Very High Coronary Artery Calcium (≥1000) and Association With Cardiovascular Disease Events, Non-Cardiovascular Disease Outcomes, and Mortality: Results From MESA.

BACKGROUND: There are limited data on the unique cardiovascular disease (CVD), non-CVD, and mortality risks of primary prevention individuals with very high coronary artery calcium (CAC; ≥1000), especially compared with rates observed in secondary prevention populations. METHODS: Our study population consisted of 6814 ethnically diverse individuals 45 to 84 years of age who were free of known CVD from MESA (Multi-Ethnic Study of Atherosclerosis), a prospective, observational, community-based cohort. Mean follow-up time was 13.6±4.4 years. Hazard ratios of CAC ≥1000 were compared with both CAC 0 and CAC 400 to 999 for CVD, non-CVD, and mortality outcomes with the use of Cox proportional hazards regression adjusted for age, sex, and traditional risk factors. Using a sex-adjusted logarithmic model, we calculated event rates in MESA as a function of CAC and compared them with those observed in the placebo group of stable secondary prevention patients in the FOURIER clinical trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). RESULTS: Compared with CAC 400 to 999, those with CAC ≥1000 (n=257) had a greater mean number of coronary vessels with CAC (3.4±0.5), greater total area of CAC (586.5±275.2 mm2), similar CAC density, and more extensive extracoronary calcification. After full adjustment, CAC ≥1000 demonstrated a 4.71- (3.63-6.11), 7.57- (5.50-10.42), 4.86-(3.32-7.11), and 1.94-fold (1.57-2.41) increased risk for all CVD events, all coronary heart disease events, hard coronary heart disease events, and all-cause mortality, respectively, compared with CAC 0 and a 1.65- (1.25-2.16), 1.66- (1.22-2.25), 1.51- (1.03-2.23), and 1.34-fold (1.05-1.71) increased risk compared with CAC 400 to 999. With increasing CAC, hazard ratios increased for all event types, with no apparent upper CAC threshold. CAC ≥1000 was associated with a 1.95- (1.57-2.41) and 1.43-fold (1.12-1.83) increased risk for a first non-CVD event compared with CAC 0 and CAC 400 to 999, respectively. CAC 1000 corresponded to an annualized 3-point major adverse cardiovascular event rate of 3.4 per 100 person-years, similar to that of the total FOURIER population (3.3) and higher than those of the lower-risk FOURIER subgroups. CONCLUSIONS: Individuals with very high CAC (≥1000) are a unique population at substantially higher risk for CVD events, non-CVD outcomes, and mortality than those with lower CAC, with 3-point major adverse cardiovascular event rates similar to those of a stable treated secondary prevention population. Future guidelines should consider a less distinct stratification algorithm between primary and secondary prevention patients in guiding aggressive preventive pharmacotherapy.

The Development and Validation of Simplified Machine Learning Algorithms to Predict Prognosis of Hospitalized Patients With COVID-19: Multicenter, Retrospective Study.

BACKGROUND: The current COVID-19 pandemic is unprecedented; under resource-constrained settings, predictive algorithms can help to stratify disease severity, alerting physicians of high-risk patients; however, there are only few risk scores derived from a substantially large electronic health record (EHR) data set, using simplified predictors as input. OBJECTIVE: The objectives of this study were to develop and validate simplified machine learning algorithms that predict COVID-19 adverse outcomes; to evaluate the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and calibration of the algorithms; and to derive clinically meaningful thresholds. METHODS: We performed machine learning model development and validation via a cohort study using multicenter, patient-level, longitudinal EHRs from the Optum COVID-19 database that provides anonymized, longitudinal EHR from across the United States. The models were developed based on clinical characteristics to predict 28-day in-hospital mortality, intensive care unit (ICU) admission, respiratory failure, and mechanical ventilator usages at inpatient setting. Data from patients who were admitted from February 1, 2020, to September 7, 2020, were randomly sampled into development, validation, and test data sets; data collected from September 7, 2020, to November 15, 2020, were reserved as the postdevelopment prospective test data set. RESULTS: Of the 3.7 million patients in the analysis, 585,867 patients were diagnosed or tested positive for SARS-CoV-2, and 50,703 adult patients were hospitalized with COVID-19 between February 1 and November 15, 2020. Among the study cohort (n=50,703), there were 6204 deaths, 9564 ICU admissions, 6478 mechanically ventilated or EMCO patients, and 25,169 patients developed acute respiratory distress syndrome or respiratory failure within 28 days since hospital admission. The algorithms demonstrated high accuracy (AUC 0.89, 95% CI 0.89-0.89 on the test data set [n=10,752]), consistent prediction through the second wave of the pandemic from September to November (AUC 0.85, 95% CI 0.85-0.86) on the postdevelopment prospective test data set [n=14,863], great clinical relevance, and utility. Besides, a comprehensive set of 386 input covariates from baseline or at admission were included in the analysis; the end-to-end pipeline automates feature selection and model development. The parsimonious model with only 10 input predictors produced comparably accurate predictions; these 10 predictors (age, blood urea nitrogen, SpO2, systolic and diastolic blood pressures, respiration rate, pulse, temperature, albumin, and major cognitive disorder excluding stroke) are commonly measured and concordant with recognized risk factors for COVID-19. CONCLUSIONS: The systematic approach and rigorous validation demonstrate consistent model performance to predict even beyond the period of data collection, with satisfactory discriminatory power and great clinical utility. Overall, the study offers an accurate, validated, and reliable prediction model based on only 10 clinical features as a prognostic tool to stratifying patients with COVID-19 into intermediate-, high-, and very high-risk groups. This simple predictive tool is shared with a wider health care community, to enable service as an early warning system to alert physicians of possible high-risk patients, or as a resource triaging tool to optimize health care resources.

Characteristics associated with pediatric growth measurement collection in electronic medical records: a retrospective observational study.

BACKGROUND: Complete growth measurements are an essential part of pediatric care providing a proxy for a child's overall health. This study describes the frequency of well-child visits, documented growth measurements, and clinic and provider factors associated with measurement. METHODS: Retrospective cross-sectional study utilizing electronic medical records (EMRs) from primary care clinics between 2015 and 2017 in Manitoba, Canada. This study assessed the presence of recorded height, weight and head circumference among children (0-24 months) who visited one of 212 providers participating in the Manitoba Primary Care Research Network. Descriptive and multivariable logistic regression analyses assessed clinic, provider, and patient factors associated with children having complete growth measurements. RESULTS: Our sample included 4369 children. The most frequent growth measure recorded was weight (79.2% n = 3460) followed by height (70.8% n = 3093) and head circumference (51.4% n = 2246). 67.5% of children (n = 2947) had at least one complete growth measurement recorded (i.e. weight, height and head circumference) and 13.7% (n = 599) had complete growth measurements at all well-child intervals attended. Pediatricians had 2.7 higher odds of documenting complete growth measures within well-child intervals compared to family physicians (95% CI 1.8-3.8). Additionally, urban located clinics (OR 1.7, 95% CI 1.2-2.5), Canadian trained providers (OR 2.3, 95% CI 1.4-3.7), small practice size (OR 1.6, 95% CI 1.2-2.2) and salaried providers (OR 3.4, 95% CI 2.2-5.2) had higher odds of documented growth measures. CONCLUSIONS: Growth measurements are recorded in EMRs but documentation is variable based on clinic and provider factors. Pediatric growth measures at primary care appointments can improve primary prevention and surveillance of child health outcomes.

A Study of Novel Febrile Neutropenia Risk Factors Related to Bone Marrow or Immune Suppression, Barrier Function, and Bacterial Flora.

Background: Previously identified patient-level risk factors for chemotherapy-induced febrile neutropenia (FN) indicate several potential underlying pathogenic mechanisms, including bone marrow suppression, impaired neutrophil function, or disturbances of barrier function. This study evaluated whether additional clinical characteristics related to these pathogenic mechanisms were risk factors for FN. Patients and Methods: The study population included patients diagnosed with non-Hodgkin's lymphoma or breast, lung, colorectal, ovarian, or gastric cancer between 2000 and 2009 at Kaiser Permanente Southern California and treated with myelosuppressive chemotherapy. Those who received prophylactic granulocyte colony-stimulating factor or antibiotics were excluded. Potential risk factors of interest included surgery, radiation therapy, selected dermatologic/mucosal conditions, and use of antibiotics and corticosteroids. All data were collected using electronic medical records. Multivariable Cox models were used to evaluate associations between these factors and risk of FN in the first chemotherapy cycle, and adjusted using propensity score-based functions. Results: A total of 15,971 patients were included. Of these, 4.3% developed FN in the first chemotherapy cycle. Use of corticosteroids was significantly associated with increased risk of FN (adjusted hazard ratio [aHR], 1.53; 95% CI, 1.17-1.98). Selected dermatologic/mucosal conditions and intravenous antibiotic use were marginally associated with increased risk of FN (aHR, 1.40; 95% CI, 0.98-1.93, and 1.35; 95% CI, 0.97-1.87, respectively). Surgery, radiation therapy, and oral antibiotic use were not statistically significantly associated with FN. Conclusions: Dermatologic or mucosal conditions that might affect barrier integrity and use of corticosteroids and intravenous antibiotics prior to chemotherapy may increase risk of FN and should be considered in prophylaxis use and FN prediction modeling.

Impact of Strong Scattering Resonances on Ballistic and Diffusive Wave Transport.

The strong impact of scattering resonances on all the key transport parameters of classical waves in disordered media is demonstrated through ultrasonic experiments on monodisperse emulsions. Through accurate measurements of both ballistic and diffusive transport over a wide range of frequencies, we show that the group velocity is large near sharp resonances, whereas the energy velocity (as well as the diffusion coefficient) is significantly slowed down by resonant scattering delay. Excellent agreement between theory and experiment is found, elucidating the effects of resonant scattering on wave transport in both acoustics and optics.

Risk of Febrile Neutropenia Associated With Select Myelosuppressive Chemotherapy Regimens in a Large Community-Based Oncology Practice.

Background: NCCN has classified commonly used chemotherapy regimens into high (>20%), intermediate (10%-20%), or low (<10%) febrile neutropenia (FN) risk categories based primarily on clinical trial evidence. Many chemotherapy regimens, however, remain unclassified by NCCN or lack FN incidence data in real-world clinical practice. Patients and Methods: We evaluated incidence proportions of FN and grade 4 and 3/4 neutropenia during the first chemotherapy course among patients from Kaiser Permanente Southern California who received selected chemotherapy regimens without well-established FN risk. Patients given granulocyte colony-stimulating factor (G-CSF) prophylaxis were excluded. Sensitivity analyses were performed to account for FN misclassification and censoring. Results: From 2008 to 2013, 1,312 patients with breast cancer who received docetaxel and cyclophosphamide (TC; n=853) or docetaxel, carboplatin, and trastuzumab (TCH; n=459); 1,321 patients with colorectal cancer who received capecitabine and oxaliplatin (XELOX; n=401) or leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX6; n=920); 307 patients with non-Hodgkin's lymphoma who received bendamustine with or without rituximab; and 181 patients with multiple myeloma who received lenalidomide with or without dexamethasone were included. Crude FN risk was >20% for both breast cancer regimens (TC and TCH). Crude FN risks for XELOX, FOLFOX6, bendamustine, and lenalidomide were <10%; however, when potential FN misclassification and censoring were considered, FN risks were >10%. Conclusions: Our results support published literature highlighting the real-world, "high" FN risk of the TC and TCH regimens for breast cancer. There is strong suggestive evidence that FN risks for XELOX, FOLFOX6, bendamustine, and lenalidomide are >10%. Calculation of chemotherapy course-level FN incidence without controlling for differential censoring for patients who discontinued regimens early, or possible FN misclassification, might have resulted in bias toward an underestimation of the true FN risk. These findings help define FN risk of the selected regimens in the real-world setting and inform prophylactic G-CSF use.

Relation between ultrasonic properties, rheology and baking quality for bread doughs of widely differing formulation.

BACKGROUND: The objective was to evaluate whether an ultrasonic reflectance technique has predictive capacity for breadmaking performance of doughs made under a wide range of formulation conditions. Two flours of contrasting dough strength augmented with different levels of ingredients (inulin, oil, emulsifier or salt) were used to produce different bread doughs with a wide range of properties. Breadmaking performance was evaluated by conventional large-strain rheological tests on the dough and by assessment of loaf quality. The ultrasound tests were performed with a broadband reflectance technique in the frequency range of 0.3-6 MHz. RESULTS: Principal component analysis showed that ultrasonic attenuation and phase velocity at frequencies between 0.3 and 3 MHz are good predictors for rheological and bread scoring characteristics. CONCLUSIONS: Ultrasonic parameters had predictive capacity for breadmaking performance for a wide range of dough formulations. Lower frequency attenuation coefficients correlated well with conventional quality indices of both the dough and the bread. © 2016 Society of Chemical Industry.

Relationship between severity and duration of chemotherapy-induced neutropenia and risk of infection among patients with nonmyeloid malignancies.

PURPOSE: Chemotherapy-induced neutropenia (CIN) may increase infection risk for cancer patients; however, there is limited understanding on the quantitative relationships between severity and duration of CIN and infection risk. METHODS: This study combined individual data from adult cancer patients receiving no granulocyte colony-stimulating factor during the first chemotherapy cycle in six trials. We used area over the curve (AOC) of absolute neutrophil count (ANC) time-response curve (below different thresholds) to measure the combined effect of severity and duration of CIN. Time-dependent Cox proportional hazards models quantified the hazard of first infection associated with duration of grade 4 or grade 3/4 CIN and the hazard associated with AOC. RESULTS: We analyzed data from 271 patients who had small cell lung cancer, non-Hodgkin's lymphoma, head and neck cancer, or breast cancer; 63.8 % of the patients had advanced cancer, and 77.5 % received chemotherapy regimens with high risk of febrile neutropenia. In the first cycle, 18.8 % of the patients had infection-related hospitalizations. Each additional day patients had grade 3/4 or grade 4 CIN was associated with 28 % (95 % CI 7, 51 %) and 30 % (95 % CI 10, 54 %) increased risk of infection-related hospitalization, respectively. Each unit increase in AOC (day × 10(9)/L ANC), with threshold of ANC < 0.5 × 10(9)/L, was associated with a significantly increased risk of infection-related hospitalization (hazard ratio 1.98; 95 % CI 1.35, 2.90). CONCLUSIONS: Infection risk increases dramatically with each additional day of grade 3 or 4 CIN. Interventions limiting CIN severity and duration are of critical importance to reduce infection risk in cancer patients receiving chemotherapy.

Trends in anemia treatment among patients with five non-myeloid malignancies treated with chemotherapy in a large integrated health care delivery system in California, 2000-2013.

PURPOSE: The aim of this study is to examine treatment patterns for chemotherapy-induced anemia (CIA) between calendar periods when the changes in the US prescribing information, for erythropoiesis-stimulating agents (ESAs) took place. METHODS: Patients diagnosed with breast, lung, colorectal, ovarian, or gastric cancer (2000-2012) who developed grade 2+ CIA (hemoglobin (Hb) <10 g/dl) were identified from Kaiser Permanente Southern California Health Plan. We estimated the proportions of CIA episodes with ESA use, red blood cell (RBC) transfusion, or prescription nutritional supplements in three calendar periods: January 1, 2000-December 31, 2006 (P1), January 1, 2007-March 24, 2010 (P2), and March 25, 2010-June 30, 2013 (P3). Multivariable regressions were used to test the differences of CIA treatment approaches and Hb concentration prior to CIA treatment across these calendar periods. RESULTS: The proportions of CIA episodes with ESA use were 28 % in P1, 21 % in P2, and 3 % in P3. For RBC transfusion, they were 8 % in P1, 14 % in P2 and 16 % in P3. The trend of decreasing ESA use and increasing transfusion use were statistically significant. Relative to P1, the odds ratio (OR) was 0.69 (95% CI: 0.55, 0.86) for P2 and 0.08 (0.30, 0.88) for P3 for ESA use. For RBC transfusion, OR was 2.00 (1.56, 2.56) for P2 and 2.37 (1.88, 3.00) for P3. Use of prescription nutritional supplement was rare across calendar periods. There was a decreasing trend of Hb concentration prior to ESA use (p value <0.01), but no difference in Hb concentrations prior to transfusion. CONCLUSION: In the management of CIA, use of ESA has decreased over time, while use of RBC transfusion has increased.

The effect of chemotherapy-induced anemia on dose reduction and dose delay.

PURPOSE: To evaluate moderate (grade 2, hemoglobin <10 g/dl) and severe (grade 3+, hemoglobin <8 g/dl) anemia as potential risk factors for DDR in the first line course of chemotherapy. While chemotherapy-induced neutropenia has been shown to be associated with dose delay/reduction (DDR) in several studies, the effect of anemia is less well studied. METHODS: We identified 3955 Kaiser Permanente patients diagnosed with incident non-Hodgkin's lymphoma (n = 574), breast (n = 2043), lung (n = 463), gastric (n = 113), ovarian (n = 204), or colorectal cancers (n = 558) between 2010 and 2012. Generalized linear mixed effects models were used to study the effect of anemia in subsequent cycles, adjusting for demographics, comorbidities, chemotherapy cycle, neutropenia, thrombocytopenia, and liver and renal function. RESULTS: We found that moderate (grade 2) to severe (grade 3-4) anemia increased the risk of DDR in subsequent chemotherapy cycles [odds ratio (OR) = 1.46, 95 % CI (1.32, 1.62) and OR = 2.02 (1.41, 2.89)], respectively, compared to grade 1 or no anemia. Both stage I-III and IV patients with grade 2 or greater anemia were at higher risk for DDR than patients with grade 1 or no anemia [ORstage IV, grade 2 = 1.94 (1.58, 2.38); ORstage IV, grade 3/4 = 2.83 (1.42, 5.62) and ORstage I-III, grade 2 = 1.33 (1.18, 1.49); ORstage I-III, grade 3-4 = 1.81 (1.18, 2.76)]. CONCLUSIONS: These results provide insight into novel risk factors for chemotherapy dose modification that may inform clinicians on management strategies to optimize treatment outcomes.

The impact of primary prophylaxis with granulocyte colony-stimulating factors on febrile neutropenia during chemotherapy: a systematic review and meta-analysis of randomized controlled trials.

PURPOSE: The study aims to assess the relative efficacy of granulocyte colony-stimulating factor (G-CSF) products administered as primary prophylaxis (PP) to patients with cancer receiving myelosuppressive chemotherapy. METHODS: A systematic literature review identified publications (January 1990 to September 2013) of randomized controlled trials evaluating PP with filgrastim, pegfilgrastim, lenograstim, or lipegfilgrastim in adults receiving myelosuppressive chemotherapy for solid tumors or non-Hodgkin lymphoma. Direct, indirect, and mixed-treatment comparison (MTC) were used to estimate the odds ratio and 95 % credible interval of febrile neutropenia (FN) during cycle 1 and all cycles of chemotherapy combined without adjusting for differences in relative dose intensity (RDI) between study treatment arms. RESULTS: Twenty-seven publications representing 30 randomized controlled trials were included. Using MTC over all chemotherapy cycles, PP with filgrastim, pegfilgrastim, lenograstim, and lipegfilgrastim versus no G-CSF PP or placebo were associated with statistically significantly reduced FN risk. FN risk was also significantly reduced with pegfilgrastim PP versus filgrastim PP. Over all chemotherapy cycles, there was a numerical but statistically nonsignificant increase in the FN risk for lipegfilgrastim PP versus pegfilgrastim PP. Using MTC in cycle 1, PP with filgrastim, pegfilgrastim, and lipegfilgrastim versus no G-CSF PP or placebo were associated with statistically significantly reduced FN risk. CONCLUSIONS: In this meta-analysis, using MTC without adjustment for RDI, PP with all G-CSFs evaluated reduced the FN risk in patients receiving myelosuppressive chemotherapy. Future studies are needed to assess the influence of RDI on FN outcomes and to eliminate potential bias between G-CSF arms receiving more intensive chemotherapy than control arms.

Use of pegfilgrastim primary prophylaxis and risk of infection, by chemotherapy cycle and regimen, among patients with breast cancer or non-Hodgkin's lymphoma.

PURPOSE: This study aims to examine granulocyte colony-stimulating factor (G-CSF) prophylaxis by cancer type, chemotherapy regimen, and cycle in a real-world setting to assess if practice conforms to clinical guidelines, which recommend G-CSF prophylaxis every cycle when a patient's risk of febrile neutropenia (FN) is 20% or greater, and to describe the incidence of FN among patients who discontinue pegfilgrastim (peg) prophylaxis. METHODS: The cohort was selected from administrative claims data and includes adults diagnosed with non-Hodgkin's lymphoma (NHL) or breast cancer (BC) who began chemotherapy 2005-2010. RESULTS: About 83.2% of the 4,470 patients with BC treated with dose-dense doxorubicin, cyclophosphamide (ddAC), 83.6% of 2,197 patients with BC treated with docetaxel, doxorubicin, cyclophosphamide (TAC), and about 55.6% of the 2,722 patients with NHL treated with cyclophosphamide, doxorubicin, vincristine, with or without prednisone for 3-week cycles (CHOP-R Q3W) received peg prophylaxis in cycle 1. Among patients on these regimens who received peg prophylaxis in cycle 1 and were still on the regimen in cycle 4, about 90% received peg prophylaxis in that cycle. Among patients with BC or NHL who discontinued G-CSF, the incidence proportion of infection or FN varied by regimen and cycle, with a range from 0 to 14%. CONCLUSIONS: Despite clinical guidelines recommending G-CSF prophylaxis with chemotherapy regimens with a high risk of FN, many NHL and BC patients do not receive FN prophylaxis in cycle 1. However, among patients who receive G-CSF in cycle 1 and remain on the regimen, the majority appear to continue prophylaxis as indicated.

Granulocyte colony-stimulating factor (G-CSF) patterns of use in cancer patients receiving myelosuppressive chemotherapy.

PURPOSE: Febrile neutropenia (FN) is a common and serious complication of myelosuppressive chemotherapy. Guidelines recommend primary granulocyte colony-stimulating factors (G-CSF) prophylaxis (PPG) in patients with a high risk (HR, >20 %) of developing FN. We performed a retrospective analysis using a subset of the Medicare 5 % database to assess patterns of G-CSF use and FN occurrence among elderly cancer patients receiving myelosuppressive chemotherapy. METHODS: Chemotherapy courses for patients aged 65+ years were identified; only the first course was used for this analysis. Using clinical guidelines, chemotherapy regimens were classified as HR or intermediate risk (IR) for FN. The first administration of G-CSF was classified as either PPG (within the first 5 days of the first cycle), secondary prophylaxis, or reactive. RESULTS: Twelve thousand seven hundred seven courses across five tumor types were classified as having a HR or IR regimen. G-CSF was used in 24.5-73.8 % of patients receiving a HR FN regimen, with the highest use in breast cancer or NHL. Except for breast cancer (where PPG was used in 52.1 %), PPG was given in less than half of patients receiving a HR regimen. Depending on the tumor type, 4.8-22.6 % of patients with a HR regimen had a neutropenia-related hospitalization. CONCLUSIONS: Guidelines recommend PPG with HR FN regimens and older age (>65 years), an important risk factor for developing severe neutropenic complications. However, our results show that in this elderly population, PPG was not routinely used (range 4.8-52.1 %) in patients receiving HR FN regimens. Careful attention to FN risk factors, including chemotherapy regimen and patient age, is needed when planning treatment strategies.

Loss of Slc35a2 alters development of the mouse cerebral cortex.

Brain somatic variants in SLC35A2, an intracellular UDP-galactose transporter, are commonly identified mutations associated with drug-resistant neocortical epilepsy and developmental brain malformations, including focal cortical dysplasia type I and mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). However, the causal effects of altered SLC35A2 function on cortical development remain untested. We hypothesized that focal Slc35a2 knockout (KO) or knockdown (KD) in the developing mouse cortex would disrupt cortical development and change network excitability. Through two independent studies, we used in utero electroporation (IUE) to introduce CRISPR/Cas9/targeted guide RNAs or short-hairpin RNAs into the embryonic mouse brain at day 14.5-15.5 to achieve Slc35a2 KO or KD, respectively, from neural precursor cells. Slc35a2 KO or KD caused disrupted radial migration of electroporated neurons evidenced by heterotopic cells located in lower cortical layers and in the sub-cortical white matter. Slc35a2 KO in neurons did not induce changes in oligodendrocyte number, importantly suggesting that the oligodendroglial hyperplasia observed in MOGHE originates from distinct cell autonomous effects of Slc35a2 mutations. Adult KO mice were implanted with EEG electrodes for 72-hour continuous recording. Spontaneous seizures were not observed in focal Slc35a2 KO mice, but there was reduced seizure threshold following pentylenetetrazol injection. Here we demonstrate that focal Slc35a2 KO or KD in vivo disrupts corticogenesis through altered neuronal migration and that KO leads to reduced seizure threshold. Together these results demonstrate a direct causal role for SLC35A2 in cortical development.

Chronic comorbid conditions associated with risk of febrile neutropenia in breast cancer patients treated with chemotherapy.

Chemotherapy-induced febrile neutropenia (FN) is associated with increased patient mortality and health care costs. Comorbid conditions such as liver and renal dysfunction have been linked to increased risk of FN. However, the effects of other chronic comorbid conditions on risk of FN have not been well studied. To examine the association between chronic comorbid conditions and FN in breast cancer patients, we identified incident breast cancer patients from 2000 to 2009 treated with chemotherapy at Kaiser Permanente Southern California, a large managed care organization. Patients who received primary prophylactic granulocyte colony-stimulating factor (G-CSF) were excluded. We assessed history of comorbid conditions prior to cancer diagnosis using ICD-9 codes and disease registries. FN events were identified in the first chemotherapy cycle using a combination of ICD-9 codes and hospital discharge diagnoses. For each comorbid condition, propensity scores that included patient characteristics and other predisposing comorbid conditions were calculated and adjusted for in Cox models to determine associations between that comorbid condition and FN. We also evaluated secondary models that additionally adjusted for cancer stage, baseline absolute neutrophil count (ANC), chemotherapy regimen, and dose reductions. A total of 7,127 breast cancer patients were included; median age was 55 years, and the majority had localized (47 %) or regional (49 %) disease at diagnosis. In the first chemotherapy cycle, 335 (4.7 %) patients developed FN. Congestive heart failure (HR = 3.0; 95 % CI: 1.3-5.9), osteoarthritis (HR = 2.0; 95 % CI: 1.4-2.8), previous cancer (HR = 3.4; 95 % CI: 1.2-7.5), and thyroid disorder (HR = 1.6; 95 % CI: 1.1-2.3) were associated with increased risk of FN. These estimates were similar to those from secondary models that also adjusted for additional cancer and treatment-related covariates. Our findings suggest that several chronic comorbid conditions may be associated with risk of FN. This information, if confirmed by others, may aid clinical decision making with respect to use of prophylactic G-CSF during chemotherapy treatment.

Effect of micronutrient supplementation on disease progression in asymptomatic, antiretroviral-naive, HIV-infected adults in Botswana: a randomized clinical trial.

IMPORTANCE: Micronutrient deficiencies occur early in human immunodeficiency virus (HIV) infection, and supplementation with micronutrients may be beneficial; however, its effectiveness has not been investigated early in HIV disease among adults who are antiretroviral therapy (ART) naive. OBJECTIVE: To investigate whether long-term micronutrient supplementation is effective and safe in delaying disease progression when implemented early in adults infected with HIV subtype C who are ART-naive. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of supplementation with either daily multivitamins (B vitamins and vitamins C and E), selenium alone, or multivitamins with selenium vs placebo in a factorial design for 24 months. The study was conducted in 878 patients infected with HIV subtype C with a CD4 cell count greater than 350/µL who were not receiving ART at Princess Marina Hospital in Gaborone, Botswana, between December 2004 and July 2009. INTERVENTIONS: Daily oral supplements of B vitamins and vitamins C and E, selenium alone, or multivitamins plus selenium, compared with placebo. MAIN OUTCOMES AND MEASURES: Reaching a CD4 cell count less than 200/µL until May 2008; after this date, reaching a CD4 cell count of 250/µL or less, consistent with the standard of care in Botswana for initiation of ART at the time of the study. RESULTS: There were 878 participants enrolled and randomized into the study. All participants were ART-naive throughout the study. In intent-to-treat analysis, participants receiving the combined supplement of multivitamins plus selenium had a significantly lower risk vs placebo of reaching CD4 cell count 250/µL or less (adjusted hazard ratio [HR], 0.46; 95% CI, 0.25-0.85; P = .01; absolute event rate [AER], 4.79/100 person-years; censoring rate, 0.92; 17 events; placebo AER, 9.22/100 person-years; censoring rate, 0.85; 32 events). Multivitamins plus selenium in a single supplement, vs placebo, also reduced the risk of secondary events of combined outcomes for disease progression (CD4 cell count ≤250/µL, AIDS-defining conditions, or AIDS-related death, whichever occurred earlier [adjusted HR, 0.56; 95% CI, 0.33-0.95; P = .03; AER, 6.48/100 person-years; censoring rate, 0.90; 23 events]). There was no effect of supplementation on HIV viral load. Multivitamins alone and selenium supplementation alone were not statistically different from placebo for any end point. Reported adverse events were adjudicated as unlikely to be related to the intervention, and there were no notable differences in incidence of HIV-related and health-related events among study groups. CONCLUSIONS AND RELEVANCE: In ART-naive HIV-infected adults, 24-month supplementation with a single supplement containing multivitamins and selenium was safe and significantly reduced the risk of immune decline and morbidity. Micronutrient supplementation may be effective when started in the early stages of HIV disease.

Opportunistic CT Screening-Machine Learning Algorithm Identifies Majority of Vertebral Compression Fractures: A Cohort Study.

Vertebral compression fractures (VCF) are common in patients older than 50 years but are often undiagnosed. Zebra Medical Imaging developed a VCF detection algorithm, with machine learning, to detect VCFs from CT images of the chest and/or abdomen/pelvis. In this study, we evaluated the diagnostic performance of the algorithm in identifying VCF. We conducted a blinded validation study to estimate the operating characteristics of the algorithm in identifying VCFs using previously completed CT scans from 1200 women and men aged 50 years and older at a tertiary-care center. Each scan was independently evaluated by two of three neuroradiologists to identify and grade VCF. Disagreements were resolved by a senior neuroradiologist. The algorithm evaluated the CT scans in a separate workstream. The VCF algorithm was not able to evaluate CT scans for 113 participants. Of the remaining 1087 study participants, 588 (54%) were women. Median age was 73 years (range 51-102 years; interquartile range 66-81). For the 1087 algorithm-evaluated participants, the sensitivity and specificity of the VCF algorithm in diagnosing any VCF were 0.66 (95% confidence interval [CI] 0.59-0.72) and 0.90 (95% CI 0.88-0.92), respectively, and for diagnosing moderate/severe VCF were 0.78 (95% CI 0.70-0.85) and 0.87 (95% CI 0.85-0.89), respectively. Implementing this VCF algorithm within radiology systems may help to identify patients at increased fracture risk and could support the diagnosis of osteoporosis and facilitate appropriate therapy. © 2023 Amgen, Inc. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Trends in Palliative Care Utilization in Deceased Veterans With Heart Failure.

Background: Specialist-level palliative care in the final days does not allow time to alleviate symptoms and suffering. This analysis examined the change in the time from initial specialty-level palliative care to death among Veterans with heart failure. Methods: This retrospective cohort study examined Veterans with a diagnosis of heart failure (HF) who died between 2011 and 2021. We examined the decedents from each year as a separate cohort. The primary outcome was time from specialty-level palliative care (SPC) encounter to death in the year death occurred. Results: Of the cohort (n = 232,079), 56.5% did not receive SPC. Specialist-level palliative care >90 days before death more than doubled from 10.1% (2011) to 26.2% (2021), and Specialist-level palliative care in the last day of life was cut from 2.5% to 0.9%. Conclusion: For Veterans with HF, specialist-level palliative care moved earlier in the disease course and has a substantial growth opportunity.

Loss of Slc35a2 alters development of the mouse cerebral cortex.

Brain somatic variants in SLC35A2 are associated with clinically drug-resistant epilepsy and developmental brain malformations, including mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). SLC35A2 encodes a uridine diphosphate galactose translocator that is essential for protein glycosylation; however, the neurodevelopmental mechanisms by which SLC35A2 disruption leads to clinical and histopathological features remain unspecified. We hypothesized that focal knockout (KO) or knockdown (KD) of Slc35a2 in the developing mouse cortex would disrupt cerebral cortical development through altered neuronal migration and cause changes in network excitability. We used in utero electroporation (IUE) to introduce CRISPR/Cas9 and targeted guide RNAs or short-hairpin RNAs to achieve Slc35a2 KO or KD, respectively, during early corticogenesis. Following Slc35a2 KO or KD, we observed disrupted radial migration of transfected neurons evidenced by heterotopic cells located in lower cortical layers and in the sub-cortical white matter. Slc35a2 KO in neurons did not induce changes in oligodendrocyte number, suggesting that the oligodendroglial hyperplasia observed in MOGHE originates from distinct cell autonomous effects. Spontaneous seizures were not observed, but intracranial EEG recordings after focal KO showed a reduced seizure threshold following pentylenetetrazol injection. These results demonstrate that Slc35a2 KO or KD in vivo disrupts corticogenesis through altered neuronal migration.

Up-regulation of cholesterol synthesis pathways and limited neurodegeneration in a knock-in Sod1 mutant mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder affecting brain and spinal cord motor neurons. Mutations in the copper/zinc superoxide dismutase gene ( SOD1 ) are associated with ∼20% of inherited and 1-2% of sporadic ALS cases. Much has been learned from mice expressing transgenic copies of mutant SOD1, which typically involve high-level transgene expression, thereby differing from ALS patients expressing one mutant gene copy. To generate a model that more closely represents patient gene expression, we created a knock-in point mutation (G85R, a human ALS-causing mutation) in the endogenous mouse Sod1 gene, leading to mutant SOD1 G85R protein expression. Heterozygous Sod1 G85R mutant mice resemble wild type, whereas homozygous mutants have reduced body weight and lifespan, a mild neurodegenerative phenotype, and express very low mutant SOD1 protein levels with no detectable SOD1 activity. Homozygous mutants exhibit partial neuromuscular junction denervation at 3-4 months of age. Spinal cord motor neuron transcriptome analyses of homozygous Sod1 G85R mice revealed up-regulation of cholesterol synthesis pathway genes compared to wild type. Transcriptome and phenotypic features of these mice are similar to Sod1 knock-out mice, suggesting the Sod1 G85R phenotype is largely driven by loss of SOD1 function. By contrast, cholesterol synthesis genes are down-regulated in severely affected human TgSOD1 G93A transgenic mice at 4 months. Our analyses implicate dysregulation of cholesterol or related lipid pathway genes in ALS pathogenesis. The Sod1 G85R knock-in mouse is a useful ALS model to examine the importance of SOD1 activity in control of cholesterol homeostasis and motor neuron survival. SIGNIFICANCE STATEMENT: Amyotrophic lateral sclerosis is a devastating disease involving the progressive loss of motor neurons and motor function for which there is currently no cure. Understanding biological mechanisms leading to motor neuron death is critical for developing new treatments. Using a new knock-in mutant mouse model carrying a Sod1 mutation that causes ALS in patients, and in the mouse, causes a limited neurodegenerative phenotype similar to Sod1 loss-of-function, we show that cholesterol synthesis pathway genes are up-regulated in mutant motor neurons, whereas the same genes are down-regulated in transgenic SOD1 mice with a severe phenotype. Our data implicate dysregulation of cholesterol or other related lipid genes in ALS pathogenesis and provide new insights that could contribute to strategies for disease intervention.