Increased frequency and mortality in persons with neurological disorders during COVID-19.

Determining the frequency and outcomes of neurological disorders associated with coronavirus disease 2019 (COVID-19) is imperative for understanding risks and for recognition of emerging neurological disorders. We investigated the susceptibility and impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among persons with premorbid neurological disorders, in addition to the post-infection incidence of neurological sequelae, in a case-control population-based cohort. Using health service data collected between 1 March 2020 and 30 June 2021, we constructed a cohort of SARS-CoV-2 RNA-positive (n = 177 892) and -negative (n = 177 800) adults who were age, sex and comorbidity matched and underwent RT-PCR testing at similar times. COVID-19-associated mortality rates were examined within the cohort. Neurological sequelae were analysed during the acute (<3 months) and the post-acute (3-9 months) phases post-infection. The risk of death was significantly greater in the SARS-CoV-2 RNA-positive (2140 per 100 000 person years) compared with RNA-negative (922 per 100 000 person years) over a follow-up of 9 months, particularly amongst those with premorbid neurological disorders: adjusted odds ratios (95% confidence interval) in persons with a prior history of parkinsonism, 1.65 (1.15-2.37); dementia, 1.30 (1.11-1.52); seizures, 1.91 (1.26-2.87); encephalopathy, 1.82 (1.02-3.23); and stroke, 1.74 (1.05-2.86). There was also a significantly increased risk for diagnosis of new neurological sequelae during the acute time phase after COVID-19, including encephalopathy, 2.0 (1.10-3.64); dementia, 1.36 (1.07-1.73); seizure, 1.77 (1.22-2.56); and brain fog, 1.96 (1.20-3.20). These risks persisted into the post-acute phase after COVID-19, during which inflammatory myopathy (2.57, 1.07-6.15) and coma (1.87, 1.22-2.87) also became significantly increased. Thus, persons with SARS-CoV-2 infection and premorbid neurological disorders are at greater risk of death, and SARS-CoV-2 infection was complicated by increased risk of new-onset neurological disorders in both the acute and post-acute phases of COVID-19.

Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome.

A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC. The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group. Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-ß and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.

Increased Virtual Visits to Physicians During the COVID-19 Pandemic and Estimated Impact on Physician Compensation: The Case of Lung and Colorectal Cancers, Chronic Obstructive Pulmonary Diseases, and Heart Failure in Alberta, Canada.

Introduction: The COVID-19 pandemic started in Alberta in March 2020 and significantly increased telehealth service use and provision reducing the risk of virus transmission. We examined the change in the number and proportion of virtual visits by physician specialty and condition (chronic obstructive pulmonary diseases [COPD], heart failure [HF], colorectal and lung cancers), as well as associated changes in physician compensation. Methods: A population-based design was used to analyze all processed physician claims comparing the number and proportion of virtual visits and associated physician billings relative to in-person between pre- (2019/2020) and intra-pandemic (2020/2021). Physician compensations were the claim amounts paid by the health insurance. Results: Pre-pandemic (intra-), there were 8,981 (8,897) lung cancer, 9,245 (9,029) colorectal, 37,558 (36,292) HF, and 68,270 (52,308) COPD patients. Each patient had totally 2.3-4.7 (of which 0.4-0.6% were virtual) general practitioner (GP) visits and 0.9-2.3 (0.2-0.7% were virtual) specialist visits per year pre-pandemic. The average number and proportion of per-patient virtual visits to GPs and specialists grew significantly pre- to intra-pandemic by 2,138-4,567%, and 2,201-7,104%, respectively. Given the lower fees of virtual compared with in-person visits, the reduction in physician compensation associated with the increased use of virtual care was estimated at $3.85 million, with $2.44 million attributed to specialist and $1.41 million to GP. Discussion: Utilization of telehealth increased significantly, while the physician billings per patient and physician compensation declined early in the pandemic in Alberta for the four chronic diseases considered. This study forms the basis for future study in understanding the impact of virtual care, now part of the fabric of health care delivery, on quality of care and patient safety, overall health service utilization (such as diagnostic imaging and other investigations), as well as economic impacts to patients, health care systems, and society.

Extreme Sensitivity of Fitness to Environmental Conditions: Lessons from #1BigBatch.

The phrase "survival of the fittest" has become an iconic descriptor of how natural selection works. And yet, precisely measuring fitness, even for single-celled microbial populations growing in controlled laboratory conditions, remains a challenge. While numerous methods exist to perform these measurements, including recently developed methods utilizing DNA barcodes, all methods are limited in their precision to differentiate strains with small fitness differences. In this study, we rule out some major sources of imprecision, but still find that fitness measurements vary substantially from replicate to replicate. Our data suggest that very subtle and difficult to avoid environmental differences between replicates create systematic variation across fitness measurements. We conclude by discussing how fitness measurements should be interpreted given their extreme environment dependence. This work was inspired by the scientific community who followed us and gave us tips as we live tweeted a high-replicate fitness measurement experiment at #1BigBatch.

Cystic fibrosis related diabetes (CFRD) in the era of modulators: A scoping review.

Cystic fibrosis-related diabetes (CFRD) is a common complication of CF that increases in incidence as patients age. Poor glycemic control has been shown to negatively impact lung function and weight, resulting in higher risk of recurrent pulmonary exacerbations. With the advent of highly effective modulator therapies (HEMT), patients with CF are living longer and healthier lives. Consequently, CFRD and its microvascular complications are rising in prominence, becoming one of the most urgent clinical concerns. As HEMT were developed with the primary focus of improving pulmonary outcomes, it is not clear from the original phase III studies what the short- or long-term benefits of modulators might be on CFRD development and trajectory. In this review, we will examine the pathophysiology of CFRD, summarize and synthesize the available evidence of HEMT impact on CFRD and describe the emerging research needs in this field.

"None of us are lying": an interpretive description of the search for legitimacy and the journey to access quality health services by individuals living with Long COVID.

BACKGROUND: Understanding of Long COVID has advanced through patient-led initiatives. However, research about barriers to accessing Long COVID services is limited. This study aimed to better understand the need for, access to, and quality of, Long COVID services. We explored health needs and experiences of services, including ability of services to address needs. METHODS: Our study was informed by the Levesque et al.'s (2013) "conceptual framework of access to health care." We used Interpretive Description, a qualitative approach partly aimed at informing clinical decisions. We recruited participants across five settings. Participants engaged in one-time, semi-structured, virtual interviews. Interviews were transcribed verbatim. We used reflexive thematic analysis. Best practice to ensure methodological rigour was employed. RESULTS: Three key themes were generated from 56 interviews. The first theme illustrated the rollercoaster-like nature of participants' Long COVID symptoms and the resulting impact on function and health. The second theme highlighted participants' attempts to access Long COVID services. Guidance received from healthcare professionals and self-advocacy impacted initial access. When navigating Long COVID services within the broader system, participants encountered barriers to access around stigma; appointment logistics; testing and 'normal' results; and financial precarity and affordability of services. The third theme illuminated common factors participants liked and disliked about Long COVID services. We framed each sub-theme as the key lesson (stemming from all likes and dislikes) that, if acted upon, the health system can use to improve the quality of Long COVID services. This provides tangible ways to improve the system based directly on what we heard from participants. CONCLUSION: With Long COVID services continuously evolving, our findings can inform decision makers within the health system to better understand the lived experiences of Long COVID and tailor services and policies appropriately.

COVID-19 hospitalization is associated with pulmonary/diffusion abnormalities but not post-acute sequelae of COVID-19 severity.

Coronavirus disease-19 (COVID-19) has resulted in much acute morbidity and mortality worldwide. There is now a growing recognition of the post-acute sequela of COVID-19, termed long COVID. However, the risk factors contributing to this condition remain unclear. Here, we address the growing controversy in the literature of whether hospitalization is a risk factor for long COVID. We found that hospitalization is associated with worse pulmonary restriction and reduction in diffusion capacity at 3 months post-infection. However, the impact on mental health, functional and quality of life is equally severe in those who have and have not been hospitalized during the acute infection. These findings suggest that hospitalization is a risk factor for pulmonary complications of long COVID but not the overall severity of long COVID.

ABCC4, ITPA, NUDT15, TPMT and their interaction as genetic predictors of 6-mercaptopurine intolerance in chinese patients with acute lymphoblastic leukemia.

Inter-individual variance in 6-mercaptopurine (6-MP) dose intensity is common in patients with acute lymphoblastic leukemia (ALL). We aimed to evaluate the association of common variants of ABCC4, ITPA, NUDT15, and TPMT with 6-MP dose intensity and toxicity in pediatric ALL patients. In this cohort, 13.8% of patients were intolerant to 6-MP with actual dosage less than 50% of scheduled dose. Twenty percent of patients were found to be heterozygous or homozygous mutated with NUDT15. NUDT15 c.415C > T and the genotype-predicted NUDT15 activity were significantly associated with 6-MP intolerance. TPMT*3C variants were not common in this cohort (2.8%). NUDT15 polymorphisms and genotype predicted NUDT15 activity were significantly associated with 6-MP dose intensity and leukopenia episodes. Combination of ABCC4 and ITPA variants (ABCC4 c.912G > T and ITPA c.94C > A) also showed significant positive association with 6-MP intolerance in Chinese children with ALL. Further study on pharmacogenetic screening for ALL patients to avoid 6-MP induced toxicity is recommended.Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1973628.

Exertional intolerance and dyspnea with preserved lung function: an emerging long COVID phenotype?

The COVID-19 pandemic has resulted in significant acute morbidity and mortality worldwide. There is now a growing recognition of the longer-term sequelae of this infection, termed "long COVID". However, little is known about this condition. Here, we describe a distinct phenotype seen in a subset of patients with long COVID who have reduced exercise tolerance as measured by the 6 min walk test. They are associated with significant exertional dyspnea, reduced health-related quality of life and poor functional status. However, surprisingly, they do not appear to have any major pulmonary function abnormalities or increased burden of neurologic, musculoskeletal or fatigue symptoms.

Double-unit unrelated cord blood transplantation for thalassemia major: Comparison with HLA-identical sibling bone marrow transplantation.

UCBT recipients with TM are at high risk of EF related to low number of stem cells and prior alloimmunization after multiple blood transfusions. Here, we evaluated the safety and efficacy of double-unit UCBT using TT-containing conditioning regimens in TM. Retrospective analysis of children who underwent double-unit UCBT for TM in the Prince of Wales Hospital between August 2007 and January 2017, and outcome of double-unit UCBT for TM was compared with outcome of HLA-matched sibling BMT. Ten patients, median age 4.2 years, received double-unit UCBT. All patients except one engrafted at a median of 19 days. None of the patients with successful engraftment had grade III or IV aGVHD. Among nine patients with successful engraftment, six of nine patients evaluable after day 100 developed cGVHD. All patients with cGVHD were well controlled after treatment with steroids and/or supportive care and maintained good quality of life. In comparison with patients receiving BMT, those given UCBT had slower platelet recovery, and more cGVHD. With a median follow-up of 272 months after BMT and 84 months after UCBT, the 8-year OS after BMT and UCBT was 92% and 90% (P = .84), whereas 8-year DFS after BMT and UCBT was 87% and 80% (P = .54). UCB could be an acceptable source of stem cells for transplantation of TM patients when HLA-matched family bone marrow donors are NA.

t(1;22)(p13;q13) Acute Megakaryoblastic Leukemia Complicated by Hepatic Fibrosis: Antifibrosis Therapy?

BACKGROUND: There is no established effective treatment for patients with t(1;22)(p13;q13) acute megakaryoblastic leukemia (AMKL) and hepatic fibrosis. OBSERVATION: Here we report the outcomes of 2 t(1;22)(p13;q13) AMKL patients with hepatic fibrosis. One patient died from liver failure despite the control of leukemia. The other patient was successfully treated with reduced-intensity chemotherapy and antifibrosis therapy with tretinoin and α-tocopheryl acetate, the hepatic fibrosis resolved and leukemia was in remission for 3 years. CONCLUSIONS: Reduced-intensity chemotherapy plus antifibrosis therapy with tretinoin and α-tocopheryl acetate could be a treatment option for these patients with t(1;22)(p13;q13) AMKL and hepatic fibrosis.

Value of flow cytometric analysis of peripheral blood samples in children diagnosed with acute lymphoblastic leukemia.

Diagnostic procedures in children with acute lymphoblastic leukemia (ALL) are typically performed under general anesthesia. Anticipation of the diagnosis based on findings in peripheral blood allows scheduling of the first dose of intrathecal chemotherapy and diagnostic bone marrow (BM) aspirate during a single anesthetic. We retrospectively compared paired results of peripheral blood (PB) flow cytometric analysis and BM evaluation in 383 children with ALL diagnosed consecutively at a single center and found very high concordance of results between both tests. We conclude that PB flow cytometry may help streamline planning of procedure-related anesthetics during diagnosis and early treatment of childhood ALL.

Primary Effusion Lymphoma (PEL)-Like Lymphoma in a Child With Congenital Immunodeficiency.

Primary effusion lymphoma (PEL) is a rare lymphoma that occurs more frequently in immunocompromised adults and has a poor survival. We report a 9-year-old female with combined immunodeficiency with an Epstein-Barr virus positive/human herpes virus 8 negative PEL-like lymphoma. The treatment with systemic chemotherapy for non-Hodgkin lymphoma, zidovudine, and interferon-α failed to control disease progression. This is the first reported pediatric case of PEL-like lymphoma. Increased diagnostic awareness and more effective treatment strategies are needed for this rare lymphoma.

Acute Leukemia in Down Syndrome Children in Hong Kong: Retrospective Review.

BACKGROUND: Children with Down syndrome (DS) are at higher risk of developing acute leukemia. Treatment continues to evolve as we accumulate better understanding of the distinctive clinical and biological features of acute leukemia in DS patients. PROCEDURE: A retrospective review of the clinical features, treatment outcomes, and survival of DS children with acute leukemia in Hong Kong from 1993 to 2013 was conducted. Patients were identified from the registry of the Hong Kong Pediatric Hematology and Oncology study group. RESULTS: This cohort included a total of 29 patients with DS. Ten were diagnosed with acute lymphoblastic leukemia and 19 had acute myeloid leukemia (AML). The mean follow-up duration was 8.3 years (range, 0.6 mo to 18.1 y). The 5-year overall survival and event-free survival for DS-acute lymphoblastic leukemia and DS-AML were 65.6%, 54.9%, 89.5%, and 89.5%, respectively. CONCLUSIONS: The clinical characteristics and treatment outcomes of DS patients with acute leukemia in Hong Kong were comparable with results from other international study groups. Patients with DS-AML had a better prognosis.

Digesting all the options: laboratory testing for celiac disease.

Celiac disease is a complex immune-mediated disorder that is triggered by ingestion of gluten and related proteins in genetically susceptible individuals. Under conditions of increased intestinal permeability, gluten-derived peptides can travel across the intestinal epithelium and undergo deamidation catalyzed by the tissue transglutaminase (TTG) enzyme. This renders them immunogenic in individuals expressing specific human leukocyte antigen (HLA) DQ heterodimers. The resulting immune response is characterized by the production of antibodies against both deamidated gliadin peptides (DGP) and TTG, generation of pro-inflammatory cytokines and activation of cytotoxic T cells. This response damages the intestinal epithelium resulting in the wide range of gastrointestinal and systemic symptoms observed in those with celiac disease. Celiac disease diagnosis has traditionally been based on biopsy and histological examination of the small intestine. While this approach is still considered the gold standard, it is invasive and susceptible to both false-positive and false-negative results. Several laboratory tests have become available to aid in the diagnosis and monitoring of celiac disease, and are the focus of this review. These include serological tests for celiac disease-specific antibodies such as anti-endomysial antibodies, anti-TTG antibodies and anti-DGP antibodies of both the immunoglobulin A (IgA) and immunoglobulin G (IgG) class, genetic tests to elucidate HLA DQ status and ancillary tests such as total IgA. While some have suggested that laboratory tests may replace intestinal biopsy in specific circumstances, others maintain that this procedure remains a critical component of celiac disease diagnosis. We review the analytical methodology, strengths, weaknesses, diagnostic performance and clinical utility of the various laboratory tests for celiac disease. Potential future markers and tests that are now considered obsolete are also discussed. Current clinical practice guidelines for the diagnosis and management of celiac disease from the European Society for Pediatric Gastroenterology, Hepatology and Nutrition, the American College of Gastroenterology and the World Gastroenterology Organisation are summarized, and important differences between these guidelines are highlighted.

Slit2 prevents neutrophil recruitment and renal ischemia-reperfusion injury.

Neutrophils recruited to the postischemic kidney contribute to the pathogenesis of ischemia-reperfusion injury (IRI), which is the most common cause of renal failure among hospitalized patients. The Slit family of secreted proteins inhibits chemotaxis of leukocytes by preventing activation of Rho-family GTPases, suggesting that members of this family might modulate the recruitment of neutrophils and the resulting IRI. Here, in static and microfluidic shear assays, Slit2 inhibited multiple steps required for the infiltration of neutrophils into tissue. Specifically, Slit2 blocked the capture and firm adhesion of human neutrophils to inflamed vascular endothelial barriers as well as their subsequent transmigration. To examine whether these observations were relevant to renal IRI, we administered Slit2 to mice before bilateral clamping of the renal pedicles. Assessed at 18 hours after reperfusion, Slit2 significantly inhibited renal tubular necrosis, neutrophil and macrophage infiltration, and rise in plasma creatinine. In vitro, Slit2 did not impair the protective functions of neutrophils, including phagocytosis and superoxide production, and did not inhibit neutrophils from killing the extracellular pathogen Staphylococcus aureus. In vivo, administration of Slit2 did not attenuate neutrophil recruitment or bacterial clearance in mice with ascending Escherichia coli urinary tract infections and did not increase the bacterial load in the livers of mice infected with the intracellular pathogen Listeria monocytogenes. Collectively, these results suggest that Slit2 may hold promise as a strategy to combat renal IRI without compromising the protective innate immune response.