KIFC1 Regulates the Trajectory of Neuronal Migration.

During neuronal migration, forces generated by cytoplasmic dynein yank on microtubules extending from the centrosome into the leading process and move the nucleus along microtubules that extend behind the centrosome. Scaffolds, such as radial glia, guide neuronal migration outward from the ventricles, but little is known about the internal machinery that ensures that the soma migrates along its proper path rather than moving backward or off the path. Here we report that depletion of KIFC1, a minus-end-directed kinesin called HSET in humans, causes neurons to migrate off their appropriate path, suggesting that this molecular motor is what ensures fidelity of the trajectory of migration. For these studies, we used rat migratory neurons in vitro and developing mouse brain in vivo, together with RNA interference and ectopic expression of mutant forms of KIFC1. We found that crosslinking of microtubules into a nonsliding mode by KIFC1 is necessary for dynein-driven forces to achieve sufficient traction to thrust the soma forward. Asymmetric bouts of microtubule sliding driven by KIFC1 thereby enable the soma to tilt in one direction or another, thus providing midcourse corrections that keep the neuron on its appropriate trajectory. KIFC1-driven sliding of microtubules further assists neurons in remaining on their appropriate path by allowing the nucleus to rotate directionally as it moves, which is consistent with how we found that KIFC1 contributes to interkinetic nuclear migration at an earlier stage of neuronal development.SIGNIFICANCE STATEMENT Resolving the mechanisms of neuronal migration is medically important because many developmental disorders of the brain involve flaws in neuronal migration and because deployment of newly born neurons may be important in the adult for cognition and memory. Drugs that inhibit KIFC1 are candidates for chemotherapy and therefore should be used with caution if they are allowed to enter the brain.

Shackling and pregnancy care policies in US prisons and jails.

OBJECTIVES: The number of incarcerated women in the United States has risen exponentially. Many are of childbearing age with 3-4% being pregnant at intake. Despite the need for comprehensive pregnancy-related health care in prisons and jails, there is no oversight that requires adherence to the established standards. The objective of this study was to assess prison and jail pregnancy policies and practices with an emphasis on restraint use and compliance with anti-shackling legislation. METHODS: We conducted a survey of 22 state prisons and six jails, including the five largest jails, from 2016-2017 regarding pregnancy policies and practices including restraint use, prenatal care, delivery and birth, and other pregnancy accommodations. We compared reported restraint policies to state legislation at the time of the survey. RESULTS: Data indicate that pregnancy policies and services in prisons and jails vary and compliance inconsistencies with anti-shackling legislation exist. A third of the prisons and half of the jails did not have accredited health care services. All study facilities provided prenatal vitamins and most provided supplemental snacks. Most facilities stationed an officer inside the hospital room during labor and delivery, but nearly one-third of facilities did not require a female-identifying officer. CONCLUSIONS FOR PRACTICE: Limited oversight and standardization of carceral health care and accommodations for pregnant people lead to variability in prisons and jails. Prisons and jails should adopt and implement standards of care guidelines to ensure the safety and well-being of pregnant people who have unique healthcare needs. Incarcerated pregnant people should be viewed as expectant parents in need of comprehensive health care, rather than as criminals who forfeited their right to a safe, respectful, and humane childbirth.

A cellular approach to understanding and treating Gulf War Illness.

Gulf War Illness (GWI), a disorder suffered by approximately 200,000 veterans of the first Gulf War, was caused by exposure to low-level organophosphate pesticides and nerve agents in combination with battlefield stress. To elucidate the mechanistic basis of the brain-related symptoms of GWI, human-induced pluripotent stem cells (hiPSCs) derived from veterans with or without GWI were differentiated into forebrain glutamatergic neurons and then exposed to a Gulf War (GW) relevant toxicant regimen consisting of a sarin analog and cortisol, a human stress hormone. Elevated levels of total and phosphorylated tau, reduced microtubule acetylation, altered mitochondrial dynamics/transport, and decreased neuronal activity were observed in neurons exposed to the toxicant regimen. Some of the data are consistent with the possibility that some veterans may have been predisposed to acquire GWI. Wistar rats exposed to a similar toxicant regimen showed a mild learning and memory deficit, as well as cell loss and tau pathology selectively in the CA3 region of the hippocampus. These cellular responses offer a mechanistic explanation for the memory loss suffered by veterans with GWI and provide a cell-based model for screening drugs and developing personalized therapies for these veterans.

Assessment of Practices Affecting Racial and Ethnic COVID-19 Vaccination Equity in 10 Large US Cities.

CONTEXT: In the United States, COVID-19 vaccines have been unequally distributed between different racial and ethnic groups. Public reporting of race and ethnicity data for COVID-19 vaccination has the potential to help guide public health responses aimed at promoting vaccination equity. However, there is evidence that such data are not readily available. OBJECTIVES: This study sought to assess gaps and discrepancies in COVID-19 vaccination reporting in 10 large US cities in July 2021. DESIGN, SETTING, AND PARTICIPANTS: For the 10 cities selected, we collected COVID-19 vaccination and population data using publicly available resources, such as state health department Web sites and the US Census Bureau American Community Survey. We examined vaccination plans and news sources to identify initial proposals and evidence of implementation of COVID-19 vaccination best practices. MAIN OUTCOME MEASURE: We performed quantitative assessment of associations of the number of vaccination best practices implemented with COVID-19 racial and ethnic vaccination equity. We additionally assessed gaps and discrepancies in COVID-19 vaccination reporting between states. RESULTS: Our analysis did not show that COVID-19 vaccination inequity was associated with the number of vaccination best practices implemented. However, gaps and variation in reporting of racial and ethnic demographic vaccination data inhibited our ability to effectively assess whether vaccination programs were reaching minority populations. CONCLUSIONS: Lack of consistent public reporting and transparency of COVID-19 vaccination data has likely hindered public health responses by impeding the ability to track the effectiveness of strategies that target vaccine equity.

Recovery of kidney function after AKI because of COVID-19 in kidney transplant recipients.

Evidence on the evolution of graft function in kidney transplant recipients recovering from coronavirus disease-2019 (COVID-19) is lacking. This multicenter observational study evaluated the short-term clinical outcomes in recipients with acute kidney injury (AKI) secondary to COVID-19. Out of 452 recipients following up at five centers, 50 had AKI secondary to COVID-19. 42 recipients with at least 3-month follow-up were included. Median follow-up was 5.23 months [IQR 4.09-6.99]. Severe COVID-19 was seen in 21 (50%), and 12 (28.6%) had KDIGO stage 3 AKI. Complete recovery of graft function at 3 months was seen in 17 (40.5%) patients. Worsening of proteinuria was seen in 15 (37.5%) patients, and 4 (9.5%) patients had new onset proteinuria. Graft failure was seen in 6 (14.3%) patients. Kidney biopsy revealed acute tubular injury (9/11 patients), thrombotic microangiopathy (2/11), acute cellular rejection (2/11), and chronic active antibody-mediated rejection (3/11). Patients with incomplete recovery were likely to have lower eGFR and proteinuria at baseline, historical allograft rejection, higher admission SOFA score, orthostatic hypotension, and KDIGO stage 3 AKI. Baseline proteinuria and the presence of orthostatic hypotension independently predicted incomplete graft recovery. This shows that graft recovery may remain incomplete after AKI secondary to COVID-19.

Pharmacologically increasing microtubule acetylation corrects stress-exacerbated effects of organophosphates on neurons.

Many veterans of the 1990-1991 Gulf War contracted Gulf War Illness (GWI), a multisymptom disease that primarily affects the nervous system. Here, we treated cultures of human or rat neurons with diisopropyl fluorophosphate (DFP), an analog of sarin, one of the organophosphate (OP) toxicants to which the military veterans were exposed. All observed cellular defects produced by DFP were exacerbated by pretreatment with corticosterone or cortisol, which, in rat and human neurons, respectively, serves in our experiments to mimic the physical stress endured by soldiers during the war. To best mimic the disease, DFP was used below the level needed to inhibit acetylcholinesterase. We observed a diminution in the ratio of acetylated to total tubulin that was correctable by treatment with tubacin, a drug that inhibits HDAC6, the tubulin deacetylase. The reduction in microtubule acetylation was coupled with deficits in microtubule dynamics, which were correctable by HDAC6 inhibition. Deficits in mitochondrial transport and dopamine release were also improved by tubacin. Thus, various negative effects of the toxicant/stress exposures were at least partially correctable by restoring microtubule acetylation to a more normal status. Such an approach may have therapeutic benefit for individuals suffering from GWI or other neurological disorders linked to OP exposure.

Guillain Barré Syndrome, Systemic Lupus Erythematosus and Acute Intermittent Porphyria ­ A Deadly Trio.

Peripheral nervous system involvement occurs in 3-18% patients of systemic lupus erythematosus (SLE) cases. American College of Rheumatology (ACR) includes 19 neuropsychiatric syndromes for diagnosis of SLE divided into neurological syndromes of central, peripheral and autonomic nervous systems along with the psychiatric syndromes. Sensorimotor quadriparesis in a suspected case of SLE could be due to a Guillain Barré (GBS)-like illness, mononeuritis multiplex presenting as plexopathies, an anterior spinal artery syndrome or it can present like an acute transverse myelitis or hypokalemic periodic paralysis related to Sjogren's syndrome with renal tubular acidosis. We here report a case of a fulminant quadriparesis due to a SLE flare which subsequently was also found to be a case of Acute Intermittent Porphyria.

Immunodeficiency-Related Vaccine-Derived Poliovirus (iVDPV) Excretion in an Infant with Severe Combined Immune Deficiency with Spillover to a Parent.

In order to maintain the polio eradication status, it has become evident that the surveillance of cases with acute flaccid paralysis and of environmental samples must be urgently supplemented with the surveillance of poliovirus excretions among individuals with inborn errors of immunity (IEI). All children with IEI were screened for the excretion of poliovirus during a collaborative study conducted by the ICMR-National Institute of Virology, Mumbai Unit, ICMR-National Institute of Immunohaematology, and World Health Organization, India. A seven-month -old male baby who presented with persistent pneumonia and lymphopenia was found to have severe combined immune deficiency (SCID) due to a missense variant in the RAG1 gene. He had received OPV at birth and at 20 weeks. Four stool samples collected at 4 weekly intervals yielded iVDPV type 1. The child's father, an asymptomatic 32-year-old male, was also found to be excreting iVDPV. A haploidentical hematopoietic stem cell transplant was performed, but the child succumbed due to severe myocarditis and pneumonia three weeks later. We report a rare case of transmission of iVDPV from an individual with IEI to a healthy household contact, demonstrating the threat of the spread of iVDPV from persons with IEI and the necessity to develop effective antivirals.

Excess mortality in U.S. prisons during the COVID-19 pandemic.

U.S. prisons were especially susceptible to COVID-19 infection and death; however, data limitations have precluded a national accounting of prison mortality (including but not limited to COVID-19 mortality) during the pandemic. Our analysis of mortality data collected from public records requests (supplemented with publicly available data) from 48 Departments of Corrections provides the most comprehensive understanding to date of in-custody mortality during 2020. We find that total mortality increased by 77% in 2020 relative to 2019, corresponding to 3.4 times the mortality increase in the general population, and that mortality in prisons increased across all age groups (49 and under, 50 to 64, and 65 and older). COVID-19 was the primary driver for increases in mortality due to natural causes; some states also experienced substantial increases due to unnatural causes. These findings provide critical information about the pandemic's toll on some of the country's most vulnerable individuals while underscoring the need for data transparency and standardized reporting in carceral settings.

Conditions of Confinement in U.S. Carceral Facilities During COVID-19: Individuals Speak-Incarcerated During the COVID-19 Epidemic.

Objectives: We aimed to describe conditions of confinement among people incarcerated in the United States during the coronavirus disease 2019 (COVID-19) pandemic using a community-science data collection approach. Methods: We developed a web-based survey with community partners to collect information on confinement conditions (COVID-19 safety, basic needs, support). Formerly incarcerated adults released after March 1, 2020, or nonincarcerated adults in communication with an incarcerated person (proxy) were recruited through social media from July 25, 2020 to March 27, 2021. Descriptive statistics were estimated in aggregate and separately by proxy or formerly incarcerated status. Responses between proxy and formerly incarcerated respondents were compared using Chi-square or Fisher's exact tests based on α=0.05. Results: Of 378 responses, 94% were by proxy, and 76% reflected state prison conditions. Participants reported inability to physically distance (≥6 ft at all times; 92%), inadequate access to soap (89%), water (46%), toilet paper (49%), and showers (68%) for incarcerated people. Among those receiving prepandemic mental health care, 75% reported reduced care for incarcerated people. Responses were consistent between formerly incarcerated and proxy respondents, although responses by formerly incarcerated people were limited. Conclusions: Our findings suggest that a web-based community-science data collection approach through nonincarcerated community members is feasible; however, recruitment of recently released individuals may require additional resources. Our data obtained primarily through individuals in communication with an incarcerated person suggest COVID-19 safety and basic needs were not sufficiently addressed within some carceral settings in 2020-2021. The perspectives of incarcerated individuals should be leveraged in assessing crisis-response strategies.

Blood supply management amid COVID 19 pandemic: Challenges and strategies.

Background: Blood supply management amid the coronavirus disease 2019 (COVID-19) pandemic became a cause of concern. Blood donations in the pandemic reduced significantly because of travel restrictions and fear of contracting the virus by visiting blood banks. The WHO (World Health Organization), NACO (National AIDS Control Organization) and the SBTC (State Blood Transfusion Council) published guidelines to ensure the safety of blood donors and staff during the pandemic and to ensure correct procedures are followed. The blood centre physicians took measures for appropriate clinical use of blood and blood products, which reduced the number of transfusions and thereby safeguarded the blood supply for those who needed it the most. Materials and Methods: The study was conducted at the All India Institute of Medical Sciences, Bhopal, and 33 blood banks from 33 districts of Madhya Pradesh in collaboration with the National Health Mission and NACO. This was a retrospective study from pre-lockdown to lockdown and unlock phases 1 to 5 for nine months (February 2020 to October 2020) from 33 district-level blood centres of Central India, and the study compared the impact on blood supply from pre-pandemic time to the COVID-19 pandemic time. During the stipulated time period of 9 months, which included the pre-pandemic blood supply, the phases of lockdown when Section 144 was imposed in the country and the unlock phases, the management of transfusion services by the district blood banks of Central India during the COVID-19 pandemic was evaluated. The strategies adopted to maintain the blood supply and adequate inventory were studied. Results: The blood donation percentage in the district hospitals of Madhya Pradesh dropped drastically by 61.5% in February 2020 (pre-pandemic time) to 3.35% in April 2020 (COVID-19 pandemic). The nadir of fall in blood donations was seen in April 2020 (phase 1 of COVID-19 pandemic lockdown) with a zenith in February 2020 (pre-pandemic time). The minimum number of donations 8,037 (3.32%) in all 33 districts of Central India was seen in April, when the lockdown restrictions in the country were the strictest. In response to the reduced blood supply, the blood centres adopted strategies to maintain the inventory. Routine requests and inventory were monitored strictly for judicious and rational use of blood and its components. Conclusion: The motivation, dedication and the judicious use of blood products in addition to blood conservation strategies, first-in-first-out policy, maintaining an emergency stock of blood and strict monitoring by blood centre physicians led to the gradual upward trend of blood stocks, and hence blood supply management amid the COVID-19 pandemic could be sustained.

Examining COVID-19 mortality rates by race and ethnicity among incarcerated people in 11 U.S. state prisons (March-October 2021).

Background: Populations who are incarcerated have experienced disproportionately high coronavirus disease 2019 (COVID-2019) mortality rates compared to the general population. However, mortality rates by race/ethnicity from federal, state, and local carceral settings are largely unavailable due to unregulated reporting; therefore, racial/ethnic inequities have yet to be examined. We aimed to estimate coronavirus disease 2019 (COVID-19) mortality rates among individuals incarcerated in U.S. state prisons by race and ethnicity (RE). Methods: Public records requests to state Departments of Corrections were used to identify deaths from COVID-19 among incarcerated adults occurring from March 1-October 1, 2020. We requested race, ethnicity, and age specific data on deaths and custody populations; sufficient data to calculate age-adjusted rates were obtained for 11 state systems. Race and ethnic specific unadjusted deaths rates per 100,000 persons were calculated overall and by state, based on March 1, 2020 custody populations. Rate ratios (RR) and 95% confidence intervals (95%CI) compared aggregated age-adjusted death rates by race and ethnicity, with White individuals as the reference group. Results: Of all COVID-related deaths in U.S. prisons through October 2020, 23.35% (272 of 1165) were captured in our analyses. The average age at COVID-19 death was 63 years (SD = 10 years) and was significantly lower among Black (60 years, SD = 11 years) compared to White adults (66 years, SD = 10 years; p < 0.001). In age-standardized analysis, COVID-19 death rates were significantly higher among Black (RR = 1.93, 95% CI: 1.25-2.99), Hispanic (RR = 1.81, 95% CI: 1.10-2.96) and those of Other racial and ethnic groups (RR = 2.60, 95% CI: 1.01-6.67) when compared to White individuals. Conclusions: Age-standardized death rates were higher among incarcerated Black, Hispanic and those of Other racial and ethnic groups compared to their White counterparts. Greater data transparency from all carceral systems is needed to better understand populations at disproportionate risk of COVID-19 morbidity and mortality.

Cardiovascular Complications in Kidney Transplant Recipients with COVID-19: A Case Series.

Kidney transplant recipients (KTRs) are at a higher risk for developing severe COVID-19 which can be associated with cardiovascular complications. We studied five KTRs recipients infected with COVID-19 who developed severe cardiovascular complications. Two patients presented with ST segment myocardial infarction and two with clinically suspected myocarditis. One patient presented with atrial fibrillation. Two of these patients developed cardiogenic shock. Inflammatory markers were at peak during the event in four of these who had presented with severe COVID-19. Coronary angiography done in two patients with STEMI did not reveal any evidence of atherosclerotic coronary artery disease. Also, based on the cardiovascular (CV) risk estimation by Framingham score, four patients had low CV risk and one patient had intermediate CV risk. All five patients survived. Even with low CV risk, KTRs can develop myocardial injury and arrhythmias solely because of severe COVID-19.

High dependency renal unit for the management of COVID-19 in patients with severe acute or chronic kidney disease.

Coronavirus disease 2019 (COVID-19) in patients with severe impairment of kidney function is associated with high mortality. We evaluated the effect of high dependency renal unit (HDRU), with nephrologists as primary care physicians, as a quality improvement initiative for the management of these patients. This was a quasi-experimental observational study conducted at a tertiary care hospital in western India. Patients hospitalized for COVID-19 with pre-existing end-stage-renal-disease and those with severe AKI requiring dialysis (AKI-D) were included. For the first 2 months, these patients were cared for in medical wards designated for COVID-19, after which HDRU was set up for their management. With nephrologists as primary care providers, the 4 key components of care in HDRU included: care bundles focusing on key nephrology and COVID-19 related issues, checklist-based clinical monitoring, integration of multi-specialty care, and training of nurses and doctors. Primary outcome of the study was in-hospital mortality before and after institution of the HDRU care. Secondary outcomes were dialysis dependence in AKI-D and predictors of death. A total of 238 out of 4254 (5.59%) patients with COVID-19, admitted from 28th March to 30th September 2020, had severe renal impairment (116 AKI-D and 122 end-stage-renal-disease). 145 (62%) had severe COVID-19. From 28th May to 31st August 2020, these patients were managed in HDRU. Kaplan-Meier analysis showed significant improvement in survival during HDRU care [19 of 52 (36.5%) in pre-HDRU versus 35 of 160 (21.9%) in HDRU died, P ≤ .01]. 44 (67.7%) AKI-D survivors were dialysis dependent at discharge. Breathlessness and altered mental status at presentation, development of shock during hospital stay, and leukocytosis predicted mortality. HDRU managed by nephrologists is a feasible and potentially effective approach to improve the outcomes of patients with COVID-19 and severe renal impairment.

Clinical Course and Outcomes of COVID-19 in Kidney Transplant Recipients.

Introduction: Kidney transplant recipients (KTR) are at increased risk of morbidity and mortality due to coronavirus disease 2019 (COVID-19). This study aimed to explore the clinical characteristics and outcomes of COVID-19 in KTR. Methods: We reviewed the clinical profile, outcomes, and immunological responses of recipients admitted with COVID-19. We determined the risk factors for mortality and severe COVID-19. Results: Out of 452 recipients on follow-up, 60 were admitted with COVID-19. Prevalent comorbidities were hypertension (71%), diabetes (40%), lung disease (17%). About 27% had tuberculosis. The median Sequential Organ Failure Assessment score at presentation was 3 (interquartile range [IQR] 1-5). There was a high incidence of diarrhea (52%) and anemia (82%). Treatment strategies included antimetabolite withdrawal (85%), calcineurin inhibitor decrease or withdrawal (64%), increased steroids (53%), hydroxychloroquine (21%), remdesivir (28.3%), and tocilizumab (3.3%). Severe COVID-19 occurred in 34 (56.4%) patients. During a median follow-up of 42.5 days (IQR 21-81 days), 83% developed acute kidney injury (AKI) and eight (13%) died. Mortality was associated with the baseline graft dysfunction, hypoxia at admission, lower hemoglobin and platelets, higher transaminases, higher C reactive protein, diffuse radiological lung involvement, hypotension requiring inotropes, and Kidney Diseases Improving Global Outcomes (KDIGO) stage 3 AKI (univariate analysis). Around 57% of patients remained RT-PCR positive at the time of discharge. By the last follow-up, 66.6% of patients developed IgM (immunoglobulin M) antibodies and 82.3% of patients developed IgG antibodies. Conclusion: COVID-19 in kidney transplant recipients is associated with a high risk of AKI and significant mortality.

Mini-review: Microtubule sliding in neurons.

Microtubule sliding is an underappreciated mechanism that contributes to the establishment, organization, preservation, and plasticity of neuronal microtubule arrays. Powered by molecular motor proteins and regulated in part by static crosslinker proteins, microtubule sliding is the movement of microtubules relative to other microtubules or to non-microtubule structures such as the actin cytoskeleton. In addition to other important functions, microtubule sliding significantly contributes to the establishment and maintenance of microtubule polarity patterns in different regions of the neuron. The purpose of this article is to review the state of knowledge on microtubule sliding in the neuron, with emphasis on its mechanistic underpinnings as well as its functional significance.