DNA-PKcs has KU-dependent function in rRNA processing and haematopoiesis.

The DNA-dependent protein kinase (DNA-PK), which comprises the KU heterodimer and a catalytic subunit (DNA-PKcs), is a classical non-homologous end-joining (cNHEJ) factor1. KU binds to DNA ends, initiates cNHEJ, and recruits and activates DNA-PKcs. KU also binds to RNA, but the relevance of this interaction in mammals is unclear. Here we use mouse models to show that DNA-PK has an unexpected role in the biogenesis of ribosomal RNA (rRNA) and in haematopoiesis. The expression of kinase-dead DNA-PKcs abrogates cNHEJ2. However, most mice that both expressed kinase-dead DNA-PKcs and lacked the tumour suppressor TP53 developed myeloid disease, whereas all other previously characterized mice deficient in both cNHEJ and TP53 expression succumbed to pro-B cell lymphoma3. DNA-PK autophosphorylates DNA-PKcs, which is its best characterized substrate. Blocking the phosphorylation of DNA-PKcs at the T2609 cluster, but not the S2056 cluster, led to KU-dependent defects in 18S rRNA processing, compromised global protein synthesis in haematopoietic cells and caused bone marrow failure in mice. KU drives the assembly of DNA-PKcs on a wide range of cellular RNAs, including the U3 small nucleolar RNA, which is essential for processing of 18S rRNA4. U3 activates purified DNA-PK and triggers phosphorylation of DNA-PKcs at T2609. DNA-PK, but not other cNHEJ factors, resides in nucleoli in an rRNA-dependent manner and is co-purified with the small subunit processome. Together our data show that DNA-PK has RNA-dependent, cNHEJ-independent functions during ribosome biogenesis that require the kinase activity of DNA-PKcs and its phosphorylation at the T2609 cluster.

Differential phosphorylation of DNA-PKcs regulates the interplay between end-processing and end-ligation during nonhomologous end-joining.

Nonhomologous end-joining (NHEJ) is a major DNA double-strand break repair pathway that is conserved in eukaryotes. In vertebrates, NHEJ further acquires end-processing capacities (e.g., hairpin opening) in addition to direct end-ligation. The catalytic subunit of DNA-PK (DNA-PKcs) is a vertebrate-specific NHEJ factor that can be autophosphorylated or transphosphorylated by ATM kinase. Using a mouse model expressing a kinase-dead (KD) DNA-PKcs protein, we show that ATM-mediated transphosphorylation of DNA-PKcs regulates end-processing at the level of Artemis recruitment, while strict autophosphorylation of DNA-PKcs is necessary to relieve the physical blockage on end-ligation imposed by the DNA-PKcs protein itself. Accordingly, DNA-PKcs(KD/KD) mice and cells show severe end-ligation defects and p53- and Ku-dependent embryonic lethality, but open hairpin-sealed ends normally in the presence of ATM kinase activity. Together, our findings identify DNA-PKcs as the molecular switch that coordinates end-processing and end-ligation at the DNA ends through differential phosphorylations.

DNA-PKcs phosphorylation at the T2609 cluster alters the repair pathway choice during immunoglobulin class switch recombination.

The DNA-dependent protein kinase (DNA-PK), which is composed of the KU heterodimer and the large catalytic subunit (DNA-PKcs), is a classical nonhomologous end-joining (cNHEJ) factor. Naïve B cells undergo class switch recombination (CSR) to generate antibodies with different isotypes by joining two DNA double-strand breaks at different switching regions via the cNHEJ pathway. DNA-PK and the cNHEJ pathway play important roles in the DNA repair phase of CSR. To initiate cNHEJ, KU binds to DNA ends and recruits and activates DNA-PK. Activated DNA-PK phosphorylates DNA-PKcs at the S2056 and T2609 clusters. Loss of T2609 cluster phosphorylation increases radiation sensitivity but whether T2609 phosphorylation has a role in physiological DNA repair remains elusive. Using the DNA-PKcs5A mouse model carrying alanine substitutions at the T2609 cluster, here we show that loss of T2609 phosphorylation of DNA-PKcs does not affect the CSR efficiency. Yet, the CSR junctions recovered from DNA-PKcs5A/5A B cells reveal increased chromosomal translocations, extensive use of distal switch regions (consistent with end resection), and preferential usage of microhomology-all signs of the alternative end-joining pathway. Thus, these results uncover a role of DNA-PKcs T2609 phosphorylation in promoting cNHEJ repair pathway choice during CSR.

Phosphorylation at S2053 in Murine (S2056 in Human) DNA-PKcs Is Dispensable for Lymphocyte Development and Class Switch Recombination.

The classical nonhomologous end-joining (cNHEJ) pathway is a major DNA double-strand break repair pathway in mammalian cells and is required for lymphocyte development and maturation. The DNA-dependent protein kinase (DNA-PK) is a cNHEJ factor that encompasses the Ku70-Ku80 (KU) heterodimer and the large DNA-PK catalytic subunit (DNA-PKcs). In mouse models, loss of DNA-PKcs (DNA-PKcs-/- ) abrogates end processing (e.g., hairpin opening), but not end-ligation, whereas expression of the kinase-dead DNA-PKcs protein (DNA-PKcsKD/KD ) abrogates end-ligation, suggesting a kinase-dependent structural function of DNA-PKcs during cNHEJ. Lymphocyte development is abolished in DNA-PKcs-/- and DNA-PKcsKD/KD mice because of the requirement for both hairpin opening and end-ligation during V(D)J recombination. DNA-PKcs itself is the best-characterized substrate of DNA-PK. The S2056 cluster is the best-characterized autophosphorylation site in human DNA-PKcs. In this study, we show that radiation can induce phosphorylation of murine DNA-PKcs at the corresponding S2053. We also generated knockin mouse models with alanine- (DNA-PKcsPQR) or phospho-mimetic aspartate (DNA-PKcsSD) substitutions at the S2053 cluster. Despite moderate radiation sensitivity in the DNA-PKcsPQR/PQR fibroblasts and lymphocytes, both DNA-PKcsPQR/PQR and DNA-PKcsSD/SD mice retained normal kinase activity and underwent efficient V(D)J recombination and class switch recombination, indicating that phosphorylation at the S2053 cluster of murine DNA-PKcs (corresponding to S2056 of human DNA-PKcs), although important for radiation resistance, is dispensable for the end-ligation and hairpin-opening function of DNA-PK essential for lymphocyte development.

Kinase-dependent structural role of DNA-PKcs during immunoglobulin class switch recombination.

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is a classical nonhomologous end-joining (cNHEJ) factor. Loss of DNA-PKcs diminished mature B cell class switch recombination (CSR) to other isotypes, but not IgG1. Here, we show that expression of the kinase-dead DNA-PKcs (DNA-PKcsKD/KD ) severely compromises CSR to IgG1. High-throughput sequencing analyses of CSR junctions reveal frequent accumulation of nonproductive interchromosomal translocations, inversions, and extensive end resection in DNA-PKcsKD/KD , but not DNA-PKcs-/- , B cells. Meanwhile, the residual joints from DNA-PKcsKD/KD cells and the efficient Sµ-Sγ1 junctions from DNA-PKcs-/- B cells both display similar preferences for small (2-6 nt) microhomologies (MH). In DNA-PKcs-/- cells, Sµ-Sγ1 joints are more resistant to inversions and extensive resection than Sµ-Sε and Sµ-Sµ joints, providing a mechanism for the isotype-specific CSR defects. Together, our findings identify a kinase-dependent role of DNA-PKcs in suppressing MH-mediated end joining and a structural role of DNA-PKcs protein in the orientation of CSR.

New diagnosis of atypical ataxia-telangiectasia in a 17-year-old boy with T-cell acute lymphoblastic leukemia and a novel ATM mutation.

Ataxia-telangiectasia (A-T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM gene. Typically, it presents in early childhood with progressive cerebellar dysfunction along with immunodeficiency and oculocutaneous telangiectasia. An increased risk of malignancy is also associated with the syndrome and, rarely, may be the presenting feature in small children. We describe a 17-year-old boy with slurred speech, mild motor delays and learning disability diagnosed with atypical A-T in the setting of T-cell acute lymphoblastic leukemia. Suspicion for A-T was raised after review of a peripheral blood karyotype demonstrating rearrangements involving chromosomes 7 and/or 14. The diagnosis was confirmed after molecular testing identified a novel homozygous missense variant in ATM (c.5585T>A; p.Leu1862His) that resulted in protein instability and abolished serine/threonine protein kinase activity. To our knowledge, this is the first report of concurrent A-T and lymphoid malignancy diagnoses in an older child or adult with only mild neurological disease. Our experience suggests that screening for the disorder should be considered in any individual with lymphoid malignancy and neurological findings, especially as radiation and certain chemotherapy protocols are contraindicated in A-T.

Hematopoietic stem cell dysfunction underlies the progressive lymphocytopenia in XLF/Cernunnos deficiency.

XRCC4-like factor (XLF/Cernunnos) is a component of the nonhomologous end-joining (NHEJ) pathway of double-strand DNA break repair. XLF-deficient patients develop a severe progressive lymphocytopenia. Although NHEJ is required for V(D)J recombination and lymphocyte development, XLF-deficient mice have normal V(D)J recombination, highlighting the need for an alternative mechanism for the lymphocytopenia. Here, we report that XLF-deficient mice recapitulate the age-dependent lymphocytopenia of patients. We show that XLF deficiency leads to premature aging of hematopoietic stem cells (HSCs), measured by decreased functional capacity in transplantation assays, preferential myeloid reconstitution, and reduced self-renewal at a young age. We propose that premature aging of HSCs, together with previously reported defects in class-switch recombination and memory immune response, underlies the progressive and severe lymphocytopenia in XLF-deficient patients in the absence of measurable V(D)J recombination defects.

Mesoamerican nephropathy: geographical distribution and time trends of chronic kidney disease mortality between 1970 and 2012 in Costa Rica.

OBJECTIVES: Mesoamerican nephropathy is an epidemic of chronic kidney disease (CKD) unrelated to traditional causes, mostly observed in sugarcane workers. We analysed CKD mortality in Costa Rica to explore when and where the epidemic emerged, sex and age patterns, and relationship with altitude, climate and sugarcane production. METHODS: SMRs for CKD deaths (1970-2012) among population aged ≥20 were computed for 7 provinces and 81 counties over 4 time periods. Time trends were assessed with age-standardised mortality rates. We qualitatively examined relations between mortality and data on altitude, climate and sugarcane production. RESULTS: During 1970-2012, age-adjusted mortality rates in the Guanacaste province increased among men from 4.4 to 38.5 per 100,000 vs. 3.6-8.4 in the rest of Costa Rica, and among women from 2.3 to 10.7 per 100,000 vs. 2.6-5.0 in the rest of Costa Rica. A significant moderate excess mortality was observed among men in Guanacaste already in the mid-1970s, steeply increasing thereafter; a similar female excess mortality appeared a decade later, remaining stable. Male age-specific rates were high in Guanacaste for age categories ≥30, and since the late 1990s also for age range 20-29. The male spatiotemporal patterns roughly followed sugarcane expansion in hot, dry lowlands with manual harvesting. CONCLUSIONS: Excess CKD mortality occurs primarily in Guanacaste lowlands and was already present 4 decades ago. The increasing rates among Guanacaste men in hot, dry lowland counties with sugarcane are consistent with an occupational component. Stable moderate increases among women, and among men in counties without sugarcane, suggest coexisting environmental risk factors.

Heat-related symptoms in sugarcane harvesters.

BACKGROUND: Exposure to heat stress is a documented risk for Central American sugarcane harvesters. However, little is known about heat-related illness in this population. METHODS: This study examined the frequency of heat-related health effects among harvesters (n = 106) exposed to occupational heat stress compared to non-harvesters (n = 63). Chi-square test and gamma statistic were used to evaluate differences in self-reported symptoms and trends over heat exposure categories. RESULTS: Heat and dehydration symptoms (headache, tachycardia, muscle cramps, fever, nausea, difficulty breathing, dizziness, swelling of hands/feet, and dysuria) were experienced at least once per week significantly more frequently among harvesters. Percentages of workers reporting heat and dehydration symptoms increased in accordance with increasing heat exposure categories. CONCLUSIONS: A large percentage of harvesters are experiencing heat illness throughout the harvest demonstrating an urgent need for improved workplace practices, particularly in light of climate change and the epidemic of chronic kidney disease prevalent in this population.

Resolving the enigma of the mesoamerican nephropathy: a research workshop summary.

The First International Research Workshop on Mesoamerican Nephropathy (MeN) met in Costa Rica in November 2012 to discuss how to establish the extent and degree of MeN, examine relevant causal hypotheses, and focus efforts to control or eliminate the disease burden. MeN describes a devastating epidemic of chronic kidney disease of unknown origin predominantly observed among young male sugarcane cutters. The cause of MeN remains uncertain; however, the strongest hypothesis pursued to date is repeated episodes of occupational heat stress and water and solute loss, probably in combination with other potential risk factor(s), such as nonsteroidal anti-inflammatory drug and other nephrotoxic medication use, inorganic arsenic, leptospirosis, or pesticides. At the research workshop, clinical and epidemiologic case definitions were proposed in order to facilitate both public health and research efforts. Recommendations emanating from the workshop included measuring workload, heat, and water and solute loss among workers; quantifying nephrotoxic agents in drinking water and food; using biomarkers of early kidney injury to explore potential causes of MeN; and characterizing social and working conditions together with methods for valid data collection of exposures and personal risk factors. Advantages and disadvantages of different population study designs were detailed. To elucidate the etiology of MeN, multicountry studies with prospective cohort design, preferably integrating an ecosystem health approach, were considered the most promising. In addition, genetic, experimental, and mechanistic methods and designs were addressed, specifically the need for kidney biopsy analysis, studies in animal models, advances in biomarkers, genetic and epigenetic studies, a common registry and repository of biological and demographic data and/or specimens, and other areas of potential chronic kidney disease experimental research. Finally, in order to improve international collaboration on MeN, workshop participants agreed to establish a research consortium to link these Mesoamerican efforts to other efforts worldwide.

Heat exposure in sugarcane harvesters in Costa Rica.

BACKGROUND: Occupational heat stress is a major concern in sugarcane production and has been hypothesized as a causal factor of a chronic kidney disease epidemic in Central America. This study described working conditions of sugarcane harvesters in Costa Rica and quantified their exposure to heat. METHODS: Non-participatory observation and Wet Bulb Globe Temperatures (WBGT) according to Spanish NTP (Technical Prevention Notes) guidelines were utilized to quantify the risk of heat stress. OSHA recommendations were used to identify corresponding exposure limit values. RESULTS: Sugarcane harvesters carried out labor-intensive work with a metabolic load of 261 W/m² (6.8 kcal/min), corresponding to a limit value of 26° WBGT which was reached by 7:30 am on most days. After 9:15 am, OSHA recommendations would require that workers only work 25% of each hour to avoid health risks from heat. CONCLUSIONS: Sugarcane harvesters are at risk for heat stress for the majority of the work shift. Immediate action is warranted to reduce such exposures.

Kidney Function in Rice Workers Exposed to Heat and Dehydration in Costa Rica.

The aim of this study was to evaluate heat exposure, dehydration, and kidney function in rice workers over the course of three months, in Guanacaste, Costa Rica. We collected biological and questionnaire data across a three-month-period in male field (n = 27) and other (n = 45) workers from a rice company where chronic kidney disease of unknown origin (CKDu) is endemic. We used stepwise forward regression to determine variables associated with estimated glomerular filtration rate eGFR at enrollment and/or change in eGFR, and Poisson regression to assess associations with incident kidney injury (IKI) over the course of three months. Participants were 20−62 years old (median = 40 in both groups). Dehydration was common (≥37%) in both groups, particularly among other workers at enrollment, but field workers were more exposed to heat and had higher workloads. Low eGFR (<60 mL/min/1.73 m2) was more prevalent in field workers at enrollment (19% vs. 4%) and follow-up (26% vs. 7%). Field workers experienced incident kidney injury (IKI) more frequently than other workers: 26% versus 2%, respectively. Age (ß = −0.71, 95%CI: −1.1, −0.4), current position as a field worker (ß = −2.75, 95%CI: −6.49, 0.99) and past work in construction (ß = 3.8, 95%CI: −0.1, 7.6) were included in the multivariate regression model to explain eGFR at enrollment. The multivariate regression model for decreased in eGFR over three month included current field worker (ß = −3.9, 95%CI: −8.2, 0.4), current smoking (ß= −6.2, 95%CI: −13.7−1.3), dehydration (USG ≥ 1.025) at both visits (ß= −3.19, 95%CI: −7.6, 1.2) and pain medication at follow-up (ß= −3.2, 95%CI: −8.2, 1.95). Current fieldwork [IR (incidence rate) = 2.2, 95%CI 1.1, 5.8) and being diabetic (IR = 1.8, 95%CI 0.9, 3.6) were associated with IKI. Low eGFR was common in field workers from a rice company in Guanacaste, and being a field worker was a risk factor for IKI, consistent with the hypothesis that occupational heat exposure is a critical risk factor for CKDu in Mesoamerica.

Rapid evolution of fluoroquinolone-resistant Escherichia coli in Nigeria is temporally associated with fluoroquinolone use.

BACKGROUND: Antibiotic resistance has necessitated fluoroquinolone use but little is known about the selective forces and resistance trajectory in malaria-endemic settings, where selection from the antimalarial chloroquine for fluoroquinolone-resistant bacteria has been proposed. METHODS: Antimicrobial resistance was studied in fecal Escherichia coli isolates in a Nigerian community. Quinolone-resistance determining regions of gyrA and parC were sequenced in nalidixic acid resistant strains and horizontally-transmitted quinolone-resistance genes were sought by PCR. Antimicrobial prescription practices were compared with antimicrobial resistance rates over a period spanning three decades. RESULTS: Before 2005, quinolone resistance was limited to low-level nalixidic acid resistance in fewer than 4% of E. coli isolates. In 2005, the proportion of isolates demonstrating low-level quinolone resistance due to elevated efflux increased and high-level quinolone resistance and resistance to the fluoroquinolones appeared. Fluoroquinolone resistance was attributable to single nucleotide polymorphisms in quinolone target genes gyrA and/or parC. By 2009, 35 (34.5%) of isolates were quinolone non-susceptible with nine carrying gyrA and parC SNPs and six bearing identical qnrS1 alleles. The antimalarial chloroquine was heavily used throughout the entire period but E. coli with quinolone-specific resistance mechanisms were only detected in the final half decade, immediately following the introduction of the fluoroquinolone antibacterial ciprofloxacin. CONCLUSIONS: Fluoroquinolones, and not chloroquine, appear to be the selective force for fluoroquinolone-resistant fecal E. coli in this setting. Rapid evolution to resistance following fluoroquinolone introduction points the need to implement resistant containment strategies when new antibacterials are introduced into resource-poor settings with high infectious disease burdens.

Climate change, workplace heat exposure, and occupational health and productivity in Central America.

Climate change is increasing heat exposure in places such as Central America, a tropical region with generally hot/humid conditions. Working people are at particular risk of heat stress because of the intrabody heat production caused by physical labor. This article aims to describe the risks of occupational heat exposure on health and productivity in Central America, and to make tentative estimates of the impact of ongoing climate change on these risks. A review of relevant literature and estimation of the heat exposure variable wet bulb globe temperature (WBGT) in different locations within the region were used to estimate the effects. We found that heat stress at work is a real threat. Literature from Central America and heat exposure estimates show that some workers are already at risk under current conditions. These conditions will likely worsen with climate change, demonstrating the need to create solutions that will protect worker health and productivity.

Accuracy and reliability of buccal bone height and thickness measurements from cone-beam computed tomography imaging.

INTRODUCTION: Cone-beam computed tomography (CBCT) imaging has broadened opportunities for examining morphologic aspects of the craniofacial complex, including alveolar bone, but limitations of the technology have yet to be defined. Through the use of comparisons with direct measurements, the purpose of this study was to investigate the accuracy and reliability of buccal alveolar bone height and thickness measurements derived from CBCT images. METHODS: Twelve embalmed cadaver heads (5 female, 7 male; mean age: 77 years) were scanned with an i-CAT 17-19 unit (Imaging Sciences International, Hatfield, Pa) at 0.3 mm voxel size. Buccal alveolar bone height and thickness measurements of 65 teeth were made in standardized radiographic slices and compared with direct measurements made by dissection. All measurements were repeated 3 times by 2 independent raters and examined for intrarater and interrater reliability. Measurement means were compared with 2-tailed t tests. Agreement between direct and CBCT measurements was assessed by concordance correlation coefficients, Pearson correlation coefficients, and Bland-Altman plots. RESULTS: Intrarater reliability was high as were interrater correlations for all measurements (≥0.97) except CBCT buccal bone thickness (0.90). CBCT measurements did not differ significantly from direct measurements, and there was no pattern of underestimation or overestimation. The mean absolute differences were 0.30 mm in buccal bone height and 0.13 mm in buccal bone thickness with 95% limits of agreement of -0.77 to 0.81 mm, and -0.32 to 0.38 mm, respectively. Agreement between the 2 methods was higher for the measurements of buccal bone height than buccal bone thickness, as demonstrated by concordance correlation coefficients of 0.98 and 0.86, respectively. CONCLUSIONS: For the protocol used in this study, CBCT can be used to quantitatively assess buccal bone height and buccal bone thickness with high precision and accuracy. Comparing the 2 sets of CBCT measurements, buccal bone height had greater reliability and agreement with direct measurements than did the buccal bone thickness measurements.

Exertional rhabdomyolysis and acute kidney injury in endurance sports: A systematic review.

The increase of wide-spread participation in endurance events in sports such as open water swimming, cycling, running and triathlons, has given rise to a concern about potential implications for renal function and kidney health. This study aimed to delve into the findings on exertional rhabdomyolysis (ER) and acute kidney injury (AKI) in endurance sports, emphasizing the diagnostic criteria used, physical and environmental contextual conditions in which ER and AKI are reported. Following PRISMA guidelines for systematic reviews and meta-analysis, topic related studies were searched digital sources (from 2009 to 2020). Studies with biomarkers of ER and AKI reported in endurance or ultra-endurance events were included. A total of 43 publications (sample = 813) were extracted, and 345 (43.5%) individuals were diagnosed with ER (creatinine kinase > 5000 UI/L) and 130 (16.39%) with ER + AKI (creatinine ≥ 1.88 mg/dL). Out of the total cases of ER + AKI, 96.92% were in ultra-endurance runners. There were inconsistences between studies in diagnosis criteria for ER and AKI, which represented a difficulty in the interpretation of the data. Increased levels of muscle and kidney injury immediately after endurance events were reported, but after 5.86 days these levels usually returned to baseline. There is a lack of knowledge around the potential of repeated ER and AKI predisposing to long-term chronic kidney disease. More accurate markers for subclinical and functional AKI diagnosis are needed in the analysis of kidney health after endurance events. ER and AKI are serious clinical problems with significant morbidity. Further research may be in order to help define future prevention strategies.

Association Between Achieving Inpatient Glycemic Control and Clinical Outcomes in Hospitalized Patients With COVID-19: A Multicenter, Retrospective Hospital-Based Analysis.

OBJECTIVE: Diabetes and hyperglycemia are important risk factors for poor outcomes in hospitalized patients with coronavirus disease 2019 (COVID-19). We hypothesized that achieving glycemic control soon after admission, in both intensive care unit (ICU) and non-ICU settings, could affect outcomes in patients with COVID-19. RESEARCH DESIGN AND METHODS: We analyzed pooled data from the Glytec national database including 1,544 patients with COVID-19 from 91 hospitals in 12 states. Patients were stratified according to achieved mean glucose category in mg/dL (≤7.77, 7.83-10, 10.1-13.88, and >13.88 mmol/L; ≤140, 141-180, 181-250, and >250 mg/dL) during days 2-3 in non-ICU patients or on day 2 in ICU patients. We conducted a survival analysis to determine the association between glucose category and hospital mortality. RESULTS: Overall, 18.1% (279/1,544) of patients died in the hospital. In non-ICU patients, severe hyperglycemia (blood glucose [BG] >13.88 mmol/L [250 mg/dL]) on days 2-3 was independently associated with high mortality (adjusted hazard ratio [HR] 7.17; 95% CI 2.62-19.62) compared with patients with BG <7.77 mmol/L (140 mg/dL). This relationship was not significant for admission glucose (HR 1.465; 95% CI 0.683-3.143). In patients admitted directly to the ICU, severe hyperglycemia on admission was associated with increased mortality (adjusted HR 3.14; 95% CI 1.44-6.88). This relationship was not significant on day 2 (HR 1.40; 95% CI 0.53-3.69). Hypoglycemia (BG <70 mg/dL) was also associated with increased mortality (odds ratio 2.2; 95% CI 1.35-3.60). CONCLUSIONS: Both hyperglycemia and hypoglycemia were associated with poor outcomes in patients with COVID-19. Admission glucose was a strong predictor of death among patients directly admitted to the ICU. Severe hyperglycemia after admission was a strong predictor of death among non-ICU patients.

Glycemic Characteristics and Clinical Outcomes of COVID-19 Patients Hospitalized in the United States.

INTRODUCTION: Diabetes has emerged as an important risk factor for severe illness and death from COVID-19. There is a paucity of information on glycemic control among hospitalized COVID-19 patients with diabetes and acute hyperglycemia. METHODS: This retrospective observational study of laboratory-confirmed COVID-19 adults evaluated glycemic and clinical outcomes in patients with and without diabetes and/or acutely uncontrolled hyperglycemia hospitalized March 1 to April 6, 2020. Diabetes was defined as A1C ≥6.5%. Uncontrolled hyperglycemia was defined as ≥2 blood glucoses (BGs) > 180 mg/dL within any 24-hour period. Data were abstracted from Glytec's data warehouse. RESULTS: Among 1122 patients in 88 U.S. hospitals, 451 patients with diabetes and/or uncontrolled hyperglycemia spent 37.8% of patient days having a mean BG > 180 mg/dL. Among 570 patients who died or were discharged, the mortality rate was 28.8% in 184 diabetes and/or uncontrolled hyperglycemia patients, compared with 6.2% of 386 patients without diabetes or hyperglycemia (P < .001). Among the 184 patients with diabetes and/or hyperglycemia who died or were discharged, 40 of 96 uncontrolled hyperglycemia patients (41.7%) died compared with 13 of 88 patients with diabetes (14.8%, P < .001). Among 493 discharged survivors, median length of stay (LOS) was longer in 184 patients with diabetes and/or uncontrolled hyperglycemia compared with 386 patients without diabetes or hyperglycemia (5.7 vs 4.3 days, P < .001). CONCLUSION: Among hospitalized patients with COVID-19, diabetes and/or uncontrolled hyperglycemia occurred frequently. These COVID-19 patients with diabetes and/or uncontrolled hyperglycemia had a longer LOS and markedly higher mortality than patients without diabetes or uncontrolled hyperglycemia. Patients with uncontrolled hyperglycemia had a particularly high mortality rate. We recommend health systems which ensure that inpatient hyperglycemia is safely and effectively treated.