Prognostic factors and overall survival of breast cancer in Benin: a hospital-based study.

BACKGROUND: In Benin, a country in West Africa, breast cancer is the leading cancer in women, both in terms of incidence and mortality. However, evidence on the mortality of breast cancer and its associated factors is lacking in this country. Our aim was to describe and analyze the clinical, histopathological, and prognostic aspects of breast cancer in Benin. METHODS: A descriptive and analytical study was carried out at the CNHU-HKM and the CHU-MEL, two major tertiary referral hospitals for breast cancer management located in Cotonou, the capital city of Benin. All breast cancer medical records with histological evidence and immunohistochemistry studies were retrospectively collected between January 1, 2014, and September 30, 2020, in these two tertiary referral hospitals and analyzed in the current study. RESULTS: Finally, 319 medical records were included. The mean age at diagnosis was 48.74 years. The tumors were most frequently classified as T4 (47.6%) with lymph node involvement N2 (34.5%), and metastases were clinically noted in 21.9% of cases. Stage was reported in the medical records of 284 patients. Tumors were diagnosed at very late AJCC stages: stage III (47.5%) and stage IV (24.7%). Grades SBR 2 (49.2%) and SBR 3 (32.6%) were the most frequent grades. Triple-negative breast cancer (31.3%) was the most common molecular type. The overall 5-year survival was 48.49%. In multivariable analysis, the poor prognostic factors were lymph node invasion (HR = 2.63; p = 0.026; CI: [1.12, 6.17]), the presence of metastasis (HR = 3.64; p < 0.001); CI: [2.36, 5.62] and the immunohistochemical profile (HR = 1.29; p < 0.001; CI: [1.13, 1.48]). CONCLUSIONS: Breast cancer in Beninese is predominant in young adults and is often diagnosed at a late stage. The survival of breast cancer patients in Benin can be improved by enhancing early diagnosis and multidisciplinary management.

The association of benzodiazepine and benzodiazepine-related drugs with outcomes after surgery for colorectal cancer.

Benzodiazepines increase plasma brain-derived neurotrophic factor (BDNF) level which, in turn, may improve survival in colorectal cancer (CRC) patients. This study aimed to evaluate the associations between benzodiazepine and benzodiazepine-related drugs (BZRD) use and outcomes of patients operated for CRC. This is a retrospective cohort study including patients operated for CRC at Limoges' University Hospital between 2010 and 2019. Data were collected from two sources: medical records of patients in the digestive, general and endocrine surgery department at Limoges University Hospital and from the Haute-Vienne general cancer registry. Patients were divided into benzodiazepine users and non-users. Outcomes were overall survival (OS) and recurrence-free survival (RFS). Among 504 patients who underwent surgery for CRC, 125 (24.8%) patients were treated with benzodiazepine/BZRD drugs. Users and non-users of benzodiazepine/BZRD showed no statistically significant differences in 5-year OS (45.5 ± 1.9% vs. 46.5 ± 1.1% p = 0.25) and 5-year RFS (41.0 ± 2.1% vs. 39.6 ± 1.3%, p = 0.94), even after adjustment for confounders and propensity score (OS: aHR=1.02, 95%CI: 0.71-1.48; RFS: aHR=1.00, 95%CI: 0.72-1.40). Subgroup analysis on CRC patients with psychiatric disorders revealed that benzodiazepine users had better RFS (aHR=0.58, 95%CI: 0.35-0.96) compared with non-users, particularly, patients with stages III or IV of CRC had better OS (aHR=0.27; 95%CI: 0.12-0.59) and RFS (aHR=0.30, 95%CI: 0.15-0.62). OS and RFS was significantly better in patients taking benzodiazepines classified as anxiolytics, having longer half-life, and producing active metabolites. In conclusion, benzodiazepine use was not associated with outcomes in CRC patients. Nevertheless, in subgroup of patients with psychiatric disorders and advanced CRC stage, benzodiazepine could improve survival.

The Longitudinal Impact Of A Multistate Commercial Accountable Care Program On Cost, Use, And Quality.

The prevalence of accountable care organizations (ACOs) has grown significantly across Medicare and commercial payers in the past decade, but there are limited insights regarding the effect of ACOs on costs in the commercial population. We used longitudinal administrative claims data over the course of nineteen calendar quarters from 2016 to 2021 to assess the ongoing incremental impact of Elevance Health's commercial ACO program on cost and use across fifteen US states. We also analyzed the program's impact on spending subcategories (inpatient, outpatient, professional, and pharmacy) and measured differences in quality performance. The program was associated with incremental savings during this period. Incremental savings were greater in the fully insured population relative to the administrative services only population and were due to outpatient and pharmacy savings. ACO providers had superior quality performance measures relative to contracted providers not participating in ACOs. Payers should be aware of the potential for diminishing marginal returns of ACO contracting on containing health care costs.

PHEXL222P Mutation Increases Phex Expression in a New ENU Mouse Model for XLH Disease.

PhexL222P mouse is a new ENU mouse model for XLH disease due to Leu to Pro amino acid modification at position 222. PhexL222P mouse is characterized by growth retardation, hypophosphatemia, hypocalcemia, reduced body bone length, and increased epiphyseal growth plate thickness and femur diameter despite the increase in PHEXL222P expression. Actually, PhexL222P mice show an increase in Fgf23, Dmp1, and Mepe and Slc34a1 (Na-Pi IIa cotransporter) mRNA expression similar to those observed in Hyp mice. Femoral osteocalcin and sclerostin and Slc34a1 do not show any significant variation in PhexL222P mice. Molecular dynamics simulations support the experimental data. P222 might locally break the E217-Q224 ß-sheet, which in turn might disrupt inter-ß-sheet interactions. We can thus expect local protein misfolding, which might be responsible for the experimentally observed PHEXL222P loss of function. This model could be a valuable addition to the existing XLH model for further comprehension of the disease occurrence and testing of new therapies.

Perceptions of Telehealth Among Commercial Members Who Responded to a Patient-Experience Survey During the Onset of the Coronavirus-19 Pandemic.

Introduction: The body of literature on telehealth perception among commercial members is limited. Therefore, we administered a patient-experienced survey (Clinician and Group Consumer Assessment of Healthcare Providers and Systems [CG-CAHPS]) to determine member perceptions of telehealth, including willingness to pay for it and the likelihood to access it again. Methods: This study used a cross-sectional design, and members were assigned into two groups: those who had a telehealth visit with their primary care provider (PCP) or a provider in the same practice and those who had a telehealth visit with a provider outside of their PCP's practice. Logistic regression models were used to observe group differences in telehealth perception. Results: A total of 444 members replied to the CG-CAHPS survey and had a virtual visit; 21.1% had a telehealth visit with a provider outside of their PCP's practice, and 78.8% had a telehealth visit with their PCP or a provider in the same practice. Compared with members who saw a provider outside of their PCP's practice, members who saw their PCP or a provider in the same practice had 3.76 higher odds (confidence interval [95% CI]: 1.49-9.44) of rating in-person care as no different than virtual care; 2.29 higher odds (95% CI: 1.30-4.04) of reporting they would likely use telehealth again in the future; and 1.70 higher odds (95% CI: 0.99-2.91) of responding that they would be willing to pay an in-office visit copay for a telehealth visit. Conclusion: These results suggest that the familiarity of a member's PCP extends to the provider's practice and impacts member outlook on telehealth.

Health care resource utilization and costs of recurrent Clostridioides difficile infection in the elderly: a real-world claims analysis.

BACKGROUND: Clostridioides difficile infection (CDI) affected an estimated 365,000 persons in the United States in 2017. Despite a nationally decreasing trend of CDI cases, the population incidence of recurrent CDI (rCDI) has not improved. Elderly individuals (aged ≥ 65 years) are at higher risk of CDI, rCDI, and complicated CDI compared with younger individuals. OBJECTIVE: To analyze Medicare fee-for-service data for 12 months after an initial CDI episode, in order to obtain real-world data on health care resource utilization (HRU) and costs for elderly patients with CDI and rCDI. METHODS: A retrospective cohort study of patients who were aged ≥ 65 years and had a first (index) CDI diagnosis from January 1, 2010, to December 31, 2016, and continuous enrollment in Medicare Parts A, B, and D during the 12-month pre-index and 12-month post-index periods was conducted. A CDI episode was identified by either an inpatient stay with CDI diagnosis code or an outpatient medical claim with a CDI diagnosis code plus a CDI treatment. Each CDI episode was followed by a 14-day CDI claim-free period after the last CDI claim or end of CDI treatment. rCDI was a second or subsequent episode of CDI that occurred within an 8-week window after the 14-day CDI claim-free period. The number of CDI and rCDI episodes, HRU, time to recurrence, and total all-cause direct medical costs were calculated over the 12-month pre-index (baseline) and 12-month follow-up periods and stratified by number of rCDI episodes (No rCDI, 1 rCDI, 2 rCDI, 3+ rCDI). RESULTS: A total of 268,762 patients with an index CDI were included. Mean age was 78.3 years, and 69.0% were female. HRU was higher during the 6 months immediately pre-index versus 7-12 months pre-index, including a higher proportion of patients with a hospital admission (55.1% vs. 27.5%) or emergency department visit (41.3% vs. 27.4%), respectively. Moreover, 34.7% of the study population experienced rCDI. Of those who experienced 1 recurrence, 59.1% had a second recurrence, and of those who had 2 recurrences, 58.4% had a third. During the 12-month follow-up, postacute care was used by at least 70% of each rCDI cohort. The proportion of patients with ≥ 4 hospital admissions during follow-up was highest for the 3+ rCDI cohort (24.9% of patients). During the 12-month follow-up, mean total all-cause direct costs were $76,024, $99,348, $96,148, and $96,517 for the No rCDI, 1 rCDI, 2 rCDI, and 3+ rCDI cohorts, respectively, largely driven by inpatient costs. Adjusted all-cause total costs were significantly higher for all 3 rCDI cohorts compared with the No rCDI cohort. CONCLUSIONS: Elderly individuals experienced high rates of recurrence after their first CDI episode, and especially after a prior recurrence. The intensity of HRU during follow-up was higher for patients who suffered recurrences. Patients with rCDI had the burden of higher costs of care, including the patient out-of-pocket responsibility, versus patients with a single CDI episode. DISCLOSURES: Funding for this study was provided by Ferring Pharmaceuticals. Nelson is an employee of Ferring Pharmaceuticals, and Scott, Boules, and Unni were employees of Ferring Pharmaceuticals at the time of this study. Teigland and Parente are employees of Avalere Health and provided consulting services to Ferring Pharmaceuticals. Feuerstadt has served as a consultant to and on the speakers bureau for Merck and Co. and has served as a consultant for Ferring Pharmaceuticals and Roche Pharmaceuticals. Portions of the data contained in this study appeared as an abstract/ePoster for the AMCP Annual Meeting 2020, April 2020.

Incremental burden of mental health conditions in adult patients with focal seizures.

INTRODUCTION: Clinical research has consistently established mental health conditions (MHCs) as frequent comorbidities of epilepsy. However, the extent of economic burden of comorbid MHC in patients with focal seizures has not been systematically investigated. This retrospective cohort analysis of health plan claims compared healthcare use and costs among adult patients with focal seizures with and without comorbid MHC. METHODS: We utilized the Inovalon Medical Outcomes Research for Effectiveness and Economics (MORE2) Registry, longitudinal data from over 150 commercial, Medicare Advantage, and managed Medicaid health plans for the analysis, and identified a cohort of patients with focal (partial-onset) seizure with relevant ICD9/10 diagnosis codes with and without MHC. Mental health conditions were defined as diagnoses for anxiety, bipolar condition/mania, attention-deficit conduct condition, major depression, schizophrenia, and other psychotic conditions, and patients without MHC were propensity score-matched to patients with preexisting MHC on baseline patient characteristics. The assessment examined a series of outcomes, including 1) direct healthcare resource utilization and 2) total provider reimbursement. RESULTS: Patients with preexisting MHC were more likely to receive adjunctive epilepsy therapy as well as broad-spectrum antiepileptic drugs/antiseizure medications (ASMs). Additionally, patients with focal seizures and MHC were significantly more likely to utilize high-cost healthcare services. The presence of MHC was associated with approximately 50% greater utilization of emergency department (ED), physician, and inpatient services. Consequently, healthcare expenditures were significantly higher among patients with MHC ($17,596 vs. $10,857; 62% higher, p < 0.001), with the trend consistent across all care settings. CONCLUSIONS: This analysis illustrates the health service utilization and cost implications of MHC among patients with focal seizures. The data suggest that patients with MHC have a greater overall clinical burden, which may be associated with higher healthcare resource use and expenditures. Because of the potential burden and costs associated with MHC, neurologists should consider screening patients with focal seizures for mental health disorders to identify and initiate treatment for comorbid mental health disorders.

GASP-2 overexpressing mice exhibit a hypermuscular phenotype with contrasting molecular effects compared to GASP-1 transgenics.

Muscle atrophy is associated with many diseases including genetic disorders, sarcopenia, or cachexia syndromes. Myostatin (Mstn), a transforming growth factor-beta (TGF-ß) member, plays a key role in skeletal muscle homeostasis as a powerful negative regulator. Over the last decade, about 15 clinical trials aimed at inhibiting the Mstn pathway, failed to produce conclusive results. In this context, we investigated whether growth and differentiation factor-associated serum protein-1 (GASP-1) or GASP-2, two natural inhibitors of Mstn, might represent a potential therapeutic. As we previously reported, mice overexpressing Gasp-1 (Tg(Gasp-1)) present an increase of muscle mass but develop metabolic disorders with aging. Here, we showed that overexpression of Gasp-2 increases the muscular mass without metabolic defects. We also found that Tg(Gasp-2) mice displayed, like Mstn-/- mice, a switch from slow- to fast-twitch myofibers whereas Tg(Gasp-1) mice exhibit a reverse switch. Our studies supported the fact that GASP-2 has less affinity than GASP-1 for Mstn, leading to a constitutive Mstn upregulation only in Tg(Gasp-1) mice, responsible for the observed phenotypic differences. Altogether, our findings highlighted a gene expression regulatory network of TGF-ß members and their inhibitors in muscle.

GASP-1 and GASP-2, two closely structurally related proteins with a functional duality in antitrypsin inhibition specificity: a mechanistic point of view.

While GASP-1 and GASP-2 proteins are known to regulate myogenesis by inhibiting myostatin, their structural organization suggests a putative role as multivalent protease inhibitors controlling different protease activities. In this study, we show the noncompetitive and competitive antitrypsin activities of the full-length GASP-1 and GASP-2 proteins, respectively, by using a bacterial system production and in vitro enzymatic experiments. The role of the second Kunitz domain in this functional duality is described by assessing the antitrypsin activity of GASP-1/2 chimeric proteins. Molecular dynamics simulations support the experimental data to rationalize differences in binding modes between trypsin and the GASP-1 and GASP-2 second Kunitz domains. A new inhibition mechanism was evidenced for the second Kunitz domain of GASP-2, in which the conventional cationic residue of trypsin inhibitors was substituted by the strongly interacting glutamine residue.

A siRNA Mediated Screen During C2C12 Myogenesis.

Myogenesis is a multistep process taking place during pre- and postnatal stages for muscle formation, growth, and regeneration. It is a highly regulated process involving many molecular factors which act during myoblast proliferation and differentiation. To provide new insights into the molecular mechanisms and interactions behind the regulation of these different steps, RNA interference is an efficient methodology to implement. We developed a high-throughput siRNA screen in C2C12 murine myoblast cells for identification of genes relevant to signaling pathways controlling muscle growth. The proposed protocol is based on (1) the analyses of a maximum number of cells/myotubes to detect and quantify both clear and subtle phenotypes during proliferation/fusion cells and (2) the use of two cellular fluorescent markers, DAPI and myosin, decorating nuclei and myotubes respectively. Four phenotypic criteria were quantitatively assessed: cellular density, myotubes quantity, fusion index, and size and morphology of myotubes.

Outcome evaluation of a pharmacy-based therapy management program for patients with cystic fibrosis.

OBJECTIVE: To compare medication adherence, pulmonary exacerbations, healthcare utilization, and costs for patients with cystic fibrosis (CF) who utilized a pharmacy-based therapy management program to a matched control group. We hypothesized that patient management services would be associated with better medication adherence, and thus require fewer visits to the emergency room or hospitalizations. METHODS: This retrospective, observational cohort study used claims data from the MORE2 claims Registry®. The sample consisted of CF patients, aged 6+, who had ≥1 pharmacy claim for inhaled tobramycin, inhaled aztreonam, ivacaftor, or dornase alfa from 6/2/2014-5/31/2015. Adherence was measured as proportion of days covered (PDC). Propensity score matching and multivariable regression techniques were used to compare outcomes in program participants to matched controls. RESULTS: Of the 236 intervention and 724 control patients meeting selection criteria, 202 were propensity-matched from each cohort. Relative to the control cohort, program patients had 23% higher mean PDC for tobramycin (IRR = 1.23, P = 0.01) and were twice as likely to be adherent to tobramycin (PDC ≥ 80%) than matched controls (OR = 2.14, P = 0.04). Program patients had fewer ER visits (IRR = 0.52, P < 0.01) and slightly lower ER costs (IRR = 0.66, P = 0.06) than the control patients. CONCLUSION: A pharmacy-based therapy management program for CF patients was associated with higher adherence to inhaled tobramycin and lower ER rates. Pharmacies that provide therapy management can support effective CF care management.

Alterations in Adiposity and Glucose Homeostasis in Adult Gasp-1 Overexpressing Mice.

BACKGROUND/AIMS: Myostatin is known as a powerful negative regulator of muscle growth playing a key role in skeletal muscle homeostasis. Recent studies revealed that myostatin-deficient mice lead to an increase of insulin sensitivity, a decrease of adiposity and a resistance to obesity, showing that myostatin can also impact on metabolism. Thus, myostatin appeared as a potential therapeutic target to treat insulin resistance. METHODS: We generated transgenic mice overexpressing Gasp-1, a myostatin inhibitor. RESULTS: Surprisingly, we found that these mice gained weight with age due to an increase in fat mass associated with ectopic fat accumulation. In addition, these mice developed an adipocyte hypertrophy, hyperglycemia, hyperinsulinemia, muscle and hepatic insulin resistance. Understanding the molecular networks controlling this insulin resistance responsiveness in overexpressing Gasp-1 mice is essential. Molecular analyses revealed a deregulation of adipokines and muscle cytokines expression, but also an increase in plasma myostatin levels. The increase in myostatin bioactivity by a positive feedback mechanism in the Tg(Gasp-1) transgenic mice could lead to this combination of phenotypes. CONCLUSION: Altogether, these data suggested that overexpressing Gasp-1 mice develop most of the symptoms associated with metabolic syndrome and could be a relevant model for the study of obesity or type 2 diabetes.

Enhancement of C2C12 myoblast proliferation and differentiation by GASP-2, a myostatin inhibitor.

BACKGROUND: GASP-2 is a secreted multi-domain glycoprotein known as a specific inhibitor of myostatin and GDF-11. Here we investigate the role of GASP-2 on myogenesis and the effect of its glycosylation on its activity. METHODS: GASP-2 overexpression or knockdown by shRNAs were carried out on C2C12 myoblasts cells. In silico analysis of GASP-2 protein was performed to identify its glycosylation sites. We produced a mouse recombinant GASP-2 protein in a prokaryotic system to obtain a fully deglycosylated protein allowing us to study the importance of this post-translational modification on GASP-2 activity. RESULTS: Both mature and deglycosylated GASP-2 proteins increase C2C12 proliferation and differentiation by inhibiting the myostatin pathway. In silico and western-blot analyses revealed that GASP-2 presents one consensus sequence for N-glycosylation and six potential sites of mucin-type O-glycosylation. CONCLUSIONS: GASP-2 promotes myogenesis and thus independently of its glycosylation. GENERAL SIGNIFICANCE: This is the first report demonstrating that GASP-2 promotes proliferation and differentiation of myoblasts by inhibiting the canonical pathway of myostatin.

Mind-operated devices: mental control of a computer using biofeedback.

This study investigated whether people could learn to control a computer using a biofeedback interface that integrated their galvanic skin response (GSR), heart rate, and temperature. Twenty participants played a computer game using the biofeedback device, both individually and in pairs. Results indicated that most people learned to control the game after a single training session. The GSR measure was the most sensitive means of control. Pairs of participants controlled the device more effectively than single individuals did.