Faculty Bibliography

INTRODUCTION/UNASSIGNED:Respiratory syncytial virus (RSV) causes significant morbidity and mortality in young children. For 25 years, palivizumab has been the only effective pharmaceutical RSV preventive. AREAS COVERED/UNASSIGNED:We summarize the development and a quarter-century of real-world evidence with palivizumab. We highlight its positive impact on the burden of RSV in high-risk children. Based on lessons learnt from its implementation, we suggest strategies for effective and equitable deployment of newer RSV preventives. EXPERT OPINION/UNASSIGNED:Following failure of the formalin-inactivated RSV vaccine in 1967, RSV intravenous immunoglobulin was approved in 1996 after three decades' research. Subsequently, palivizumab emerged as the most effective and safe RSV preventive, demonstrated by the IMpact trial, and was licensed in 1998 in the United States. Over the last 25 years, the benefits of palivizumab have been firmly established through a wealth of evidence, predominantly from high-income countries (HICs). To achieve a global impact with the newer RSV preventives, evidenced-based universal guidelines must be developed and endorsed by regulatory authorities and relevant scientific societies. Independent economic evaluations should incorporate all RSV-associated healthcare costs, reduction of long-term respiratory sequelae, and standardized outcomes. Most importantly, equity in product availability and implementation, particularly in low- and middle-income countries (LMICs) is essential.

BACKGROUND:Despite widespread use of Roux-en-Y gastric bypass (RYGB), there are no standardized limb lengths in the United States. METHODS:A multi-center retrospective cohort study was conducted from 2020 to 2023. Eligible patients who had undergone RYGB were divided into subgroups based on BP limb lengths: short (50-75 cm), intermediate (80-125 cm), and long (150-175 cm). Primary outcomes were total weight loss (TWL) and % TWL at 1 and 2 years. Secondary outcomes were post-operative BMI and % BMI change at 1 and 2 years, micronutrient deficiencies, hypothyroidism, acute kidney injury (AKI) requiring treatment, and remission in associated medical problems. Subgroups were compared using multivariate analysis. RESULTS:Two hundred twenty-eight patients received a long BP limb, 194 patients received an intermediate BP limb, while 152 patients received a short BP limb. Primary outcomes TWL and % TWL were significantly different between the groups at 1 year: TWL and % TWL were greater in patients with long BP limbs. The difference between the long and short BP limb groups increased at the 2-year mark. Patients who had long BP limbs had higher rates of DM remission (12.3% vs 11.9% 6.6%), HTN (8.8% vs 5.7% vs 7.9%), GERD symptoms (14.5% vs 9.8% vs 5.3%), and OSA (8.8% vs 7.7% vs 5.3%). Vitamin A deficiency rates were higher in the long BP limb group. CONCLUSIONS:The results suggest that longer BP limb lengths are conducive to TWL and overall treatment of obesity-related problems without severe rates of complications. Additional longer longitudinal studies are needed to assess the impact of long BP limbs on nutrition and weight loss in the long term.

Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant neurodegenerative disorder characterized by adult-onset cerebellar ataxia, and occasionally pyramidal signs, cognitive changes, sensory changes, myoclonus, and tremor. SCA14 results from heterozygous gain-of-function pathogenic variants in PRKCG, which encodes protein kinase Cγ. The aim was to elucidate the molecular mechanism of disease in a 60-year-old man with SCA14 due to a novel heterozygous variant in PRKCG c.154T > C p.(C52R). Next-generation sequencing was completed in the proband, targeted variant analysis was conducted in his family, and biochemical functional assays were performed. The C52R variant segregated with disease. Like other C1A domain variants, it had increased basal activity yet was unresponsive to agonist stimulation and was relatively resistant to down-regulation. This expands the genetic landscape of SCA14 and supports the condition as a gain-of-function disease, with variants in the C1A domain having leaky activity yet unresponsiveness to agonist stimulation.

OBJECTIVE:To assess the association between skilled nursing facility (SNF) utilization and Alzheimer's disease and related dementias (ADRD) both before and during the COVID-19 pandemic. DESIGN/METHODS:An observational cohort study. SETTING AND PARTICIPANTS/METHODS:The study included community-dwelling respondents aged 65 or older. METHODS:This study analyzed data from 3 waves of the Health and Retirement Study and employed multivariable, individual-level regressions. The primary outcomes were any SNF stays, the number of SNF stays, and the total number of SNF days, in the past 2 years of the survey. Respondents were classified as cognitively normal, having cognitive impairment but not dementia (CIND), or having ADRD. RESULTS:The study included 23,654 respondent-years, representing 12,529 unique respondents. Before the pandemic, differences in any SNF stays, and the number of SNF stays between the cognitively normal and CIND and ADRD groups were statistically insignificant in multivariable regressions. During the pandemic, compared with respondents with normal cognition, those with CIND had higher odds of any SNF stays (OR, 1.53; 95% CI, 1.06-2.20) and more SNF stays (incidence rate ratio [IRR], 2.40; 95% CI, 1.30-4.40); similarly, the ADRD group showed higher odds of any SNF stays (OR, 1.68; 95% CI, 1.08-2.59) and more SNF stays (IRR, 2.48; 95% CI, 1.36-4.47) than cognitively normal older adults. The total number of SNF days for CIND and ADRD respondents remained statistically insignificantly different from those of the cognitively normal group, both before and during the pandemic, in regression analyses. CONCLUSIONS AND IMPLICATIONS/CONCLUSIONS:This cohort study suggests that the pandemic was associated with increased differences in any SNF stays and number of transitions to SNFs between cognitively normal individuals and those with CIND or ADRD. These findings provide a foundation for understanding the potential impact of a public health emergency on post-acute care utilization among older adults with varying degrees of cognitive impairment.

OBJECTIVE:Recent guidelines suggest that non-invasive prenatal screening (NIPS) should be offered to all patients with singleton and twin pregnancies. Accurate determination of fetal fraction in cell-free DNA (cfDNA) is vital for reliable NIPS outcomes. We propose a methylation-based approach using droplet digital PCR (ddPCR) and methylation-sensitive restriction enzyme (MSRE) digestion for fetal fraction quantification as an affordable and fast solution. METHOD/METHODS:Following biomarker discovery using early pregnancy placental genomic DNA (gDNA) and cfDNA from non-pregnant female individuals, we designed assays targeting MSRE-compatible regions based on contrasting methylation patterns between maternal and fetal cfDNA. We established a proof-of-concept ddPCR workflow on the Bio-Rad Droplet Digital PCR QX600 instrument. RESULTS:Testing the fetal fraction assay multiplex on 137 prospective clinical samples demonstrated high concordance with NGS results for both female and male pregnancies as well as with chromosome Y-based calculations for samples with a male fetus. Reproducibility analysis indicated lower variability compared to previously reported NGS performance. CONCLUSION/CONCLUSIONS:This study showcases the potential of this novel, 6-color, high-multiplex methylation ddPCR panel for accurate measurement of fetal fraction in cfDNA samples. It presents opportunities to integrate such methodology as a standalone measurement to assess the quality of samples undergoing NIPS.

Tardive dyskinesia (TD) is a syndrome that causes chronic, involuntary, and disruptive movements of the body and/or face that is a severe, potentially irreversible adverse effect of long-term antipsychotic use. It has wide-reaching effects on patients' well-being, quality of life,¹ and treatment adherence.² Thus, TD is debilitating, leading to social withdrawal,³ and workplace absenteeism.¹ Current data on tardive dyskinesia treatment are limited, and prevention, primarily through the modification of antipsychotic regimens, remains the most effective strategy.⁴ Recent systematic review has shown valbenazine and vitamin E are the only treatments significantly more effective compared to placebo in treatment of TD, although valbenazine is associated with significant side effects.⁵ We present a case of a 76-year-old female with a diagnosis of Bipolar II Disorder (BD) who developed TD after treatment with lurasidone for 10 years. After struggling with both her BD and TD symptoms for 3 years, she sought care at our clinic where we prescribed 300 mg daily of lithium. At her follow-up visit 5 weeks later, her TD symptoms were greatly improved, with sustained benefits observed at following visits. This article reviews the literature discussing the interplay between lithium and TD and presents a case report of TD improvement after lithium augmentation for treatment-resistant depression. While this case suggests a potential role in TD treatment, the role of lithium in TD treatment remains controversial.

BACKGROUND:EUS-guided gastroenterostomy (EUS-GE) is a minimally invasive therapy for the management of gastric outlet obstruction (GOO). EUS-GE has demonstrated excellent short-term efficacy without the risks of surgical bypass. However, there is limited data on follow-up outcomes. In this study, we collected 6-month follow-up data on patients who underwent EUS-GE for benign and malignant etiologies, to aim to show the shift in paradigm in their management algorithm. METHODS:This was a retrospective multicenter study across 7 international centers of consecutive patients undergoing EUS-GE over a 4-year period who were entered in a dedicated registry. Demographic characteristics, procedure-related information, and follow-up data were collected. Primary outcome was the 6-month data on clinical resolution of GOO. RESULTS:Ninety-one patients were included (71 malignant and 20 benign cases). Technical success was 99% due to high expertise and volume. Clinical success at 48 hours was 97% (88/90) with an average procedure time of 47 minutes and length of stay of 5.86 days. At 3 months, 87 (95.6%) patients had achieved clinical resolution. At 6 months, 48 (53%) subjects were alive, 40 (44%) were deceased, 3 were lost to follow-up (3.3%) and 1 (1%) had a recurrence of GOO. Clinical success at 6 months follow-up was 98% (47/48). CONCLUSIONS:The majority of patients with GOO who undergo EUS-GE showed clinical resolution at 6-month follow-up. Patients with malignant etiology are appropriately palliated during their life span. Further prospective studies are necessary to obtain long-term data regarding EUS-GE for benign etiologies.

Worldwide, nearly 40% of adults are overweight and 13% are obese. Health consequences of excess weight include cardiovascular diseases, type 2 diabetes, dyslipidemia, and increased mortality. Treating obesity is challenging and calorie restriction often leads to rebound weight gain. Treatments such as bariatric surgery create hesitancy among patients due to their invasiveness. GLP-1 medications have revolutionized weight loss and can reduce body weight in obese patients by between 15% and 25% on average after about 1 year. Their mode of action is to mimic the endogenous GLP-1, an intestinal hormone that regulates glucose metabolism and satiety. However, GLP-1 drugs carry known risks and, since their use for weight loss is recent, may carry unforeseen risks as well. They carry a boxed warning for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Gastrointestinal adverse events (nausea, vomiting, diarrhea) are fairly common while pancreatitis and intestinal obstruction are rarer. There may be a loss of lean body mass as well as premature facial aging. A significant disadvantage of using these medications is the high rate of weight regain when they are discontinued. Achieving success with pharmacologic treatment and then weaning to avoid future negative effects would be ideal.

OBJECTIVE:To evaluate the early effects of Pathways to Success implementation on utilization, as measured by quarterly price-standardized Medicare spending per beneficiary. STUDY SETTING AND DESIGN/METHODS:This study was a nationwide retrospective cohort analysis of Traditional Medicare beneficiaries. The primary outcome was overall utilization, as measured by adjusted quarterly price standardized spending per beneficiary. Secondary outcomes included adjusted quarterly price standardized spending by component type (inpatient, outpatient institutional, Part B, and skilled nursing facility). The primary independent variable is Pathways to Success implementation on July 1, 2019. DATA SOURCES AND ANALYTIC SAMPLE/UNASSIGNED:A 20% sample of national Medicare data from January 1, 2018, through March 31, 2020, includes Traditional Medicare beneficiaries managed in ACOs (n = 1,368,523) and outside of ACOs ("controls," n = 1,476,982) prior to Pathways implementation. PRINCIPAL FINDINGS/RESULTS:Unadjusted quarterly spending among those in ACOs and controls decreased over the study period by $13.5 (from $2614.8 before Pathways implementation to $2601.3 after Pathways implementation) and $89.8 (from $2723.1 before Pathways implementation to $2633.3 after Pathways implementation), respectively. Adjusted quarterly spending per beneficiary decreased more slowly in ACOs compared to controls (differences-in-differences estimate +$46.8 (95% CI $19.2, $74.4) in ACOs vs. controls). This difference was largely driven by a more rapid decrease in the utilization of inpatient care. Adjusted quarterly spending per beneficiary for inpatient care decreased more slowly in ACOs compared to controls (differences-in-differences estimate +$43.6 [95% CI $27.2, $60.0] in ACOs vs. controls). CONCLUSIONS:After Pathways, reductions in utilization, as measured by price-standardized spending, by ACOs occurred less rapidly than for those managed outside of the Shared Savings Program. This effect was driven by a more rapid decrease in spending for inpatient care by nonparticipants.