Are There Disparities in Breast Reconstruction After Contralateral Prophylactic Mastectomy?

INTRODUCTION: Despite national guidelines against contralateral prophylactic mastectomy (CPM) in low- to moderate-risk breast cancer, CPM use continues to rise. Breast reconstruction improves health-related quality of life and satisfaction among women undergoing mastectomy. Given the lack of data regarding factors associated with reconstruction after CPM and the known benefits of reconstruction, we sought to investigate whether disparities exist in receipt of reconstruction after CPM. METHODS: The 2004-2017 National Cancer Database was queried to identify women diagnosed with breast cancer who underwent unilateral mastectomy with CPM. Patients were divided into two groups: those who underwent planned reconstruction at any timepoint and those who did not. A secondary analysis comparing types of reconstruction (tissue, implant, combined) was conducted. Patient, tumor, and demographic characteristics were analyzed using chi-square test and odds ratios were calculated using generalized estimating equations. RESULTS: The cohort included 1,73,249 women: 95,818 (55.3%) underwent reconstruction and 77,431 (45.7%) did not. Both the rate CPM and the proportion of women undergoing reconstruction after CPM increased between 2004 and 2017. Of the women who had reconstruction, 40,840 (51.7%) received implants, 29,807 (37.7%) had tissue, and 8352 (10.6%) had combined reconstruction. After adjusted analysis, factors associated with reconstruction were young age, Hispanic ethnicity, private insurance, and living in an area with the highest education and median income (P < 0.01). Patients who underwent reconstruction were less likely to have radiation (P < 0.01) and chemotherapy (P < 0.01), more likely to have stage I disease (P < 0.01), and to be treated at an integrated cancer center (P < 0.01). CONCLUSIONS: Reconstruction after CPM is disproportionately received by younger women, Hispanics, those with private insurance, and higher socioeconomic status and education. While the rate of reconstruction after CPM is increasing, there remain significant disparities. Conscious efforts must be made to eliminate these disparities, especially given the known benefits of reconstruction after mastectomy.

Risk of Fractures With Concomitant Use of Calcium Channel Blockers and Selective Serotonin Reuptake Inhibitors.

BACKGROUND: Despite their frequent concurrent use, little is known about the concomitant use of calcium channel blockers (CCBs) and selective serotonin reuptake inhibitors (SSRIs) on fracture risk. We compared risk of fractures in patients concomitantly treated with CCBs and SSRIs versus CCB-only users. We compared risk of fractures among concomitant CCB-SSRI users initiating cytochrome P450 3A4 (CYP3A4)-inhibiting SSRIs versus non-CYP3A4 inhibiting SSRIs. METHODS: This retrospective cohort study used IBM MarketScan commercial claims and Medicare Supplemental database (2007-2019). We included adults diagnosed with hypertension and depression, newly initiating SSRIs while being treated with CCBs (ie, concomitant CCB-SSRI users) and those who did not (ie, CCB-only users). Primary outcome was the first occurrence of any fracture. We used stabilized inverse probability of treatment weighting (sIPTW) based on propensity scores to balance baseline risk between groups. Cox proportional hazard regression modeling was used to compare fracture risk. RESULTS: We identified 191 352 concomitant CCB-SSRI and 956 760 CCB-only users (mean age = 56 years, 50.1% males). After sIPTW, compared with CCB-only users, CCBs-SSRIs users had a higher risk of fractures (hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.22-1.66). No difference in the risk of fractures between concomitant users of CCB-CYP3A4-inhibiting SSRIs and those of CCB-non-CYP3A4 inhibiting SSRIs (HR: 1.10, 95% CI: 0.87-1.40) was observed. CONCLUSION AND RELEVANCE: Short-term concomitant CCB-SSRI use was associated with increased fracture risk. Concomitant CCBs and CYP3A4-inhibiting SSRIs compared with CCBs and non-CYP3A4 inhibiting SSRIs use was not associated with increased risk.

Evaluation of upper airway characteristics in patients with and without sleep apnea using cone-beam computed tomography and computational fluid dynamics.

OBJECTIVE: To determine if upper airway characteristics and airway pressure change significantly between low risk, healthy non-OSA subjects, and OSA subjects during respiration using cone-beam computed tomography (CBCT) imaging and steady-state k-ω model computational fluid dynamics (CFD) fluid flow simulations, respectively. MATERIALS AND METHODS: CBCT scans were collected at both end-inhalation and end-exhalation for 16 low-risk non-OSA subjects and compared to existing CBCT data from 7 OSA subjects. The CBCT images were imported into Dolphin Imaging and the upper airway was segmented into stereolithography (STL) files for area and volumetric measurements. Subject models that met pre-processing criteria underwent CFD simulations using ANSYS Fluent Meshing (Canonsburg, PA) in which unstructured mesh models were generated to solve the standard dual equation turbulence model (k-ω). Objective and supplemental descriptive measures were obtained and statistical analyses were performed with both parametric and non-parametric tests to evaluate statistical significance at P < .05. RESULTS: Regarding area and volumetric assessments, there were statistically significant mean differences in Total Volume and Minimum CSA between non-OSA and OSA groups at inhalation and exhalation (P = .002, .003, .004, and .007), respectively. There were also statistically significant mean differences in volume and min CSA between the inhalation and exhalation for the non-OSA group (P < .001 and .002), respectively. CONCLUSION: While analysis of the CFD simulation was limited by the collected data available, a finding consistent with published literature was that the OSA subject group simulation models depicted the point of lowest pressure coinciding with the area of maximum constriction.

Childhood cancer survivors face markedly worse overall survival after diagnosis with breast cancer, melanoma, or colorectal cancer.

BACKGROUND: Childhood cancer survivors (CCS) are at elevated risk of secondary malignancies (SM). Enhanced screening for SM is recommended, but compliance is poor. We hypothesized that CCS with adult-onset SM (colorectal cancer [CRC], melanoma, or breast cancer [BC]) would present with more advanced disease and have decreased overall survival (OS). METHODS: The Surveillance, Epidemiology, and End Results Program was queried for patients diagnosed with cancer at age less than or equal to 18 also diagnosed with adult-onset CRC, melanoma, or BC. A cohort without a history of prior malignancy was likewise identified. Tumor features and clinical outcomes were compared. RESULTS: CCS with a SM (n = 224) were compared with patients without a childhood cancer history (n = 1,392,670). CCS were diagnosed younger (BC = 37.6 vs. 61.3, p < 0.01, CRC = 35.0 vs. 67.1, p < 0.01, melanoma = 29.6 vs. 61.3 years old, p < 0.01). CCS with BC were more likely to have Stage III or IV disease (25.2% vs. 16.5%, p = 0.01). Hormone-receptor expression also differed; CCS were less likely to develop Luminal A-type tumors (48.6% vs. 66.9%, p = 0.01). After age-adjustment, CCS had worse OS (Hazard ratio: CRC = 2.449, p < 0.01, melanoma = 6.503, p < 0.01, BC = 3.383, p < 0.01). CONCLUSION: CCS were younger when diagnosed with a SM. After age-adjustment, OS was diminished. Heightened surveillance may be necessary for CCS diagnosed with SM.

Evaluating the Long-Term Impact of a Cooperative Group Trial on Radiation Use and Adjuvant Endocrine Therapy Adherence Among Older Women.

BACKGROUND: Using long-term survival data from the C9343 trial as a temporal reference point, this study aimed to determine radiation therapy (RT) treatment trends for older patients with early-stage breast cancer. The study also examined rates of adherence to adjuvant endocrine therapy (AET). METHODS: The surveillance, epidemiology, and end results-medicare database was used to identify women with a diagnosis of breast cancer from 2007 through 2016. Bivariate associations were calculated to determine variable characteristics by time frame (group 1: 2007-2012 vs. group 2: 2013-2016). Multivariate logistic regression was used to estimate the effect of group on the RT use and AET adherence. The temporal rates for both RT and AET adherence over time were plotted. RESULTS: The final study cohort included 12,210 Medicare beneficiaries. Use of RT differed significantly between the groups, with a higher proportion omitting RT in the later period (25% of group 2 vs. 20% of group 1; p < 0.001). In both groups, after adjustment for covariates, the patients with RT omitted were statistically less likely to adhere to AET [group 1: odds ratio (OR), 0.74; p < 0.001 vs. group 2: OR, 0.66; p < 0.001]. CONCLUSION: This study, 15 years after publication of the of the C9343 trial results, showed minimal change in practice, with most older women receiving RT. Importantly, AET adherence was significantly lower in the non-RT group. For women who meet the criteria to have adjuvant RT omitted, nonadherence to AET could result in undertreatment of their breast cancer, and RT should not be considered overtreatment.

Long-term Impact of CALGB 9343 on Radiation Utilization.

BACKGROUND: The results of the Cancer and Leukemia Group B (CALGB) 9343 trial showed that radiation therapy (RT) did not improve survival for women older than 70 y with early-stage estrogen receptor + breast cancer treated with breast conserving surgery and adjuvant endocrine therapy. In 2005, guidelines were modified to allow for RT omission; however, minimal change in clinical practice has occurred. The aim of this study was to determine if CALGB long-term follow-up data have affected RT utilization, and to characterize the population still receiving RT after breast conserving surgery. METHODS: The Surveillance, Epidemiology, and End Results-Medicare database was used to identify women diagnosed with early-stage breast cancer from 2004 to 2015 who matched the CALGB 9343 inclusion criteria. Multivariate logistic regression was carried out to identify the factors that affect the receipt of radiation therapy. We also plotted the overall use of RT over time juxtaposed with the temporal trends of CALGB 9343 clinical trial data, guideline recommendations, and publishing of long-term survival data. RESULTS: The study cohort included 25,723 Medicare beneficiaries, of whom 20,328 (79%) received RT and 5395 (21%) did not receive RT. In a multivariate model, the frequency of RT omission increased over time, with those diagnosed in year 2015 being 2.72 times more likely to omit RT compared with those diagnosed in 2004 (95% confidence interval 2.31-3.19). CONCLUSIONS: This study investigated the impact of long-term CALGB 9343 data on clinical practice. The results of this study support results from previous studies, extend the dates of analysis, and indicate that after long-term follow-up of CALGB 9343 data, RT was less used, but overall trends did not dramatically decrease.

Use of Social Media in Health Communication: Findings From the Health Information National Trends Survey 2013, 2014, and 2017.

The number of social media users has increased substantially in the past decade, creating an opportunity for health-care professionals and patients to leverage social media for health communication. This study examines the recent use and predictors of social media for health communication in a nationally representative sample of US adults over time. We used 2013, 2014, and 2017 National Cancer Institute's Health Information National Trends Survey to identify respondents' use of social media for sharing health information or exchanging medical information with a health-care professional. We conducted bivariate analysis using the Pearson χ2 test to assess the association of respondents' basic demographic characteristics as well as health status and the use of social media for health communication. We performed multivariable logistic regression models to examine factors associated with the use of social media for health communication. We identified 4242 respondents (weighted sample size: 343 465 241 [2-year pooled sample]) who used social media for sharing health information and 4834 respondents (weighted sample size: 354 419 489 [2-year pooled sample]) who used social media for exchanging medical information. Multivariable analyses indicated the proportion of respondents who used social media for sharing health information has decreased (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.49-0.85, P = .002), while the use of social media for exchanging medical information with a health-care professional has increased (OR, 1.88; 95% CI, 1.09-3.26, P = .025). The younger population had significantly higher odds of using social media for health communication. The study found no racial/ethnic disparities in the use of social media for health communication. Use of social media for sharing health information has declined, while exchanging medical information with health-care professionals has increased. Future research is needed to determine how to engage the population in social media-based health interventions, particularly for older adults.

Excess Costs and Economic Burden of Obesity-Related Cancers in the United States.

BACKGROUND: Obesity is a significant risk factor of several cancers that imposes a substantial economic burden on US healthcare that remains to be quantified. We estimated the excess costs and economic burden of obesity-related cancers in the United States. METHODS: From the Medical Expenditure Panel Survey (2008-2015) data, we identified 19 405 cancer survivors and 175 498 non-cancer individuals. We estimated annual health expenditures using generalized linear regression with log link and gamma distribution by cancer types (stratified by 11 obesity-related cancers and other cancer types), controlling for sociodemographic and clinical characteristics. All cost estimates were adjusted to 2015 USD value. RESULTS: The average annual total health expenditures were $21 503 (95% CI, $20 946-$22 061) for those with obesity-related cancer and $13 120 (95% CI, $12 920-$13 319) for those with other cancer types. There was a positive association between body mass index and health expenditures among cancer survivors: for each additional 5-unit increase in body mass index, the average predicted expenditures increase by $1503 among those with obesity-related cancer and by $722 among those with other cancers. With adjustments for sociodemographic and clinical characteristics, the mean incremental expenditures of treating obesity-related cancer were 2.1 times higher than those of other cancers ($4492 vs $2139) and more considerable among the non-elderly cancer population. Obesity-related cancers accounted for nearly 43.5% of total direct cancer care expenditures, estimated at $35.9 billion in 2015. CONCLUSION: The economic burden of obesity-related cancer in the United States is substantial. Our findings suggest a need for the inclusion of comprehensive obesity prevention and treatment in cancer care.

Implementation process for comprehensive medication review in the community pharmacy setting.

OBJECTIVES: To (1) describe the implementation process for comprehensive medication reviews (CMRs) among community pharmacies (e.g., processes for prioritizing patients, staffing, and information collection) and (2) examine factors associated with community pharmacies' CMR information collection process. METHODS: A survey was administered to the pharmacist responsible for implementation of CMRs (i.e., the lead pharmacist) in the community pharmacy (n = 87). The survey included questions about pharmacy characteristics, satisfaction with the NC community pharmacy enhanced services network (NC-CPESN) program, and implementation of CMRs. Frequencies and means were calculated to describe the sample characteristics and pharmacies' CMR implementation process. A multiple linear regression was conducted to examine which characteristics were associated with the CMR information collection process. RESULTS: The majority of pharmacies in the sample were either independently owned single stores (46.5%) or multiple stores under the same independent ownership (41.6%). Most pharmacies used pharmacists (97.7%) or pharmacy technicians (65.5%) for patient outreach for CMRs. A small percentage of pharmacies used administrative staff to conduct patient outreach for CMRs (9.2%). Information for prescription medications (89.5%), indication (80%), and medication adherence (81.1%) was routinely collected. Information such as date of last dose for prescription medications (48.4%) and lifestyle factors, such as physical activity (21.1%), diet (29.5%), and alcohol (31.6%), was collected less routinely. Having a clinical pharmacist (P = 0.025) and pharmacist overlap hours (P = 0.009) significantly improved the CMR information collection process. CONCLUSION: Although CMRs are important interventions for improving patient outcomes, more guidance is needed on how to effectively implement them. This would allow the process to be efficient and assure implementation with fidelity across all community pharmacies. In addition, staffing appears to influence the quality of CMR information collection. Future research is warranted on CMR implementation to develop efficient staffing models and standardize the process of information collection.

Risk for Medication Nonadherence Among Medicaid Enrollees With Fibromyalgia: Development of a Validated Risk Prediction Tool.

OBJECTIVE: To develop and validate a risk assessment tool called the Prescription Medication Non-Adherence Prediction Tool (Rx-NAPT) to predict medication nonadherence in patients with fibromyalgia. METHODS: This was a retrospective cohort study using claims data from South Carolina Medicaid. Patients with fibromyalgia who were ≥18 years old and who had filled at least 1 prescription medication for pregabalin, duloxetine, or milnacipran from January 1, 2005, through June 30, 2011 were included. Medication possession ratios (MPRs) were calculated to classify patients as adherent (MPR ≥ 80%) or nonadherent (MPR < 80%). Multivariable logistic models using 100 bootstrap replications (with replacement) were used to identify factors associated with medication nonadherence, including age, gender, race, days' supply, medication type, and fibromyalgia-related comorbidity score. Weighted ß coefficients of the predictors were used to create the Rx-NAPT. Youden's J statistic was used to classify nonadherent patients into different levels of risk. RESULTS: The study sample comprised 6,626 patients with fibromyalgia, where 4,804 (72.50%) were non-adherent and 1,822 (27.50%) were adherent to their prescribed medication(s). Logistic regression models showed that 7 predictors (gender, age, race, fibromyalgia-related comorbidity score, medication type, health maintenance organization coverage, emergency room visit) were statistically significant in ≥50% of the bootstrapped samples. The final model demonstrated reasonable discrimination (area under the curve [AUC] = 0.6224) and calibration (Hosmer-Lemeshow goodness-of-fit; P > 0.05) statistics and was validated internally (AUC = 0.6372). CONCLUSION: Poor adherence with medication remains an important barrier to providing optimal care. Our risk prediction model provides an easy tool to help clinicians better identify patients with fibromyalgia who may not take their medications as prescribed.

Elucidating the association between direct-acting antivirals and Parkinson's disease in patients with hepatitis C virus infection.

BACKGROUND: Some epidemiological studies have found an increased association between Parkinson's disease (PD) and chronic hepatitis C virus (HCV) infection. Although a few studies have also found a decreased risk of PD with interferon-α therapy, the effect of direct-acting antivirals (DAAs) on Parkinson's disease remains unclear. The current study seeks to assess and elucidate the association between DAAs and PD in patients newly diagnosed with chronic HCV infection. METHODS: We conducted a retrospective cohort study of patients ≥18 years diagnosed with HCV using MarketScan Commercial and Medicare Supplemental database (2012-2019). Follow-up started with the initiation of DAA (or randomly assigned date for the non-DAA group) and ended at occurrence of PD, disenrollment, or end of the study period. A multivariable Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals. RESULTS: We identified 48,356 patients diagnosed with HCV. The mean follow-up time of the cohort was 1.31 years. The incidence rate of PD was 53 per 100,000 person-years for the DAA group and 48 per 100,000 person-years for the non-DAA group. The adjusted HR was 1.24 (95% CI = 0.56-2.73). Results were consistent across sensitivity and subgroup analyses. CONCLUSION: This study did not find an association between DAAs and PD among patients with HCV infection.

Comparative Safety of Long-Acting vs. Short-Acting Erythropoiesis-Stimulating Agents Among Patients Undergoing Hemodialysis.

Both short-acting (epoetin alfa or beta) and long-acting (darbepoetin alfa or PEG-epoetin) erythropoiesis-stimulating agents (ESAs) are commonly prescribed for patients with kidney failure undergoing maintenance hemodialysis. We compared the risks of major adverse cardiovascular events (MACE) and of all-cause mortality associated with receipt of short- vs. long-acting ESAs. This retrospective cohort analysis included Medicare hemodialysis beneficiaries aged ≥ 18 years in the United States Renal Data System from January 2015 to December 2017. We included adults who survived > 90 days after initiating hemodialysis and received either short- or long-acting ESAs. Outcomes were MACE (first occurrence of stroke, acute myocardial infarction, or cardiovascular-related mortality) and all-cause mortality. After stabilized inverse probability of treatment weighting, Cox proportional hazards regression models were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for each outcome. Of 68,607 patients (mean age: 65 years, 45% females), 33,658 (49%) received long-acting ESAs and 34,949 (51%) received short-acting ESAs. There was no difference in the risk of MACE associated with receipt of short- vs. long-acting ESAs (HR: 1.02 (95% CI: 0.98-1.08)). However, long-acting (vs. short-acting) ESA receipt was associated with a lower risk of all-cause mortality (HR: 0.91 (95% CI: 0.87-0.96)). Compared with short-acting ESAs, long-acting ESAs were associated with a lower risk of all-cause mortality, with no difference in the risk of MACE. Future studies with a longer follow-up are needed to confirm these findings.

Risk of cardiovascular events following intermittent and continuous androgen deprivation therapy in patients with nonmetastatic prostate cancer.

BACKGROUND: Intermittent androgen deprivation therapy (iADT) alleviates some side effects of continuous (c) ADT in patients with prostate cancer (PC), but its relative impact on ADT-associated comorbidities is uncertain. We assessed real-world use of iADT and cADT and associated risk of cardiovascular and endocrine/metabolic events in patients with nonmetastatic (nm) PC. METHODS: This retrospective longitudinal cohort study included patients with nmPC initiating systemic ADT with gonadotropin-releasing hormone agonists (goserelin, histrelin, leuprolide, and triptorelin) or antagonists (degarelix) in the US Surveillance, Epidemiology and End Results-Medicare database (2010-2017), who had ≥ 36 months of continuous insurance coverage, unless death occurred, and did not receive chemotherapy or next-generation hormonal therapies during follow-up (through 2019). Risk of major adverse cardiovascular events (MACE [myocardial infarction, stroke, cardiomyopathy/heart failure, pulmonary embolism, ischemic heart disease, all-cause mortality]) and endocrine/metabolic events (diabetes, hypercholesterolemia, bone fractures, and osteoporosis) were examined between cohorts. Inverse probability of treatment-weighted Cox regression models estimated adjusted hazard ratios (HRs) of the outcomes. RESULTS: Of 10,655 eligible patients, 2,095 (19.7%) received iADT and 8,560 (80.3%) cADT. Median follow-up was 43.9 and 48.4 months and median ADT duration (excluding iADT gaps) was 22.0 and 13.5 months for the iADT and cADT cohorts, respectively. Patients receiving cADT had a lower risk of MACE vs. iADT (HR 0.90; 95% confidence interval [CI] 0.83-0.96). No difference in risk of endocrine/metabolic events was observed (HR 0.97; 95% CI 0.92-1.03). Subgroup analysis found that the difference in MACE was maintained in patients with a history of cardiovascular disease (HR 0.90; 95% CI 0.83-0.98) and eliminated in patients without (HR 0.94; 95% CI 0.82-1.08). CONCLUSIONS: Patients with nmPC who received cADT had a lower risk of MACE and similar risk of endocrine/metabolic events vs. those who received iADT. Further research assessing both regimens is needed to inform treatment decisions.

Real-World Effectiveness of Sotrovimab for the Early Treatment of COVID-19: Evidence from the US National COVID Cohort Collaborative (N3C).

BACKGROUND AND OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has been an unprecedented healthcare crisis, one that threatened to overwhelm health systems and prompted an urgent need for early treatment options for patients with mild-to-moderate COVID-19 at high risk for progression to severe disease. Randomised clinical trials established the safety and efficacy of monoclonal antibodies (mAbs) early in the pandemic; in vitro data subsequently led to use of the mAbs being discontinued, without clear evidence on how these data were linked to outcomes. In this study, we describe and compare real-world outcomes for patients with mild-to-moderate COVID-19 at high risk for progression to severe COVID-19 treated with sotrovimab versus untreated patients. METHODS: Electronic health records from the National COVID Cohort Collaborative (N3C) were used to identify US patients (aged ≥ 12 years) diagnosed with COVID-19 (positive test or ICD-10: U07.1) in an ambulatory setting (27 September 2021-30 April 2022) who met Emergency Use Authorization (EUA) high-risk criteria. Patients receiving the mAb sotrovimab within 10 days of diagnosis were assigned to the sotrovimab cohort, with the day of infusion as the index date. Untreated patients (no evidence of early mAb treatment, prophylactic mAb or oral antiviral treatment) were assigned to the untreated cohort, with an imputed index date based on the time distribution between diagnosis and sotrovimab infusion in the sotrovimab cohort. The primary endpoint was hospitalisation or death (both all-cause) within 29 days of index, reported as descriptive rate and adjusted [via inverse probability of treatment weighting (IPTW)] odds ratio (OR) and 95% confidence interval (CI). RESULTS: Of nearly 2.9 million patients diagnosed with COVID-19 during the analysis period, 4992 met the criteria for the sotrovimab cohort, and 541,325 were included in the untreated cohort. Before weighting, significant differences were noted between the cohorts; for example, patients in the sotrovimab cohort were older (60 years versus 54 years), were more likely to be white (85% versus 75%) and met more EUA criteria (mean 3.1 versus 2.2) versus the untreated cohort. The proportions of patients with 29-day hospitalisation or death were 3.5% (176/4992) and 4.5% (24,163/541,325) in the sotrovimab and untreated cohorts, respectively (unadjusted OR: 0.78; 95% CI: 0.67, 0.91; p = 0.001). In adjusted analysis, sotrovimab was associated with a 25% reduction in the odds of hospitalisation or death compared with the untreated cohort (IPTW-adjusted OR: 0.75; 95% CI: 0.61, 0.92; p = 0.005). CONCLUSIONS: Sotrovimab demonstrated clinical effectiveness in preventing severe outcomes (hospitalisation, mortality) in the period 27 September 2021-30 April 2022, which included Delta and Omicron BA.1 variants and an early surge of Omicron BA.2 variant.

IgG testing, immunoglobulin replacement therapy, and infection outcomes in patients with CLL or NHL: real-world evidence.

ABSTRACT: Patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) can develop hypogammaglobulinemia, a form of secondary immune deficiency (SID), from the disease and treatments. Patients with hypogammaglobulinemia with recurrent infections may benefit from immunoglobulin replacement therapy (IgRT). This study evaluated patterns of immunoglobulin G (IgG) testing and the effectiveness of IgRT in real-world patients with CLL or NHL. A retrospective, longitudinal study was conducted among adult patients diagnosed with CLL or NHL. Clinical data from the Massachusetts General Brigham Research Patient Data Registry were used. IgG testing, infections, and antimicrobial use were compared before vs 3, 6, and 12 months after IgRT initiation. Generalized estimating equation logistic regression models were used to estimate odds ratios, 95% confidence intervals, and P values. The study population included 17 192 patients (CLL: n = 3960; median age, 68 years; NHL: n = 13 232; median age, 64 years). In the CLL and NHL cohorts, 67% and 51.2% had IgG testing, and 6.5% and 4.7% received IgRT, respectively. After IgRT initiation, the proportion of patients with hypogammaglobulinemia, the odds of infections or severe infections, and associated antimicrobial use, decreased significantly. Increased frequency of IgG testing was associated with a significantly lower likelihood of severe infection. In conclusion, in real-world patients with CLL or NHL, IgRT was associated with significant reductions in hypogammaglobulinemia, infections, severe infections, and associated antimicrobials. Optimizing IgG testing and IgRT are warranted for the comprehensive management of SID in patients with CLL or NHL.

Residues at the cytoplasmic end of transmembrane helix 2 determine the signal output of the TarEc chemoreceptor.

Baseline signal output and communication between the periplasmic and cytoplasmic domains of the Escherichia coli aspartate chemoreceptor Tar(Ec) are both strongly influenced by residues at the C-terminus of transmembrane helix 2 (TM2). In particular, the cytoplasmic aromatic anchor, composed of residues Trp-209 and Tyr-210 in wild-type Tar(Ec), is important for determining the CheA kinase-stimulating activity of the receptor and its ability to respond to chemoeffector-induced stimuli. Here, we have studied the effect on Tar(Ec) function of the six-residue sequence at positions 207-212. Moving various combinations of aromatic residues among these positions generates substantial changes in receptor activity. Trp has the largest effect on function, both in maintaining normal activity and in altering activity when it is moved. Tyr has a weaker effect, and Phe has the weakest; however, all three aromatic residues can alter signal output when they are placed in novel positions. We also find that Gly-211 plays an important role in receptor function, perhaps because of the flexibility it introduces into the TM2-HAMP domain connector. The conservation of this Gly residue in the high-abundance chemoreceptors of E. coli and Salmonella enterica suggests that it may be important for the nuanced, bidirectional transmembrane signaling that occurs in these proteins.

Sorafenib Loaded Resealed Erythrocytes for the Treatment of Hepatocellular Carcinoma.

BACKGROUND: This study aims to formulate and characterize sorafenib-loaded resealed erythrocytes (SoRE) and investigate their anticancer activity in a rat model of hepatocellular carcinoma. METHODS: SoRE were prepared by hypotonic dialysis of red blood cells obtained from Wistar rats using a range of drug-containing dialysis mediums (2-10 mg/ml) and osmosis time (30-240 mins). Optimized SoRE (8 mg/mL and 240 mins) were characterized for size, morphology, stability, entrapment efficiency, in vitro release profiles, and in vivo efficacy evaluations. For efficacy studies, optimized SoRE were intravenously administered to Wistar rats having hepatocellular lesions induced by aflatoxin B and monitored for in vivo antineoplastic activity. RESULTS: The amount of sorafenib entrapped was directly proportional to the drug concentration in the dialysis medium and duration of osmosis; highest for 10 mg/mL and 240 minutes and lowest for 2 mg/mL and 30 minutes, respectively. Optimized SoRE were biconcave with a size of 112.7 nm and zeta potential of -11.95 ± 2.25 mV. Osmotic and turbulence fragility were comparable with native erythrocytes. CONCLUSION: Drug release follows the first-order pattern. In vivo investigations reveal better anticancer activity of SoRE formulation compared to sorafenib standard preparation. Resealed erythrocytes loaded with sorafenib displayed first-order in vitro release and promising anticancer activity in a rat model of hepatocellular carcinoma.

Economic Burden of Fatigue in Inflammatory Bowel Disease.

Background: This retrospective study gathered medical/pharmacy claims data on patients with inflammatory bowel disease (IBD) between January 01, 2000 and March 31, 2019 from the IBM MarketScan commercial claims database to assess the real-world impact of fatigue on healthcare costs in patients newly diagnosed with IBD. Methods: Eligible participants were ≥18 years, newly diagnosed with IBD (≥2 separate claims), and had ≥12 months of continuous database enrollment before and after fatigue diagnosis. The date of fatigue diagnosis was the index date; participants were followed for 12 months post-index. Patients with (cases) or without (controls) fatigue were matched 1:1 by propensity score matching. Patients with evidence of prior IBD diagnosis/treatment, or those with a chronic disease other than IBD wherein fatigue is the primary symptom, were excluded. Healthcare resource utilization (HCRU), including hospitalizations, inpatient and outpatient visits, and associated costs were compared between cases and controls. Results: Matched IBD cohorts (21 321 cases/21 321 controls) were identified (42% Crohn's disease [CD] and 58% ulcerative colitis [UC]) with similar baseline characteristics (average age: 46 years; 60% female). Cases versus controls had significantly more all-cause outpatient visits (incidence rate ratio [IRR], 95% confidence intervals [95% CI]: 1.64 [1.61, 1.67], P < .001) and all-cause hospitalizations (IRR [95% CI]: 1.92 [1.81, 2.04], P < .001); as well as significantly higher all-cause total direct healthcare costs (mean: $24 620 vs. $15 324; P < .001). Similar findings were observed for IBD-related outcomes, as well as in CD- and UC-specific subgroups. Conclusions: Presence of fatigue is associated with an increase in HCRU and total medical costs among patients newly diagnosed with IBD.

Developing a Standardized Approach to Grading the Level of Brain Dysfunction on EEG.

PURPOSE: To assess variability in interpretation of electroencephalogram (EEG) background activity and qualitative grading of cerebral dysfunction based on EEG findings, including which EEG features are deemed most important in this determination. METHODS: A web-based survey (Qualtrics) was disseminated to electroencephalographers practicing in institutions participating in the Critical Care EEG Monitoring Research Consortium between May 2017 and August 2018. Respondents answered 12 questions pertaining to their training and EEG interpretation practices and graded 40 EEG segments (15-second epochs depicting patients' most stimulated state) using a 6-grade scale. Fleiss' Kappa statistic evaluated interrater agreement. RESULTS: Of 110 respondents, 78.2% were attending electroencephalographers with a mean of 8.3 years of experience beyond training. Despite 83% supporting the need for a standardized approach to interpreting the degree of dysfunction on EEG, only 13.6% used a previously published or an institutional grading scale. The overall interrater agreement was fair ( k = 0.35). Having Critical Care EEG Monitoring Research Consortium nomenclature certification (40.9%) or EEG board certification (70%) did not improve interrater agreement ( k = 0.26). Predominant awake frequencies and posterior dominant rhythm were ranked as the most important variables in grading background dysfunction, followed by continuity and reactivity. CONCLUSIONS: Despite the preference for a standardized grading scale for background EEG interpretation, the lack of interrater agreement on levels of dysfunction even among experienced academic electroencephalographers unveils a barrier to the widespread use of EEG as a clinical and research neuromonitoring tool. There was reasonable agreement on the features that are most important in this determination. A standardized approach to grading cerebral dysfunction, currently used by the authors, and based on this work, is proposed.

Norepinephrine reuptake inhibitors and risk of antihypertensive treatment intensification and major adverse cardiovascular events in patients with stable hypertension and depression.

STUDY OBJECTIVE: To compare the risk of antihypertensive treatment intensification (TI) and major adverse cardiovascular events (MACE) with the initiation of serotonin norepinephrine reuptake inhibitors compared to selective serotonin reuptake inhibitors (SSRIs) in patients with stable hypertension and depression. DESIGN: Retrospective cohort study. DATA SOURCE: IBM MarketScan® commercial claims database and Medicare Supplemental claims database from 2007 to 2019. PATIENTS: Patients aged 18 years or older with stable treated hypertension and depression who newly initiate either serotonin norepinephrine reuptake inhibitors or SSRIs. INTERVENTION: Serotonin norepinephrine reuptake inhibitors versus SSRIs. MEASUREMENTS AND MAIN RESULTS: The primary outcomes were: (1) TI (first occurrence of antihypertensive regimen augmentation or dose escalation); (2) MACE (first occurrence of stroke or acute myocardial infarction). Baseline risk between the two groups was balanced via 1:1 propensity score (PS) matching. A Cox proportional hazard regression model was used to estimate adjusted hazard ratio (aHR) and 95% confidence intervals (95% CI). After 1:1 PS matching, we included 19,160 patients in the study cohort (mean age: 52 years, 62% females) of which 9580 initiated serotonin norepinephrine reuptake inhibitors and 9580 initiated SSRIs. Patients who initiated serotonin norepinephrine reuptake inhibitors had 15 MACE events (incidence rate per 1000 person-years [IR], 3.9) and 1675 TI events (IR, 540.2), compared with 17 MACE events (IR, 4.0) and 1774 TI events (IR, 518.5) in the SSRI group. The risk of TI (aHR: 1.01, [95% CI: 0.94, 1.08]) and MACE (aHR: 0.98, [95% CI: 0.49, 1.96]) did not differ among patients initiated serotonin norepinephrine reuptake inhibitors versus SSRIs. CONCLUSIONS: Among patients with stable hypertension and depression, initiation of serotonin norepinephrine reuptake inhibitors had a similar risk of antihypertensive TI and MACE compared to initiation of SSRIs. Future study with a larger sample size is needed to confirm our findings.