon import failure, consistent with the modification occurring in the cytosol. Moreover, SUMOylated forms of mitochondrial proteins particularly accumulate in HSP70- and proteasome-deficient cells, suggesting that SUMOylation participates in cellular protein quality control. We therefore propose that SUMO serves as a mark for nonfunctional mitochondrial proteins, which only sporadically arise in unstressed cells but strongly accumulate upon defective mitochondrial import and impaired proteostasis. Overall, our findings provide support for a role of SUMO in the cytosolic response to aberrant proteins.

Purpose While generally reducing morbidity and mortality, electrical weapons have risks associated with their usage, including burn injuries and trauma associated with uncontrolled fall impacts. However, the prevalence of significant eye injury has not been investigated. Methods We searched for incidents of penetrating eye injury from TASER® conducted electrical weapon (CEW) probes via open source media, litigation filings, and a survey of CEW law-enforcement master instructors. Results We report 20 previously-unpublished cases of penetrating eye injury from electrical weapon probes in law-enforcement field uses. Together with the 8 previously published cases, there are a total of 28 cases out of 3.44 million field uses, giving a demonstrated CEW field-use risk of penetrating eye injury of approximately 1:123 000. Confidence limits [85 000, 178 000] by Wilson score interval. There have been 18 cases of total unilateral blindness or enucleation. We also present legal decisions on this topic. Conclusions The use of electrical weapons presents a rare but real risk of total or partial unilateral blindness from electrical weapon probes. Catastrophic eye injuries appear to be the dominant non-fatal complication of electronic control.

Introduction—We have previously published on the ventricular fibrillation (VF) risk with TASER® X26 conducted electrical weapon (CEW). Our risk model accounted for realistic body mass index distributions, modeled the effects of partial or oblique dart penetration, and used epidemiological CEW statistics. As new CEWs have become available to law enforcement, their cardiac safety profile was not quantified. Therefore, we applied our VF probability model to evaluate their cardiac risk.

Introduction: We have previously published about TASER® conducted electrical weapons (CEW) compliance with international standards. CEWs deliver electrical pulses that can inhibit a person's neuromuscular control or temporarily incapacitate. An eXperimental Rotating-Field (XRF) waveform CEW and the X2 CEW are new 2-shot electrical weapon models designed to target a precise amount of delivered charge per pulse. They both can deploy 1 or 2 dart pairs, delivered by 2 separate cartridges. Additionally, the XRF controls delivery of incapacitating pulses over 4 field vectors, in a rotating sequence. As in our previous study, we were motivated by the need to understand the cardiac safety profile of these new CEWs. The goal of this paper is to analyze the nominal electrical outputs of TASER XRF and X2 CEWs in reference to provisions of all relevant international standards that specify safety requirements for electrical medical devices and electrical fences. Although these standards do not specifically mention CEWs, they are the closest electrical safety standards and hence give very relevant guidance.

Introduction: The TASER® conducted electrical weapon (CEW) is best known for delivering electrical pulses that can temporarily incapacitate subjects by overriding normal motor control. The alternative drive-stun mode is less understood and the goal of this paper is to analyze the distribution of currents in tissues when the CEW is operated in this mode. Methods and Results: Finite element modeling (FEM) was used to approximate current density in tissues with boundary electrical sources placed 40 mm apart. This separation was equivalent to the distance between drive-stun mode TASER X26™, X26P, X2 CEW electrodes located on the device itself and between those located on the expended CEW cartridge. The FEMs estimated the amount of current flowing through various body tissues located underneath the electrodes. The FEM simulated the attenuating effects of both a thin and of a normal layer of fat. The resulting current density distributions were used to compute the residual amount of current flowing through deeper layers of tissue. Numerical modeling estimated that the skin, fat and skeletal muscle layers passed at least 86% or 91% of total CEW current, assuming a thin or normal fat layer thickness, respectively. The current density and electric field strength only exceeded thresholds which have increased probability for ventricular fibrillation (VFTJ), or for cardiac capture (CCTE), in the skin and the subdermal fat layers. Conclusion: The fat layer provided significant attenuation of drive-stun CEW currents. Beyond the skeletal muscle layer, only fractional amounts of the total CEW current were estimated to flow. The regions presenting risk for VF induction or for cardiac capture were well away from the typical heart depth.

4557 Background: Previous data has suggested that patients treated with anti-PD-1/L1 antibodies who receive antibiotics during their therapy might have dramatically decreased progression-free and overall survival 1,2. This has clinical implications for management of patients with suspected bacterial infection while on treatment with these agents. We assessed the relationship between antibiotic use and tumor response rate, progression-free survival, and overall survival in a large dataset of patients with urothelial cancer treated with anti-PD-1/L1 antibodies. Methods: We examined seven trials that led to drug approval and which included 1747 patients with metastatic or locally advanced urothelial cancer treated with an anti-PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy and two enrolled patients who were cisplatin-ineligible. Six were single arm trials and one was a randomized controlled trial whose control arm is not included in these analyses. Concomitant medication datasets were searched for systemic antibiotic used by each patient while on treatment. Results: Overall, 51% of patients (n=892) were exposed to antibiotics (ABX+) and 49% (n=855) were not exposed (ABX-). In these exploratory analyses, small numeric differences in OS, PFS, and ORR were seen in ABX+ vs. ABX- patients. Median OS was 9.23 vs. 9.86 months, median PFS was 105 vs 101 days, and ORR was 20% vs. 21% in ABX+ vs. ABX- patients, respectively. Conclusions: Patients who were treated with antibiotics while on therapy with an anti-PD-1/L1 antibody for urothelial cancer had similar outcomes to those who were not treated with antibiotics. Numeric differences in outcomes were not significant and did not duplicate previous analysis demonstrating a median OS that was doubled in ABX- patients1. Our exploratory analyses do not appear to demonstrate a clear need for practitioners to avoid antibiotic use in patients treated with PD-1/L1 agents for fear of significantly impacting clinical outcomes. References: 1) Tinsley et. al., ASCO annual meeting 2018, abstract 3010 2) Routy et. al., Science 05 Jan 2018: Vol. 359, Issue 6371. [Table: see text]

Small swine are the most common model now used for electrical safety studies. Because of the significant anatomical and electrophysiological differences and the effect of animal size on the ventricular fibrillation (VF) threshold, there are concerns that these differences may exaggerate the risks of electrical devices to humans. Methods and Results — We chose, as an illustrative and relevant example, swine studies of the TASER® conducted electrical weapon (CEW) as it has numerous published VF studies. We reviewed the published electrical swine safety studies for CEWs and compared them to finite element modeling studies, electrical safety standards, and epidemiological experience from field usage. We also compared the body weights of the swine to those of law enforcement arrest-related deaths. Conclusion — Studies of small swine exaggerate the risks of CEWs to humans. This conclusion may be extrapolated to suggest that the use of small swine for electrical safety studies should be questioned in general.

On April 25, 2016, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. The approval was based on data from one randomized, open-label, multicenter study in which patients with RCC who had received prior antiangiogenic therapy were treated with either cabozantinib 60 mg orally once daily (n = 330) or everolimus 10 mg orally once daily (n = 328). The major efficacy outcome measure was progression-free survival (PFS) as assessed by a blinded independent radiology review committee in the first 375 randomized patients. A statistically significant improvement in PFS was seen, with a median PFS of 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45–0.74; P < 0.0001]. At a second interim analysis, a statistically significant improvement in overall survival (OS) in the intent-to-treat population was also demonstrated, with a median OS of 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively (HR, 0.66; 95% CI, 0.53–0.83; P = 0.0003). The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar–plantar erythrodysesthesia syndrome, hypertension, vomiting, weight loss, and constipation. Clin Cancer Res; 23(2); 330–5. ©2016 AACR.

The molecular basis for the regulation of the intestinal barrier is a very fertile research area. A growing body of knowledge supports the targeting of various components of intestinal barrier function as means to treat a variety of diseases, including the inflammatory bowel diseases. Herein, we will summarize the current state of knowledge of key xenobiotic receptor regulators of barrier function, highlighting recent advances, such that the field and its future are succinctly reviewed. We posit that these receptors confer an additional dimension of host-microbe interaction in the gut, by sensing and responding to metabolites released from the symbiotic microbiota, in innate immunity and also in host drug metabolism. The scientific evidence for involvement of the receptors and its molecular basis for the control of barrier function and innate immunity regulation would serve as a rationale towards development of non-toxic probes and ligands as drugs.

Efficient degradation of abnormal or aggregated proteins is crucial to protect the cell against proteotoxic stress. Selective targeting and disposal of such proteins usually occurs in a ubiquitin-dependent manner by proteasomes and macroautophagy/autophagy. Whereas proteasomes are efficient in degrading abnormal soluble proteins, protein aggregates are typically targeted for degradation by autophagic vesicles. Both processes require ubiquitin-binding receptors, which are targeted to proteasomes via ubiquitin-like domains or to phagophores (the precursors to autophagosomes) via Atg8/LC3 binding motifs, respectively. The use of substrate modification by ubiquitin in both pathways raised the question of how degradative pathway choice is achieved. In contrast to previous models, proposing different types of ubiquitin linkages for substrate targeting, we find that pathway choice is a late event largely determined by the oligomeric state of the receptors. Monomeric proteasome receptors bind soluble substrates more efficiently due to their higher affinity for ubiquitin. Upon substrate aggregation, autophagy receptors with lower ubiquitin binding affinity gain the upper hand due to higher avidity achieved by receptor bundling. Thus, our work suggests that ubiquitination is a shared signal of an adaptive protein quality control system, which targets substrates for the optimal proteolytic pathway.

Background: The PD-1 inhibitors release T cells from PD-L1 and PD-L2 mediated blockade, resulting in enhancement of immune responses. These immune responses include not only antitumor activity but also autoimmune reactions. The most serious toxicities of PD-1 inhibitors are immune-mediated, consistent with their mechanism of action. The purpose of this retrospective analysis was to characterize the immune-related adverse reactions (IMARs) of PD-1 inhibitor therapy in patients with cHL. Methods: Data were pooled from three single-arm trials in adults with multiply-relapsed or refractory cHL treated with nivolumab or pembrolizumab at their approved doses. The pool included 243 patients from Study CA209-205 (NCT02181738), 23 patients from Study CA209-039 (NCT01592370), and 210 patients from Study MK-3475-087 (NCT02453594). IMARs were ascertained using grouped MedDRA terms for the following categories: adrenal insufficiency, cardiac disorder, diabetes, diarrhea, encephalitis, hepatitis, hypophysitis, infusion reaction, kidney injury, myositis, pancreatitis, pneumonitis, rash, thyroid disorder, and uveitis. The pooled data set was queried for the incidence, timing, and outcome of IMARs in the population overall. Key patient characteristics assessed as risk factors for IMARs included age, sex, race, ethnicity, weight, body mass index (BMI), B symptoms, bulky disease, prior irradiation, prior autologous stem cell transplantation (aHSCT), prior brentuximab use, and prior lines of therapy. To identify risk factors, multivariable models were developed using a backward-stepping elimination procedure after the initial selection using p-value < 0.2 in the univariable analysis. In the multivariable analysis, p-values < 0.05 were considered statistically significant. Results: The study cohort included 476 patients of median age 34 years (range, 18-76 years); 56% were male, and 87% were Caucasian. Treatment consisted of a median of 13 doses over a median of 9.3 months. An IMAR was reported in 301 (63.2%) patients, and the IMAR was grade 3-4 in 52 (10.9%) patients. No fatal IMARs were reported. There were 51 (11%) patients treated with corticosteroids, and 48 (10%) had study drug interrupted or withdrawn. The most common (>10%) IMARs were rash (28.6%), diarrhea (26.5%), thyroid disorder (14.3%), infusion reaction (13.2%), and hepatitis (11.1%). The most common (>1%) grade 3-4 IMARs were pancreatitis (3.6%), hepatitis (2.9%), and diarrhea (2.3%). The table below shows the IMARs listed in order of time to onset. Risk factors for the occurrence of any IMAR were prior aHSCT (p=0.004) and elevated BMI (p=0.049). When assessed by individual IMAR, the risk factors identified were age for cardiac disorder; prior aHSCT for diarrhea; race for hepatitis; race and weight for infusion reaction; number of prior lines of therapy and BMI for kidney injury; weight and B symptoms for pneumonitis; prior aHSCT and BMI for rash; and sex and prior radiation for thyroid disorders. No risk factors were identified for adrenal insufficiency, diabetes, hypophysitis, myositis, pancreatitis, or uveitis. Conclusions: The majority of patients with cHL treated with a PD-1 inhibitor experienced an adverse event consistent with an IMAR, although few events were grade 3-4. Most of these events started after 2-3 months of treatment, but overall, they occurred at any time during treatment. Prior aHSCT was identified as a significant risk factor for IMAR, although this was driven largely by the categories rash and diarrhea. Acknowledgment: Data were provided for nivolumab by Bristol-Myers Squibb Company and for pembrolizumab by Merck Sharp & Dohme Corp. Table. Table. Disclosures No relevant conflicts of interest to declare.

Aim: The present study aimed to compare the remaining dentin thickness (RDT) and fracture resistance of conventional and conservative access and biomechanical preparation in molars using cone-beam computed tomography (CBCT). Methodology: A total of 60 freshly extracted human molars were selected and were randomly divided into two groups of conventional and conservative access preparation group (n = 30). Samples were subjected to pre-CBCT scan at the pericervical region for the measurement of total dentin thickness. For the conventional group, samples were accessed and biomechanical preparation was done using K3 XF file. For conservative group, samples were accessed using CK microendodontic burs using a dental operating microscope and biomechanical preparation was done using self-adjusting file. After obturation and postobturation with nanohybrid composite restoration, samples of both groups were subjected to post-CBCT scan at pericervical region for the measurement of RDT. The samples were then loaded to fracture in the Instron Universal Testing Machine, and the data were analyzed using paired sample t-test and independent sample t-test. Results: The mean RDT was less in conventional group than conservative group. Pericervical dentin was preserved more in conservative group. The statistical difference among both the experimental group was highly significant (

Importance Chronic cerebrospinal venous insufficiency (CCSVI) is characterized by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with multiple sclerosis (MS) and whether venous percutaneous transluminal angioplasty (PTA) is beneficial in persons with MS and CCSVI is controversial. Objective To determine the efficacy and safety of venous PTA in patients with MS and CCSVI. Design, Setting, and Participants We analyzed 177 patients with relapsing-remitting MS; 62 were ineligible, including 47 (26.6%) who did not have CCSVI on color Doppler ultrasonography screening. A total of 115 patients were recruited in the study timeframe. All patients underwent a randomized, double-blind, sham-controlled, parallel-group trial in 6 MS centers in Italy. The trial began in August 2012 and concluded in March 2016; data were analyzed from April 2016 to September 2016. The analysis was intention to treat. Interventions Patients were randomly allocated (2:1) to either venous PTA or catheter venography without venous angioplasty (sham). Main Outcomes and Measures Two primary end points were assessed at 12 months: (1) a composite functional measure (ie, walking control, balance, manual dexterity, postvoid residual urine volume, and visual acuity) and (2) a measure of new combined brain lesions on magnetic resonance imaging, including the proportion of lesion-free patients. Combined lesions included T1 gadolinium-enhancing lesions plus new or enlarged T2 lesions. Results Of the included 115 patients with relapsing-remitting MS, 76 were allocated to the PTA group (45 female [59%]; mean [SD] age, 40.0 [10.3] years) and 39 to the sham group (29 female [74%]; mean [SD] age, 37.5 [10.6] years); 112 (97.4%) completed follow-up. No serious adverse events occurred. Flow restoration was achieved in 38 of 71 patients (54%) in the PTA group. The functional composite measure did not differ between the PTA and sham groups (41.7% vs 48.7%; odds ratio, 0.75; 95% CI, 0.34-1.68;P = .49). The mean (SD) number of combined lesions on magnetic resonance imaging at 6 to 12 months were 0.47 (1.19) in the PTA group vs 1.27 (2.65) in the sham group (mean ratio, 0.37; 95% CI, 0.15-0.91;P = .03: adjustedP = .09) and were 1.40 (4.21) in the PTA group vs 1.95 (3.73) in the sham group at 0 to 12 months (mean ratio, 0.72; 95% CI, 0.32-1.63;P = .45; adjustedP = .45). At follow-up after 6 to 12 months, 58 of 70 patients (83%) in the PTA group and 22 of 33 (67%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 2.64; 95% CI, 1.11-6.28;P = .03; adjustedP = .09). At 0 to 12 months, 46 of 73 patients (63.0%) in the PTA group and 18 of 37 (49%) in the sham group were free of new lesions on magnetic resonance imaging (odds ratio, 1.80; 95% CI, 0.81-4.01;P = .15; adjustedP = .30). Conclusion and Relevance Venous PTA has proven to be a safe but largely ineffective technique; the treatment cannot be recommended in patients with MS. Trial Registration clinicaltrials.gov Identifier:NCT01371760

To examine the prevalence of common psychiatric disorders and associated treatment-seeking, stratified by gender, among American Indians/Alaska Natives and non-Hispanic whites in the United States. Lifetime and 12-month rates are estimated, both unadjusted and adjusted for sociodemographic correlates. Analyses were conducted with the American Indians/Alaska Native (n = 701) and Non-Hispanic white (n = 24,507) samples in the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions [(NESARC) n = 43,093]. Overall, 70 % of the American Indian/Alaska Native men and 63 % of the women met criteria for at least one Diagnostic and Statistical Manual-IV lifetime disorder, compared to 62 and 53 % of Non-Hispanic white men and women, respectively. Adjusting for sociodemographic correlates attenuated the differences found. Nearly half of American Indians/Alaska Natives had a psychiatric disorder in the previous year; again, sociodemographic adjustments explained some of the differences found. Overall, the comparisons to non-Hispanic whites showed differences were more common among American Indian/Alaska Native women than men. Among those with a disorder, American Indian/Alaska Native women had greater odds of treatment-seeking for 12-month anxiety disorders. As the first study to provide national estimates, by gender, of the prevalence and treatment of a broad range of psychiatric disorders among American Indians/Alaska Natives, a pattern of higher prevalence of psychiatric disorder was found relative to Non-Hispanic whites. Such differences were more common among women than men. Prevalence may be overestimated due to cultural limitations in measurement. Unmeasured risk factors, some specific to American Indians/Alaska Natives, may also partially explain these results.