Current use of estrogen-containing oral contraceptives or hormone therapy and risk of COVID-19 infection and hospitalization: a population-based cohort study.

This population-based cohort study evaluated the association between current use of oral contraceptives (OC) among women under 50 years (n=306,541), and hormone therapy (HT) among women aged 50 or older (n=323,203), and COVID-19 infection and hospitalization. Current OC/HT use was recorded monthly using prescription dispensing data. COVID-19 infections were identified March 2020-February 2021. COVID-19 infection and hospitalization were identified through diagnosis codes and laboratory tests. Weighted generalized estimating equations models estimated multivariable-adjusted odds ratios (aORs) for COVID-19 infection associated with time-varying OC/HT use. Among women with COVID-19, logistic regression models evaluated OC/HT use and COVID-19 hospitalization. Over 12 months, 11,727 (3.8%) women <50 years and 8,661 (2.7%) women ≥50 years experienced COVID-19 infections. There was no evidence of an association between OC use and infection (aOR=1.05; 95%CI: 0.97, 1.12). There was a modest association between HT use and infection (aOR=1.19; 95%CI: 1.03, 1.38). Women using OC had a 39% lower risk of hospitalization (aOR=0.61; 95%CI: 0.38, 1.00), but there was no association of HT use with hospitalization (aOR=0.89; 95%CI: 0.51, 1.53). These findings do not suggest a meaningfully greater risk of COVID-19 infection associated with OC or HT use. OC use may be associated with lower COVID-19 hospitalization risk.

Distribution of the misfolded isoform of the prion protein in peripheral tissues and spinal cord of Rocky Mountain elk (Cervus elaphus nelsoni) with naturally occurring chronic wasting disease.

Chronic wasting disease (CWD) is an infectious transmissible spongiform encephalopathy of cervids associated with the presence of a misfolded prion protein (PrPCWD). Progression of PrPCWD distribution has been described using immunohistochemistry and histologic changes in a single section of brain stem at the level of the obex resulting in scores from 0 (early) to 10 (terminal) in elk with naturally occurring CWD. Here we describe the spread and distribution of PrPCWD in peripheral tissues and spinal cord in 16 wild and 17 farmed Rocky Mountain elk (Cervus elaphus nelsoni) with naturally occurring CWD and correlate these findings with obex scores. Spinal cord and approximately 110 peripheral tissues were collected, processed, stained with hematoxylin and eosin, and immunolabeled with the anti-prion protein monoclonal antibody F99/97.6.1. The medial retropharyngeal and tracheobronchial lymph nodes were the first tissues to accumulate PrPCWD, followed by other lymphoid tissues, myenteric plexus, spinal cord, and finally tissues outside of the lymphatic and neural systems. However, the only significant histological lesion observed was mild spongiform encephalopathy in the dorsal column of the lower spinal cord in elk with an obex score of ≥9. Initial exposure to CWD prions may be through the respiratory system and spread appears to occur primarily via the autonomic nervous system. Therefore, we suggest using obex scores as a proxy for stage of disease progression and verifying with key peripheral tissues.

Bariatric Surgery is Associated With Reduced Risk of Breast Cancer in Both Premenopausal and Postmenopausal Women.

OBJECTIVE: This retrospective cohort study examined whether bariatric surgery is associated with reduced risk of breast cancer among pre- and postmenopausal women. BACKGROUND: Obesity is associated with increased risk of breast cancer, but the impact of weight loss on breast cancer risk has been difficult to quantify. METHODS: The cohort included obese (body mass index ≥35 kg/m) patients enrolled in an integrated health care delivery system between 2005 and 2012 (with follow-up through 2014). Female bariatric surgery patients (N = 17,998) were matched on body mass index, age, study site, and comorbidity index to 53,889 women with no bariatric surgery. Kaplan-Meier curves and Cox proportional hazards models were used to examine incident breast cancer up to 10 years after bariatric surgery. Pre- and postmenopausal women were examined separately, and further classified by estrogen receptor (ER) status. RESULTS: The analysis included 301 premenopausal and 399 postmenopausal breast cancer cases. In multivariable adjusted models, bariatric surgery was associated with a reduced risk of both premenopausal (HR = 0.72, 95% CI, 0.54-0.94) and postmenopausal (HR = 0.55, 95% CI, 0.42-0.72) breast cancer. Among premenopausal women, the effect of bariatric surgery was more pronounced among ER-negative cases (HR = 0.36, 95% CI, 0.16-0.79). Among postmenopausal women, the effect was more pronounced in ER-positive cases (HR = 0.52, 95% CI, 0.39-0.70). CONCLUSIONS: Bariatric surgery was associated with a reduced risk of breast cancer among severely obese women. These findings have significant public health relevance because the prevalence of obesity continues to rise, and few modifiable breast cancer risk factors have been identified, especially for premenopausal women.

Predictors of Hyperkalemia and Hypokalemia in Individuals with Diabetes: a Classification and Regression Tree Analysis.

BACKGROUND: Both hyperkalemia and hypokalemia can lead to cardiac arrhythmias and are associated with increased mortality. Information on the predictors of potassium in individuals with diabetes in routine clinical practice is lacking. OBJECTIVE: To identify predictors of hyperkalemia and hypokalemia in adults with diabetes. DESIGN: Retrospective cohort study, with classification and regression tree (CART) analysis. PARTICIPANTS: 321,856 individuals with diabetes enrolled in four large integrated health care systems from 2012 to 2013. MAIN MEASURES: We used a single serum potassium result collected in 2012 or 2013. Hyperkalemia was defined as a serum potassium ≥ 5.5 mEq/L and hypokalemia as < 3.5 mEq/L. Predictors included demographic factors, laboratory measurements, comorbidities, medication use, and health care utilization. KEY RESULTS: There were 2556 hypokalemia events (0.8%) and 1517 hyperkalemia events (0.5%). In univariate analyses, we identified concordant predictors (associated with increased probability of both hyperkalemia and hypokalemia), discordant predictors, and predictors of only hyperkalemia or hypokalemia. In CART models, the hyperkalemia "tree" had 5 nodes and a c-statistic of 0.76. The nodes were defined by prior potassium results and eGFRs, and the 5 terminal "leaves" had hyperkalemia probabilities of 0.2 to 7.2%. The hypokalemia tree had 4 nodes and a c-statistic of 0.76. The hypokalemia tree included nodes defined by prior potassium results, and the 4 terminal leaves had hypokalemia probabilities of 0.3 to 17.6%. Individuals with a recent potassium between 4.0 and 5.0 mEq/L, eGFR ≥ 45 mL/min/1.73m2, and no hypokalemia in the previous year had a < 1% rate of either hypokalemia or hyperkalemia. CONCLUSIONS: The yield of routine serum potassium testing may be low in individuals with a recent serum potassium between 4.0 and 5.0 mEq/L, eGFR ≥ 45 mL/min/1.73m2, and no recent history of hypokalemia. We did not examine the effect of recent changes in clinical condition or medications on acute potassium changes.

A population-based survey to assess the association between cannabis and quality of life among colorectal cancer survivors.

BACKGROUND: As more states legalize cannabis for medical and recreational use, people increasingly use cannabis to treat medical conditions and associated symptoms. The prevalence and utility of cannabis for cancer-related symptoms may be clarified by examining cannabis use among patients with a common cancer diagnosis. We aimed to determine the prevalence of cannabis use among colorectal cancer (CRC) survivors and its associations with quality of life (QoL) and cancer-related symptomatology. METHODS: A cross-sectional survey of patient-reported QoL outcomes and behaviors, including cannabis use, was conducted within the Patient Outcomes To Advance Learning network's (PORTAL) CRC Cohort. The cohort included a population-based sample of healthcare system members ≥18 years old diagnosed with adenocarcinoma of the colon or rectum from 2010 through 2016. We assessed the association between cannabis use and QoL using the European Organization for Research and Treatment of Cancer QLQ-C30 summary score. RESULTS: Of the 1784 respondents, 293 (16.4%) reported cannabis use following CRC diagnosis. Current tobacco smokers were more likely to use cannabis compared to former or never tobacco smokers (adjusted odds ratio [aOR] 2.71, 95% confidence interval [CI] 1.56 to 4.70). Greater alcohol use (> 4 drinks per month versus ≤4 drinks per month) was associated with cannabis use (aOR 2.17, 95% CI 1.65 to 2.85). There was an association between cannabis use and cancer stage at diagnosis, with stage 3 or 4 CRC patients more likely to use cannabis than stage 1 or 2 CRC patients (aOR 1.68, 95% CI 1.25 to 2.25). After adjusting for demographics, medical comorbidities, stage and site of CRC diagnosis, and prescription opioid use, people who used cannabis had significantly lower QoL than people who did not use cannabis (difference of - 6.14, 95% CI - 8.07 to - 4.20). CONCLUSION: Among CRC survivors, cannabis use was relatively common, associated with more advanced stages of disease, associated with tobacco and alcohol use, and not associated with better QoL. Clinicians should inquire about cannabis use among their patients and provide evidence-based recommendations for cancer-related symptoms.

Genes controlling polyunsaturated fatty acid synthesis are developmentally regulated in broiler chicks.

1. The objective of this study was to characterise the regulation of the pathways that synthesise long-chain polyunsaturated fatty acids (PUFA) on developing adipose deposits in broiler embryos and chicks. Subcutaneous adipose depots were harvested from embryos and embryonic d E13, E15 and E17. Subcutaneous, abdominal and crop (neck) adipose, as well as liver, were collected at 7 and 14 d post-hatch. 2. Targeted RNA sequencing was used to quantify expression of 6 elongation of very long-chain fatty acid (ELOVL) genes, two isoforms of stearoyl-CoA desaturase (SCD and SCD5), and three fatty acid desaturases (FADS1, FADS2, and FADS6) in each depot and in the liver. Expression levels of marker genes for fatty acid oxidation and adipogenesis (peroxisome proliferator-activated receptor gamma (PPARG)) were quantified. Fatty acid composition of subcutaneous adipose was analysed using gas chromatograph-mass spectrometry (GC/MS). 3. Genes in the PUFA synthetic pathway were differentially expressed across developmental ages and between depots. These include elongase and desaturase genes, that have not previously been characterised in chicken. Correlation analyses identified subsets of co-regulated genes and fatty acids and highlighted relationships that may influence adipose metabolism and development. 4. It was concluded that PUFA synthesis is an active and dynamically regulated pathway in developing adipose deposits in the broiler chick. These data highlighted potential novel roles for specific elongase and desaturase genes in adipose deposition and metabolism.

Bariatric Surgery and the Risk of Cancer in a Large Multisite Cohort.

OBJECTIVE: To determine whether bariatric surgery is associated with a lower risk of cancer. BACKGROUND: Obesity is strongly associated with many types of cancer. Few studies have examined the relationship between bariatric surgery and cancer risk. METHODS: We conducted a retrospective cohort study of patients undergoing bariatric surgery between 2005 and 2012 with follow-up through 2014 using data from a large integrated health insurance and care delivery systems with 5 study sites. The study included 22,198 subjects who had bariatric surgery and 66,427 nonsurgical subjects matched on sex, age, study site, body mass index, and Elixhauser comorbidity index. Multivariable Cox proportional-hazards models were used to examine incident cancer up to 10 years after bariatric surgery compared to the matched nonsurgical patients. RESULTS: After a mean follow-up of 3.5 years, we identified 2543 incident cancers. Patients undergoing bariatric surgery had a 33% lower hazard of developing any cancer during follow-up [hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.60, 0.74, P < 0.001) compared with matched patients with severe obesity who did not undergo bariatric surgery, and results were even stronger when the outcome was restricted to obesity-associated cancers (HR 0.59, 95% CI 0.51, 0.69, P < 0.001). Among the obesity-associated cancers, the risk of postmenopausal breast cancer (HR 0.58, 95% CI 0.44, 0.77, P < 0.001), colon cancer (HR 0.59, 95% CI 0.36, 0.97, P = 0.04), endometrial cancer (HR 0.50, 95% CI 0.37, 0.67, P < 0.001), and pancreatic cancer (HR 0.46, 95% CI 0.22, 0.97, P = 0.04) was each statistically significantly lower among those who had undergone bariatric surgery compared with matched nonsurgical patients. CONCLUSIONS: In this large, multisite cohort of patients with severe obesity, bariatric surgery was associated with a lower risk of incident cancer, particularly obesity-associated cancers, such as postmenopausal breast cancer, endometrial cancer, and colon cancer. More research is needed to clarify the specific mechanisms through which bariatric surgery lowers cancer risk.

Treatment patterns and survival differ between early-onset and late-onset colorectal cancer patients: the patient outcomes to advance learning network.

PURPOSE: Our objective was to describe differences in treatment patterns and survival between early-onset (< 50 years old) and late-onset colorectal cancer (CRC) patients in community-based health systems. METHODS: We used tumor registry and electronic health record data to identify and characterize patients diagnosed with adenocarcinoma of the colon or rectum from 2010 to 2014 at six US health systems in the patient outcomes to advance learning (PORTAL) network. We used logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing the distribution of tumor characteristics and treatment patterns in early-onset versus late-onset CRC. Cox regression models were used to estimate adjusted hazard ratios (HRs) and CIs comparing survival between early- and late-onset CRC patients. RESULTS: There were 1,424 early-onset and 10,810 late-onset CRC cases in our analyses. Compared to late-onset CRC, early-onset CRC was significantly associated with advanced-stage disease, high-grade histology, signet ring histology, and rectal or left colon location. After adjusting for differences in tumor and patient characteristics, early-onset patients were more likely than late-onset patients to have > 12 lymph nodes examined (OR 1.60, CI 1.37-1.87), to receive systemic therapy (chemotherapy or immunotherapy) within 6 months of diagnosis (OR 2.84, CI 2.40-3.37), and to have a reduced risk of CRC-specific death (HR 0.66, CI 0.56-0.79). CONCLUSIONS: Early-onset CRC is associated with aggressive tumor characteristics, distal location, and systemic therapy use. Despite some adverse risk factors, these patients tend to have better survival than older onset patients.

The Interferon Type I/III Response to Respiratory Syncytial Virus Infection in Airway Epithelial Cells Can Be Attenuated or Amplified by Antiviral Treatment.

UNLABELLED: Human respiratory syncytial virus (RSV) is a single-stranded RNA virus that causes acute, and occasionally fatal, lower respiratory illness in young infants, the elderly, and immunocompromised patients. Therapeutic interventions able to cut short viral replication and quickly return the airways to normal function are needed. An understanding of antiviral activities and their effects on host defense mechanisms is important for the design of safe and effective therapy. We targeted functionally and temporally distinct steps within the viral life cycle using small-molecule RSV inhibitors and studied their antiviral activities and their effects on innate interferon responses of airway epithelial cells in vitro. Antivirals acting upstream of RSV polymerase activity (i.e., compounds targeting the fusion protein or the nucleoprotein) reduced viral load immediately postinfection and partially attenuated interferon responses. In contrast, antivirals directed to the RSV polymerase demonstrated activity throughout the viral replication cycle and specifically modulated the RIG-I/mitochondrial antiviral signaling protein (MAVS)/TBK1/IRF3/interferon-stimulated gene (ISG) axis, causing either an upregulation or a downregulation of interferon responses, depending on the mechanism of polymerase inhibition. Notably, polymerase inhibition leading to the accumulation of abortive RNA products correlated with the amplification of interferon-stimulated genes to up to 10 times above normal infection levels. Understanding how antiviral activities and their modulation of innate immunity may affect recovery from RSV infection will help guide the development of safe and effective therapies. IMPORTANCE: RSV circulates seasonally, causing acute lower respiratory disease. Therapeutic interventions with efficacy throughout the viral replication cycle, rapid viral clearance, and prevention of potentially harmful inflammatory responses are desirable. Compounds targeting the RSV polymerase inhibited virus replication late in the viral life cycle and, depending on the functional domain targeted, either attenuated or amplified RIG-I and downstream interferon pathways in infected cells. These data will help guide the development of safe and effective therapies by providing new molecular evidence that the mechanism of inhibition by an antiviral compound can directly impact innate antiviral immune responses in the airway epithelium.

A phase II study of SB939, a novel pan-histone deacetylase inhibitor, in patients with translocation-associated recurrent/metastatic sarcomas-NCIC-CTG IND 200†.

BACKGROUND: A subgroup of sarcomas is characterized by defining chromosomal translocations, creating fusion transcription factor oncogenes. Resultant fusion oncoproteins associate with chromatin-modifying complexes containing histone deacetylases (HDAC), and lead to epigenetic transcriptional dysregulation. HDAC inhibitors were shown to be effective in vitro, reversing gene repression by these complexes, restoring PTEN expression and apoptosis via the PI3K/Akt/mTOR pathway. PATIENTS AND METHODS: SB939 is an oral inhibitor of classes 1 and 2 HDAC. Eligible patients with recurrent or metastatic translocation-associated sarcoma (TAS) by local pathology were treated with 60 mg/day every other day for 3 of 4 weeks. Central pathology review was conducted with fusion oncogenes characterized, and HDAC2 expression correlated with efficacy in pre-specified methods. RESULTS: Twenty-two patients were treated with a median of 2 cycles. Fourteen patients were assessable for response with confirmed specific chromosomal translocations; 8 had a best response of stable disease (SD) (median duration 5.4 months) with no confirmed objective responses. The 3-month progression-free survival (PFS) rate was 49%. Among those with HDAC2 score ≥5, 7/10 had SD, versus 0/3 with HDAC2 score <5. SB939 was considered as well tolerated with <10% patients experienced ≥grade 3 toxicity. CONCLUSION: This study was stopped prematurely due to prolonged unavailability of SB939. No objective responses were seen. Although the observed SD in HDAC2 high patients was interesting, due to the small sample size, no definitive conclusion can be drawn about the efficacy of SB939 in this patient population. CLINICAL TRIAL: NCT01112384.

The predicted role of steric specificity in crowding-mediated effects on reversible biomolecular association.

A fundamental question in biology is whether the presence of non-reacting macromolecules in the cytoplasm affects the rates and extents of reversible association reactions, a phenomenon often referred to as 'macromolecular crowding.' Under certain conditions, crowding has been proposed to dramatically alter the kinetics and thermodynamics of chemical reactions, making it difficult to quantitatively relate rates and extents of reactions measured in vitro to those occurring in vivo. In this work, we use Brownian dynamics simulation and Monte Carlo methods to (1) quantify the overall thermodynamic and kinetic effects of crowding by independently investigating each step of reversible bimolecular association (i.e. translational diffusion, steric specific binding, and dissociation), and (2) provide an explicit, quantitative investigation of how the degree of steric specificity of protein dimerization influences crowding-mediated effects on association and dissociation. We find that k on decreases by ∼2-fold for non-steric specific reactions, and increases by ∼3-fold for highly steric specific reactions. In addition, k off decreases by only ∼30%-60% in the presence of crowders, depending on the strength of the bond between the reactant pair, so that the equilibrium constant is increased by ∼4-fold, at most. These results suggest that crowding-mediated effects on globular protein dimerization reactions in the cytoplasm are modulated by the steric specificity of the reactants, and that reversible protein-protein association is relatively insensitive to the physical presence of crowders (i.e. steric repulsion effects in the cytoplasm) for crowders of similar size and shape to reactants over a range of volume fractions (0-0.3).

A phase II study of the HDAC inhibitor SB939 in patients with castration resistant prostate cancer: NCIC clinical trials group study IND195.

BACKGROUND: SB939 is a potent oral inhibitor of class 1, 2, and 4 histone deacetylases (HDACs). These three HDAC classes are highly expressed in castration resistant prostate cancer (CRPC) and associated with poor clinical outcomes. We designed a phase II study of SB939 in men with metastatic CRPC. METHODS: Patients received SB939 60 mg on alternate days three times per week for 3 weeks on a 4-week cycle. Primary endpoints were PSA response rate (RR) and progression-free survival (PFS). Secondary endpoints included objective response rate and duration; overall survival; circulating tumor cell (CTC) enumeration and safety. Exploratory correlative studies of the TMPRSS2-ERG fusion and PTEN biomarkers were also performed. RESULTS: Thirty-two patients were enrolled of whom 88 % had received no prior chemotherapy. The median number of SB939 cycles administered was three (range 1-8). Adverse events were generally grade 1-2, with five pts experiencing one or more grade three event. One patient died due to myocardial infarction. A confirmed PSA response was noted in two pts (6 %), lasting 3.0 and 21.6 months. In patients with measurable disease there were no objective responses. Six patients had stable disease lasting 1.7 to 8.0 months. CTC response (from ≥5 at baseline to <5 at 6 or 12 weeks) occurred in 9/14 evaluable patients (64 %). CONCLUSION: Although SB939 was tolerable at the dose/schedule given, and showed declines in CTC in the majority of evaluable patients, it did not show sufficient activity based on PSA RR to warrant further study as a single agent in unselected patients with CRPC.

Inhibition of CXCR7 extends survival following irradiation of brain tumours in mice and rats.

BACKGROUND: In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed. METHODS: We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro. RESULTS: CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs. CONCLUSIONS: These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.

Understanding the experience of caring for children with haemophilia: cross-sectional study of caregivers in the United States.

Congenital haemophilia is an inherited bleeding disorder typically diagnosed at birth or shortly thereafter. Haemophilia imposes a significant burden on patients and their caregivers. The aim of the study was to quantify the overall burden of haemophilia on caregivers in the USA using a novel disease-specific questionnaire and the previously validated CarerQol. Targeted literature review and a previous survey conducted by the authors was used to develop an online questionnaire with six burden domains of interest to caregivers (emotional stress, financial, sacrifice, medical management, child's pain and transportation) and several visual analogue scales (VAS). Content validity of the questionnaire was confirmed by three haemophilia caregivers. The study sample consisted of caregivers of children with haemophilia identified via a previously developed opt-in research database. Descriptive statistics were employed for demographic and clinical characteristics; a generalized linear model (GLM) was used to identify factors influencing caregiver burden. A total of 310 caregivers completed the survey (45.5% response rate). Most of the participating caregivers were mothers of a child with haemophilia (88%), between 35 and 44 years of age (48%), and with a college education or a postgraduate degree (63%). 'Child's pain' was identified as the most burdensome domain to caregivers (median score = 3.50 out of 5), followed by 'emotional stress' (2.67), 'financial' (2.40), 'transportation' (2.33), 'sacrifice' (2.17) and 'medical management' (2.00) domains. Although higher income exhibited a protective effect, episodes of bleeds, current presence of an inhibitor and lower caregiver productivity in the past month negatively affected caregiver burden per GLM results. Training and educational programs should potentially be developed to address caregiver burden.

Impact of haemophilia with inhibitors on caregiver burden in the United States.

Inhibitor development complicates haemophilia treatment and may impact caregiver burden. Compare overall burden of caregivers of children with/without inhibitors in the United States using a novel disease-specific questionnaire and the previously validated CarerQol. An on-line questionnaire with six burden domains (i.e. emotional stress, personal sacrifice, financial burden, medical management, child's pain, and transportation) and three visual analogue scales (VAS) was developed based upon a targeted literature review and previous survey findings. The study sample consisted of caregivers of children with haemophilia. The total burden score was calculated by summing the six individual burden domain scores. Higher scores represented greater burden. Descriptive statistics was performed to examine the sample characteristics. The Wilcoxon rank-sum test was performed to compare burden by inhibitor status. All variables were considered significant at P < 0.001. A total of 310 caregivers completed the survey; 30 of them reported caring for a child with an inhibitor. A majority of caregivers of children with inhibitors were mothers (80.0%) and between 35 and 44 years of age (56.7%). Caregivers of children with inhibitors reported significantly higher median total burden scores (99.0 vs. 76.5, P < 0.0001) and median burden-VAS scores (5.5 vs. 3.0, P < 0.0001), as compared to those caring for children without inhibitors. A similar trend was seen across all the six burden domains, with greatest difference in the median burden scores observed in the 'personal sacrifice' (3.2 vs. 2.0) and 'transportation' (3.3 vs. 2.3) domains. Burden of caregivers should be considered when assessing the psychosocial aspects of managing patients with inhibitors.

Association Between Patient Portal Activities and End-of-Life Outcomes Among Deceased Patients in the Last 12 Months of Life.

Objective: The objective of this study was to examine the association between portal use and end-of-life (EOL) outcomes in the last year of life. Methods: A retrospective cohort (n = 6,517) study at Kaiser Permanente Colorado among adults with serious illness deceased between January 1, 2016, and June 30, 2019. Portal use was categorized into engagement types: no use, nonactive, active without a provider, and active with a provider. EOL outcomes were hospitalizations in the month before death, last-year advance directive completion, and hospice use. Association between EOL outcomes and levels of portal use was assessed using χ2 statistics and generalized linear models. Results: Higher portal engagement types were associated with higher rates of hospitalizations (p = 0.0492), advance directive completion (p = 0.0226), and hospice use (p = 0.0070). Conclusion: Portal use in the last year of life was associated with increases in a poor EOL outcome, hospitalizations, and beneficial EOL outcomes, advance directives, and hospice care.

Development and Validation of Electronic Health Record Measures of Safety Planning Practices as Part of Zero Suicide Implementation.

OBJECTIVE: Safety planning for suicide prevention is an important quality metric for Zero Suicide implementation. We describe the development, validation, and application of electronic health record (EHR) programs to measure uptake of safety planning practices across six integrated healthcare systems as part of a Zero Suicide evaluation study. METHODS: Safety planning was documented in narrative notes and structured EHR templates using the Stanley Brown Safety Planning Intervention (SBSPI) in response to a high-risk cutoff score on the Columbia Suicide Severity Rating Scale (CSSRS). Natural Language Processing (NLP) metrics were developed and validated using chart review to characterize practices documented in narrative notes. We applied NLP to measure frequency of documentation in the narrative text and standard programming methods to examine structured SBSPI templates from 2010-2022. RESULTS: Chart reviews found three safety planning practices documented in narrative notes that were delivered to at least half of patients at risk: professional contacts, lethal means counseling for firearms, and lethal means counseling for medication access/storage. NLP methods were developed to identify these practices in clinical text with high levels of accuracy (Sensitivity, Specificity, & PPV ≥ 82%). Among visits with a high-risk CSSRS, 40% (Range 2-73% by health system) had an SBSPI template within 1 year of implementation. CONCLUSIONS: This is one of the first reports describing development of measures that leverage electronic health records to track use of suicide prevention safety plans. There are opportunities to use the methods developed here in future evaluations of safety planning.

Measuring safety planning delivery in real-world systems to understand quality of suicide prevention care is challenging.Natural Language Processing (NLP) methods effectively identified some safety planning practices in electronic health records (EHR) from all notes ensuring a comprehensive measurement, but NLP will require updates/testing for local documentation practices.Structured safety planning templates in the EHR using the Stanley Brown Safety Planning Intervention improve ease and accuracy of measurement but may be less comprehensive than NLP for capturing all instances of safety planning documentation.

Incidence and prognosis of resistant hypertension in hypertensive patients.

BACKGROUND: Despite a recent American Heart Association (AHA) consensus statement emphasizing the importance of resistant hypertension, the incidence and prognosis of this condition are largely unknown. METHODS AND RESULTS: This retrospective cohort study in 2 integrated health plans included patients with incident hypertension in whom treatment was begun between 2002 and 2006. Patients were followed up for the development of resistant hypertension based on AHA criteria of uncontrolled blood pressure despite use of ≥3 antihypertensive medications, with data collected on prescription filling information and blood pressure measurement. We determined incident cardiovascular events (death or incident myocardial infarction, heart failure, stroke, or chronic kidney disease) in patients with and without resistant hypertension with adjustment for patient and clinical characteristics. Among 205 750 patients with incident hypertension, 1.9% developed resistant hypertension within a median of 1.5 years from initial treatment (0.7 cases per 100 person-years of follow-up). These patients were more often men, were older, and had higher rates of diabetes mellitus than nonresistant patients. Over 3.8 years of median follow-up, cardiovascular event rates were significantly higher in those with resistant hypertension (unadjusted 18.0% versus 13.5%, P<0.001). After adjustment for patient and clinical characteristics, resistant hypertension was associated with a higher risk of cardiovascular events (hazard ratio, 1.47; 95% confidence interval, 1.33-1.62). CONCLUSIONS: Among patients with incident hypertension in whom treatment was begun, 1 in 50 patients developed resistant hypertension. Patients with resistant hypertension had an increased risk of cardiovascular events, which supports the need for greater efforts toward improving hypertension outcomes in this population.

Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings.

OBJECTIVE: Adult polyglucosan body disease (APBD) is an autosomal recessive leukodystrophy characterized by neurogenic bladder, progressive spastic gait, and peripheral neuropathy. Polyglucosan bodies accumulate in the central and peripheral nervous systems and are often associated with glycogen branching enzyme (GBE) deficiency. To improve clinical diagnosis and enable future evaluation of therapeutic strategies, we conducted a multinational study of the natural history and imaging features of APBD. METHODS: We gathered clinical, biochemical, and molecular findings in 50 APBD patients with GBE deficiency from Israel, the United States, France, and the Netherlands. Brain and spine magnetic resonance images were reviewed in 44 patients. RESULTS: The most common clinical findings were neurogenic bladder (100%), spastic paraplegia with vibration loss (90%), and axonal neuropathy (90%). The median age was 51 years for the onset of neurogenic bladder symptoms, 63 years for wheelchair dependence, and 70 years for death. As the disease progressed, mild cognitive decline may have affected up to half of the patients. Neuroimaging showed hyperintense white matter abnormalities on T2 and fluid attenuated inversion recovery sequences predominantly in the periventricular regions, the posterior limb of the internal capsule, the external capsule, and the pyramidal tracts and medial lemniscus of the pons and medulla. Atrophy of the medulla and spine was universal. p.Y329S was the most common GBE1 mutation, present as a single heterozygous (28%) or homozygous (48%) mutation. INTERPRETATION: APBD with GBE deficiency, with occasional exceptions, is a clinically homogenous disorder that should be suspected in patients with adult onset leukodystrophy or spastic paraplegia with early onset of urinary symptoms and spinal atrophy.