Clearing up the hazy road from bench to bedside: A framework for integrating the fourth hurdle into translational medicine

<p>Abstract</p> <p>Background</p> <p>New products evolving from research and development can only be translated to medical practice on a large scale if they are reimbursed by third-party payers. Yet the decision processes regarding reimbursement are highly complex and internationally heterogeneous. This study develops a process-oriented framework for monitoring these so-called fourth hurdle procedures in the context of product development from bench to bedside. The framework is suitable both for new drugs and other medical technologies.</p> <p>Methods</p> <p>The study is based on expert interviews and literature searches, as well as an analysis of 47 websites of coverage decision-makers in England, Germany and the USA.</p> <p>Results</p> <p>Eight key steps for monitoring fourth hurdle procedures from a company perspective were determined: entering the scope of a healthcare payer; trigger of decision process; assessment; appraisal; setting level of reimbursement; establishing rules for service provision; formal and informal participation; and publication of the decision and supplementary information. Details are given for the English National Institute for Health and Clinical Excellence, the German Federal Joint Committee, Medicare's National and Local Coverage Determinations, and for Blue Cross Blue Shield companies.</p> <p>Conclusion</p> <p>Coverage determination decisions for new procedures tend to be less formalized than for novel drugs. The analysis of coverage procedures and requirements shows that the proof of patient benefit is essential. Cost-effectiveness is likely to gain importance in future.</p

Transvenous nonfluoroscopic pacemaker implantation during pregnancy guided by 3-dimensional electroanatomic mapping

Patients with congenital heart disease are at ongoing risk of developing both bradyarrhythmias and tachyarrhythmias decades after surgical repair. Rarely, arrhythmias can be exacerbated during pregnancy and require emergent intervention. Here, we report unique experience with nonfluoroscopic pacemaker implantation during pregnancy. Ionizing radiation, even in low doses, is associated with an increased risk of malignancy, and a fetus may be at particularly increased risk.1, 2 Over the past 2 decades, the use of fluoroscopy in cardiac ablation procedures has become nearly obsolete with the development of 3-dimensional (3D) electroanatomic mapping software such as CARTO (Biosense-Webster, Diamond Bar, CA) and NavX or EnSite (St. Jude Medical, Inc., St. Paul, MN).3 However, certain procedures, such as device implants, still commonly use fluoroscopy in most instances.2 Fluoroscopy use in patients with congenital heart disease is of utmost concern because of cumulative radiation exposure from multiple lifetime catheterization, radiographic and computed tomography imaging, and electrophysiological procedures

New Evidence for P-gp-Mediated Export of Amyloid-β PEPTIDES in Molecular, Blood-Brain Barrier and Neuronal Models

Defective clearance mechanisms lead to the accumulation of amyloid-beta (Aβ) peptides in the Alzheimer’s brain. Though predominantly generated in neurons, little is known about how these hydrophobic, aggregation-prone, and tightly membrane-associated peptides exit into the extracellular space where they deposit and propagate neurotoxicity. The ability for P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter, to export Aβ across the blood-brain barrier (BBB) has previously been reported. However, controversies surrounding the P-gp–Aβ interaction persist. Here, molecular data affirm that both Aβ40 and Aβ42 peptide isoforms directly interact with and are substrates of P-gp. This was reinforced ex vivo by the inhibition of Aβ42 transport in brain capillaries from P-gp-knockout mice. Moreover, we explored whether P-gp could exert the same role in neurons. Comparison between non-neuronal CHO-APP and human neuroblastoma SK-N-SH cells revealed that P-gp is expressed and active in both cell types. Inhibiting P-gp activity using verapamil and nicardipine impaired Aβ40 and Aβ42 secretion from both cell types, as determined by ELISA. Collectively, these findings implicate P-gp in Aβ export from neurons, as well as across the BBB endothelium, and suggest that restoring or enhancing P-gp function could be a viable therapeutic approach for removing excess Aβ out of the brain in Alzheimer’s disease

Tecnologias geradas para o Estado do Amazonas.

Aves. Arroz. Bovinos. Consorciação. Diversificação. Doenças e pragas. Feijão. Guaraná. Milho. Olericultura. Ovinos. Pastagem. Seringueira. Sistema de produção. Solos.bitstream/item/108585/1/CPAA-DOC.-1-90.pd

Association between workplace absenteeism and alcohol use disorder from the National Survey on Drug Use and Health, 2015-2019

Importance: Alcohol use disorder (AUD) is common and associated with increased morbidity. The degree to which AUD currently factors into workplace absenteeism needs further characterization in the US. Objective: To examine the association between AUD and workplace absenteeism in a nationally representative sample. Design, Setting, and Participants: This cross-sectional study used data from a nationally representative sample of noninstitutionalized US residents from the 2015-2019 National Survey on Drug Use and Health to examine the association of AUD with workplace absenteeism. Eligible respondents were aged 18 years and older who reported full-time employment. Data were analyzed from March to September 2021. Main Outcomes and Measures: Primary outcomes were markers of workplace absenteeism as defined by the number of days missed from work because of illness or injury and days skipped from work in the last 30 days. Descriptive statistics, prevalence ratios, and logistic regression analyses were performed to assess the association between AUD and absenteeism. Results: A total of 110 701 adults aged 18 years and older reported current full-time employment (58 948 [53.2%] men, 51 753 [46.8%] women; 12 776 [11.5%] Black, 18 096 [16.3%] Hispanic, and 69 506 [62.8%] White respondents). Weighted prevalence of AUD in this sample of working adults was 9.3% (95% CI, 9.0%-9.5%); 6.2% (95% CI, 6.0%-6.4%) of respondents met criteria for mild AUD, 1.9% (95% CI, 1.7%-2.0%) for moderate AUD, and 1.2% (95% CI, 1.1%-1.3%) for severe AUD. Mean days missed from work annually increased in a stepwise fashion with increasing AUD severity (no AUD, 13.0 days; 95% CI, 12.7-13.2 days; mild AUD, 17.7 days; 95% CI, 16.4-19.1 days; moderate AUD, 23.6 days; 95% CI, 21.5-25.7 days; severe AUD, 32.3 days; 95% CI, 27.5-37.0 days). People with AUD represented 9.3% of the full-time workforce and contributed to 14.1% of total reported workplace absences. Conclusions and Relevance: In this cross-sectional study, AUD was disproportionately associated with an increased prevalence of workplace absenteeism, with individuals with AUD contributing over 232 million missed workdays annually. These results provide economic incentive for increased investment in AUD prevention and treatment, both for employers and policy makers

Associations between polygenic risk for psychiatric disorders and substance involvement

Despite evidence of substantial comorbidity between psychiatric disorders and substance involvement, the extent to which common genetic factors contribute to their co-occurrence remains understudied. In the current study, we tested for associations between polygenic risk for psychiatric disorders and substance involvement (i.e., ranging from ever-use to severe dependence) among 2573 non-Hispanic European-American participants from the Study of Addiction: Genetics and Environment. Polygenic risk scores (PRS) for cross-disorder psychopathology (CROSS) were generated based on the Psychiatric Genomics Consortium’s Cross-Disorder meta-analysis and then tested for associations with a factor representing general liability to alcohol, cannabis, cocaine, nicotine, and opioid involvement (GENSUB). Follow-up analyses evaluated specific associations between each of the 5 psychiatric disorders which comprised CROSS—attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (AUT), bipolar disorder (BIP), major depressive disorder (MDD), and schizophrenia (SCZ)—and involvement with each component substance included in GENSUB. CROSS PRS explained 1.10% of variance in GENSUB in our sample (p<0.001). After correction for multiple testing in our follow-up analyses of polygenic risk for each individual disorder predicting involvement with each component substance, associations remained between: A) MDD PRS and non-problem cannabis use, B) MDD PRS and severe cocaine dependence, C) SCZ PRS and non-problem cannabis use and severe cannabis dependence, and D) SCZ PRS and severe cocaine dependence. These results suggest that shared covariance from common genetic variation contributes to psychiatric and substance involvement comorbidity

Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study

Background It has been shown that the interleukin (IL)-23/IL-17 axis is critical in the pathogenesis of psoriasis. Objectives To present the primary end point (week 12) and safety and efficacy data up to week 24 from a head-to-head trial (IXORA-S) of the IL-17A inhibitor ixekizumab (IXE) vs. the IL-12/23 inhibitor ustekinumab (UST). Methods Randomized patients received IXE (160-mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks, n = 136) or UST (45 mg or 90 mg weight-based dosing per label, n = 166). The primary end point was the proportion of patients reaching ≥ 90% Psoriasis Area and Severity Index improvement (PASI 90). Hommel-adjusted key secondary end points at week 12 included PASI 75, PASI 100, static Physician's Global Assessment (sPGA) score of 0 or 1, sPGA score of 0, Dermatology Life Quality Index (DLQI) score of 0 or 1, ≥ 4-point reduction on the itch numerical rating scale (NRS) and changes in itch NRS and skin pain visual analogue scale. Results At week 12, IXE (n = 99, 72 8%) was superior to UST (n = 70, 42 2%) in PASI 90 response (response difference 32 1%, 97 5% confidence interval 19 8 44 5%, P < 0 001). Response rates for PASI 75, PASI 100 and sPGA (0,1) were significantly higher for IXE than for UST (adjusted P < 0 05). At week 24, IXEtreated patients had significantly higher response rates than UST-treated patients for PASI, sPGA and DLQI (unadjusted P < 0 05). No deaths were reported, and the treatments did not differ with regard to overall incidences of adverse events (P = 0 299). Conclusions The superior efficacy of IXE demonstrated at week 12 persisted up to week 24. The safety profiles were consistent with those previously reported for both treatments. peerReviewe

Challenges and directions: an analysis of Genetic Analysis Workshop 17 data by collapsing rare variants within family data

Recent studies suggest that the traditional case-control study design does not have sufficient power to discover rare risk variants. Two different methods—collapsing and family data—are suggested as alternatives for discovering these rare variants. Compared with common variants, rare variants have unique characteristics. In this paper, we assess the distribution of rare variants in family data. We notice that a large number of rare variants exist only in one or two families and that the association result is largely shaped by those families. Therefore we explore the possibility of integrating both the collapsing method and the family data method. This combinational approach offers a potential power boost for certain causal genes, including VEGFA, VEGFC, SIRT1, SREBF1, PIK3R3, VLDLR, PLAT, and FLT4, and thus deserves further investigation