Publishing Trends in International Humanitarian Cleft Lip and Palate Care: A Systematic Review.

Background: Humanitarian outreach delivers essential cleft lip and palate (CLP) care in low- and middle-income countries. Objective: To review the literature regarding humanitarian CLP care and determine if a shift toward more sustainable care delivery is observed. Methods: A systematic review was performed on articles describing CLP repair in humanitarian settings from 1985 to 2020. Publications were categorized into trip reports, outcomes, teaching, and public health. Articles were stratified into three 12-year intervals (T1-T3) for analysis. Results: A total of 246 publications were included. Average annual publications increased 15.4-fold from T1 to T3 (p < 0.001). Among publications focused on delivering CLP-related care, descriptive trip report articles trended downward (58% in T1 vs. 42% in T3), whereas outcome-focused publications trended upward (42% in T1 vs. 58% T3). Public health research represented the greatest percentage of publications in T3 (50%). There were 22 teaching-related publications in T3 and only one in prior years. Conclusion: Research trends demonstrate a shift away from focusing solely on the number of surgical cases completed and toward more sustainable models of care delivery that address barriers to receiving longitudinal care.

Physician experiences with and perceptions of risk evaluation and mitigation strategy programs with elements to assure safe use.

PURPOSE: The US Food and Drug Administration (FDA) Amendments Act of 2007 authorized the FDA to require risk evaluation and mitigation strategy (REMS) programs for drugs with important safety concerns. REMS can have elements to assure safe use (ETASU), such as patient registries, dispensing restrictions, and physician training and certification requirements. We aimed to understand physician experiences with and perceptions of a selection of ETASU REMS. METHODS: Physicians prescribing 1 of 4 ETASU REMS-covered drugs: natalizumab, riociguat, sodium oxybate, and vigabatrin. STUDY DESIGN: Descriptive phenomenological study based on semi-structured phone interviews. DATA COLLECTION/EXTRACTION METHODS: Qualitative content analysis to summarize physician responses to open-ended questions. RESULTS: Of 31 physicians (14 female), 6 prescribed riociguat, 6 vigabatrin, 7 sodium oxybate, and 12 natalizumab (5 for Crohn's disease, 7 for multiple sclerosis), most demonstrated good understanding of the rationale for and requirements of the ETASU REMS but believed that the programs had limited effect on clinical practice. Some physicians reported that the ETASU REMS made them more comfortable with prescribing covered drugs due to heightened oversight, facilitated discussions about treatment, and were likely more beneficial for non-specialists. Concerns were raised about the administrative effort needed to comply with the programs and the potential misuse of patient health information transmitted to manufacturers. CONCLUSIONS: Physicians are generally aware of ETASU REMS and get reassurance from the additional oversight, but the programs can be better integrated into clinical workflows and can be designed to better protect patient health information.

Longitudinal Anatomic Analysis of Primary Cleft Lip Rhinoplasty Outcomes.

Background: The unilateral cleft lip deformity is associated with nasal deformities with secondary functional and aesthetic challenges. Objectives: Compare the change in nasal symmetry before and incrementally after primary endonasal cleft rhinoplasty concurrent with lip repair. Methods: This is a retrospective chart review of infants undergoing unilateral cleft lip repair. Data collection included demographics, surgical history, and pre- and postoperative alar and nostril photographs analyzed with Image J. Statistical analysis was done using linear and multivariable mixed effect models. Results: Twenty-two patients with a near even gender distribution (46% female) and primarily left-sided cleft lips underwent unilateral lip repair at a mean age of 3.9 months (median 3.0, range 2-12). Mean pre- and postoperative alar symmetry ratios were 0.099 (standard error [SE] 0.0019) and -0.0012 (SE 0.0179), with zero representing perfect symmetry and negative values indicating overcorrection. These values at 1, 2-4, 5-7, 8-12, 13-24, and 25+ months were 0.026, 0.050, 0.046, 0.052, 0.049, and 0.052 (SE range: 0.0015-0.0096), respectively, demonstrating stability of the alar symmetry 4 months postrepair. Conclusions: In this study, patients who underwent an overcorrective primary cleft rhinoplasty concurrent with lip repair had an initial regression of symmetry within the first 4 months postoperatively, followed by observed stabilization.

Patient and Caregiver Experiences With and Perceptions of Risk Evaluation and Mitigation Strategy Programs With Elements to Assure Safe Use.

Importance: The US Food and Drug Administration (FDA) Amendments Act of 2007 authorized the FDA to impose safety requirements on drugs with important risks, such as prescriber certification or routine laboratory testing, to ensure that the benefits of use outweighed the risks. However, little is known about patient and caregiver experiences with these Risk Evaluation and Mitigation Strategy (REMS) programs with Elements to Assure Safe Use (ETASU). Objective: To understand patient and caregiver experiences with and perceptions of REMS programs with ETASU. Design, Setting, and Participants: This qualitative study included semistructured qualitative phone interviews conducted between 2016 and 2017, with initial analysis performed in 2017 and reanalysis performed in 2021. Adult patients prescribed natalizumab or sodium oxybate, adult patients or caregivers of adult patients prescribed vigabatrin, and adult female patients of reproductive age prescribed riociguat were included. Main Outcomes and Measures: Assessment of knowledge, decision-making, medication access, and perceptions of medical privacy. Results: Among 63 participants, 46 (73%) were female. Twenty-five participants (40%) had taken natalizumab, 10 (16%) riociguat, 15 (24%) sodium oxybate, and 10 (16%) vigabatrin. One participant had taken both natalizumab and vigabatrin; 4 (6%) were caregivers of patients using vigabatrin. Most participants expressed knowledge of REMS program requirements, but many lacked the insight that these requirements were part of an FDA-mandated special safety program and expressed difficulty understanding program education materials. REMS requirements made some participants more likely to initiate treatment. However, many reported burdens accessing medication, including the need to travel to certified prescribers or pharmacies. Manufacturer access to personal health information was also controversial, although some participants expressed an altruistic desire to assist others. Conclusions and Relevance: This qualitative study found that REMS programs with ETASU reassured patients and their caregivers about drug safety and helped support medication initiation. However, steps are needed to improve the quality of REMS educational materials, promote efficient medication access, and protect patient privacy.

Excess Opioid Disposal Following Orthopaedic Surgery: A Randomized Clinical Trial.

BACKGROUND: Previous research indicates low disposal rates of excess postoperative narcotics, leaving them available for diversion or abuse. This study examined the effect of introducing a portable disposal device on excess opiate opioid disposal rates after lower extremity orthopaedic surgery. METHODS: This was a single site randomized control trial within an outpatient orthopaedic clinic. All patients 18 years or older, undergoing outpatient foot and ankle surgery between December 1, 2017 and August 1, 2018 were eligible. Patients were prospectively enrolled and randomized to receive standard opioid disposal instructions or a drug deactivation device at 2-week postoperative appointments. Participants completed an anonymous survey at 6-week postoperative appointments. RESULTS: Of the 75 patients surveyed, 68% (n = 26) of the experimental group and 56% (n = 21) of the control group had unused opioid medication. Of these, 84.6% of patients who were given Deterra Drug Deactivation System deactivation pouches safely disposed of excess medication, compared with 38% of controls (P = .003). When asked if they would use a disposal device for excess medication in the future, 97.4% (n = 37) of the experimental and 83.8% (n = 31) of the control group reported that they would. CONCLUSIONS: Providing a portable disposal device with postoperative narcotic prescriptions may increase safe disposal rates of excess opioid medication following lower extremity orthopaedic surgery. LEVELS OF EVIDENCE: Level I.

The Effect of Health Insurance Coverage on Orthopaedic Patient-reported Outcome Measures.

INTRODUCTION: Patient-reported outcome measures (PROMs) are used to assess performance and value. The type of health insurance coverage may influence outcomes scores. The goal of this study was to determine if the type of insurance coverage is associated with the trends in PROMs within an orthopaedic cohort. METHODS: We reviewed the electronic medical records of 10,745 adult foot and ankle patients who completed PROMs questionnaires from 2015 to 2017. Patients completed the Foot and Ankle Ability Measure, PROMIS Global-Mental, PROMIS Global-Physical, and PROMIS Physical Function Short Form 10a. Descriptive analyses, analysis of variance, and Tukey HSD (honest significant difference) post hoc analyses were conducted. RESULTS: Patients with commercial insurance consistently had the highest outcomes scores, whereas those with Workers Comp/Motor Vehicle and Medicaid had the lowest. PROMs of patients with commercial insurance were statistically significantly higher than the pooled scores of all other patients. Markedly poorer scores were also seen for Workers Comp/Motor Vehicle and Medicaid. In addition, these differences in PROMs for Workers Comp/Motor Vehicle and Medicaid exceeded the minimal clinically important differences. Patients with Medicare or Free Care had generally lower scores than the pooled averages, but these results were not statistically significant. DISCUSSION: PROMs scores vary between the patients with different insurance types in an orthopaedic foot and ankle cohort. These data suggest that patient insurance type may affect patient-reported outcomes. LEVEL OF EVIDENCE: Level III, Retrospective Cohort.

Characteristics of early sacubitril/valsartan patients and considerations for studies in electronic health record data.

AIM: We examined characteristics of early sacubitril/valsartan users in a large US electronic health records database. PATIENTS & METHODS: We identified three cohorts of patients with heart failure (HF): sacubitril/valsartan patients with a prior HF diagnosis; patients with HF with reduced ejection fraction; and patients with HF treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and a ß-blocker. RESULTS: Sacubitril/valsartan patients were younger than patients in the other cohorts; the mean age of sacubitril/valsartan patients increased by 2 years in the first 15 months of marketing. Most sacubitril/valsartan patients had prior use of HF treatment. CONCLUSION: Overall, sacubitril/valsartan patients resembled those in the HF with reduced ejection fraction cohort, and commonly used other drugs for HF.

Evaluating The Impact Of The Orphan Drug Act's Seven-Year Market Exclusivity Period.

For thirty-five years the Orphan Drug Act of 1983 has provided incentives for pharmaceutical manufacturers to develop drugs to treat rare diseases-conditions that affect fewer than 200,000 people in the US. One key statutory incentive is an exclusive seven-year marketing right for the rare disease indication, which has been heralded as driving a dramatic increase in the number of rare disease treatments. However, most new drugs are also protected by patents. In this study we assessed all new small-molecule drugs approved in the period 1985-2014 that had at least one indication for an orphan-designated disease as of January 1, 2017. We found that orphan drug exclusivity outlasted the last expiring patent in 33 percent of cases overall, and in a smaller percentage of cases for each successive ten-year drug cohort: from 50 percent for drugs approved in 1985-94 to 35 percent for those approved in 1995-2004 and 18 percent for those approved in 2005-14. The Orphan Drug Act's market exclusivity incentive has played an increasingly smaller role in protecting rare disease drugs from competition, while rare disease drugs have substantially increased as a fraction of all new drug approvals.

Application and impact of run-in studies.

BACKGROUND: A run-in phase is often employed prior to randomization in a clinical trial to exclude non-adherent patients, placebo responders, active drug non-responders, or patients who do not tolerate the active drug. This may impact the generalizability of trial results. OBJECTIVE: To determine if clinical outcomes differed between randomized controlled trials with run-in phases compared with randomized controlled trials of the same medication without run-in phases. DESIGN, PARTICIPANTS: From 2006 to 2014, the Food and Drug Administration approved 258 new medications. Sitaglitpin, saxagliptin, linagliptin, and alogliptin were among the only drugs with a common mechanism of action that each had multiple clinical trials, some of which had run-in phases and some of which did not. We identified all published randomized controlled trials for these four medications from MEDLINE and EMBASE as well as prior systematic reviews. MAIN MEASURES: We extracted key measures of medication efficacy (reduction in hemoglobin A1C) and safety (serious adverse events) from qualifying trials. Study results were pooled for each medication using random effects meta-analysis. KEY RESULTS: We identified 106 qualifying trials for DPP4 inhibitors, of which 88 had run-in phases and 18 did not. The average run-in phase duration was 4.0 weeks (range 1-21), and 73% of run-in phases administered placebo rather than active drug. The reduction in hemoglobin A1C compared to baseline was similar for trials with and without run-in phases (0.70%, 95% confidence interval [CI] 0.65-0.75 vs 0.76%, 95% CI 0.69-0.84, p = 0.27). The proportion of patients with serious adverse events was also similar for trials with and without run-in phases (4%, 95% CI: 3-5% vs 3%, 95% CI: 1-4%, p = 0.35). CONCLUSION: Trials with run-in phases provided similar estimates for medication efficacy and safety compared to trials without run-in phases. Because run-in phases are costly and time-consuming, these results call their utility into question for clinical trials of short duration.

Methods for addressing "innocent bystanders" when evaluating safety of concomitant vaccines.

PURPOSE: The need to develop methods for studying the safety of childhood immunization schedules has been recognized by the Institute of Medicine and Department of Health and Human Services. The recommended childhood immunization schedule includes multiple vaccines in a visit. A key concern is safety of concomitant (same day) versus separate day vaccination. This paper addresses a methodological challenge for observational studies using a self-controlled design to investigate the safety of concomitant vaccination. METHODS: We propose a process for distinguishing which of several concomitantly administered vaccines is responsible for increased risk of an adverse event while adjusting for confounding due to relationships between effect modifying risk factors and concomitant vaccine combinations. We illustrate the approach by re-examining the known increase in risk of seizure 7 to 10 days after measles-mumps-rubella (MMR) vaccination and evaluating potential independent or modifying effects of other vaccines. RESULTS: Initial analyses suggested that DTaP had both an independent and potentiating effect on seizure. After accounting for the relationship between age at vaccination and vaccine combination, there was little evidence for increased risk of seizure with same day administration of DTaP and MMR; incidence rate ratio, 95% confidence interval 1.2 (0.9-1.6), P value = Î¸.226. CONCLUSION: We have shown that when using a self-controlled design to investigate safety of concomitant vaccination, it can be critically important to adjust for time-invariant effect modifying risk factors, such as age at time of vaccination, which are structurally related to vaccination patterns due to recommended immunization schedules.

Adverse Events Associated with Antipsychotic Use in Hospitalized Older Adults After Cardiac Surgery.

OBJECTIVES: To evaluate in-hospital adverse events associated with typical and atypical antipsychotic medications (APMs) after cardiac surgery. DESIGN: Retrospective cohort study. SETTING: Nationwide inpatient database, 2003 to 14. PARTICIPANTS: Individuals (mean age 70) newly treated with oral atypical (n = 2,580) or typical (n = 1,126 APMs) after coronary artery bypass grafting or valve surgery (N = 3,706). MEASUREMENTS: In-hospital mortality, arrhythmia, pneumonia, use of brain imaging (surrogate for oversedation and neurological events), and length of stay after drug initiation RESULTS: In the propensity score-matched cohort, median treatment duration was 3 days (interquartile range (IQR) 1-6 days) for atypical APMs and 2 days (IQR 1-3 days) for typical APMs. There were no large differences in in-hospital mortality (atypical 5.4%, typical 5.3%; risk difference (RD) = 0.1%, 95% confidence interval (CI) = -2.1 to 2.3%), arrhythmia (2.0% vs 2.2%; RD = 0.0%; 95% CI = -1.4 to 1.4%), pneumonia (16.1% vs 14.5%; RD = 1.6%, 95% CI = -1.9 to 5.0%), and length of stay (9.9 days vs 9.3 days; mean difference = 0.5 days, 95% CI = -1.2 to 2.2). Use of brain imaging was more common after initiating atypical APMs (17.3%) than after typical APMs (12.4%; RD = 4.9%, 95% CI = 1.4-8.4). CONCLUSION: In hospitalized individuals who underwent cardiac surgery, short-term use of typical APMs was associated with risks of adverse events similar to those with atypical APMs. Moreover, greater use of brain imaging associated with atypical APMs suggests that these drugs may cause oversedation or adverse neurological events. Because of the low event rates, the analysis could not exclude modest differences in adverse events between atypical and typical APMs.

Rapid prototyped sutureless anastomosis device from self-curing silk bio-ink.

Sutureless anastomosis devices are designed to reduce surgical time and difficulty, which may lead to quicker and less invasive cardiovascular anastomosis. The implant uses a barb-and-seat compression fitting composed of one male and two female components. The implant body is resorbable and capable of eluting heparin. Custom robotic deposition equipment was designed to fabricate the implants from a self-curing silk solution. Curing did not require deleterious processing steps but devices demonstrated high crush resistance, retention strength, and leak resistance. Radial crush resistance is in the range of metal vascular implants. Insertion force and retention strength of the anastomosis was dependent on fit sizing of the male and female components and subsequent vessel wall compression. Anastomotic burst strength was dependent on the amount of vessel wall compression, and capable of maintaining higher than physiological pressures. In initial screening using a porcine implant, the devices remained intact for 28 days (the length of study). Histological sections revealed cellular infiltration within the laminar structure of the male component, as well as at the interface between the male and female components. Initial degradation and absorption of the implant wall were observed. The speed per anastomosis using this new device was much faster than current systems, providing significant clinical improvement.

Transdermal delivery devices: fabrication, mechanics and drug release from silk.

Microneedles are a relatively simple, minimally invasive and painless approach to deliver drugs across the skin. However, there remain limitations with this approach because of the materials most commonly utilized for such systems. Silk protein, with tunable and biocompatibility properties, is a useful biomaterial to overcome the current limitations with microneedles. Silk devices preserve drug activity, offer superior mechanical properties and biocompatibility, can be tuned for biodegradability, and can be processed under aqueous, benign conditions. In the present work, the fabrication of dense microneedle arrays from silk with different drug release kinetics is reported. The mechanical properties of the microneedle patches are tuned by post-fabrication treatments or by loading the needles with silk microparticles, to increase capacity and mechanical strength. Drug release is further enhanced by the encapsulation of the drugs in the silk matrix and coating with a thin dissolvable drug layer. The microneedles are used on human cadaver skin and drugs are delivered successfully. The various attributes demonstrated suggest that silk-based microneedle devices can provide significant benefit as a platform material for transdermal drug delivery.