Impact of Patient Factors on Attendance at Remote Telehealth Swallow Therapy.

In-person swallow therapy is a primary and effective treatment for dysphagia. However, remote telehealth is now a widely utilized component of healthcare delivery for therapeutic interventions. This study evaluates potential factors influencing attendance at telehealth swallow therapy. Retrospective review of 308 patients referred for telehealth swallow therapy from April 2020-November 2021 included patient referral diagnosis, diagnostic swallowing evaluations, and sociodemographic information including age, race, health insurance, interpreter use, and socioeconomic status. Univariable and multivariable analyses compared patient and appointment factors for those who attended telehealth swallow therapy with those who did not attend. Overall, 71.8% of patients attended at least one telehealth swallow therapy appointment while 28.2% did not attend any. The most common referral diagnoses were "Cancer" (19.2%) and "Dysphagia Unspecified" (19.2%). Patients diagnosed with "Cancer" and "Muscle Tension" were significantly less likely to attend telehealth swallow therapy compared to those with "Dysphagia Unspecified," "Globus," and "Gastroesophageal Reflux Disease/Laryngopharyngeal Reflux" after adjusting for covariates. Lower socioeconomic status (p = 0.023), no interpreter use (p < 0.001), and more diagnostic evaluations (p = 0.001) correlated with higher telehealth swallow therapy attendance. Race and sex did not correlate with attendance. Most patients referred to telehealth swallow therapy attended at least one appointment. Patients with dysphagia associated with cancer and muscle tension, those with higher socioeconomic status, interpreter use, and fewer diagnostic swallowing evaluations were less likely to attend telehealth swallow therapy. Future research should investigate and compare attendance and efficacy of telehealth swallow therapy with in-person therapy.

Genicular nerve block for emergency department patient: a successful management of subacute osteoarthritic knee pain.

The genicular nerve block (GNB) performed under ultrasound is a common procedure in the perioperative and outpatient setting for the treatment of surgical knee pain and osteoarthritis. It provides motor-sparing analgesia to the knee, making it a potential alternative to other modes of pain management in the emergency department (ED). We present an elderly woman with acute-on-chronic osteoarthritic knee pain which was relieved for a week after a GNB during her ED visit. In patients with knee pain, the ultrasound guided GNB has the potential to provide short-term analgesia for patients with pain refractory to other modes of analgesia. The GNB shows promise as a reliable contribution to a multimodal approach to pain management in the ED setting.

Visualizing the randomized sham-controlled trial in orthopedic research: proposed steps to conducting a total knee arthroplasty randomized controlled trial.

Performed more than 600,000 times annually in the USA alone, total knee arthroplasty is the one of the most common and costly elective operations in the world. A primary total knee arthroplasty is generally an elective procedure, for which total index hospitalization costs are estimated around $30,000 USD. Roughly four in five patients declare they are satisfied postoperatively, justifying the procedure's frequency and high costs. It is sobering to realize, however, that the evidence base in favor of this procedure remains circumstantial. We as a profession lack randomized trials showing a subjective improvement over placebo intervention. We argue for the necessity of sham-controlled surgical trials in this setting and provide a surgical atlas showing how a sham operation may be performed.

Rapid Mobilization of Medical Students to Provide Health Care Workers With Emergency Childcare During the COVID-19 Pandemic.

PROBLEM: In March 2020, the novel coronavirus 2019 (COVID-19) pandemic spread rapidly within the United States and began overwhelming the health care system. To conserve personal protective equipment, reduce the spread of the virus, and keep student learners safe, leaders of medical schools across the country made the difficult decision to suspend in-person clinical experiences. As medical students were sent home and hospital systems ramped up their response to the virus, many essential health care workers (HCWs) faced an immediate challenge. As "nonessential" services such as schools and daycare centers abruptly closed, HCWs serving on the frontlines in inpatient settings needed a way to both fight the pandemic and care for their children. APPROACH: Medical students at Oregon Health & Science University were able to rapidly OR organize to provide childcare for essential HCWs. For roughly 8 weeks following the state of emergency (March 13 through May 15, 2020), students used Twitter and emerging technology to match families in need of childcare with a trainee volunteer. OUTCOMES: By May 15th, the service had successfully fulfilled 181 of the 202 requests for childcare (90%) over the course of 8 weeks. Of the 181 completed childcare requests, 172 (95%) were fulfilled by an individual (1:1 volunteer-to-household pairing), and 9 (5%) were fulfilled by 2 or more volunteers. NEXT STEPS: The trainees who provided childcare will apply the skills learned (e.g., clear communication, grassroots organizing, triaging, leveraging new technology) to patient care. Broader applications for this system include organizing volunteers to conduct contract tracing or to provide public health information in languages other than English. Future research includes examining the effect of the service on the productivity, morale, and mental health of both those who provided and received childcare.

Phase I trials and therapeutic intent in the age of precision oncology: What is a patient's chance of response?

The advancement of therapeutic strategies in oncology such as precision oncology has generated significant interest in better estimating the response of modern phase I cancer clinical trials. These estimates have varied widely. In this commentary, we provide an umbrella review of phase I response rates and discuss methodological reasons for variation in prior estimates which include limited use of unpublished data, the inclusion of expansion cohorts that artificially raise response rates of cumulative response rates, varying enrolment of haematologic malignancies, and increased next in class drugs.

Analysis of estimated clinical benefit of newly approved drugs for US patients with acute myeloid leukemia.

The increased number of available United States Food and Drug Administration (FDA)-approved drugs indicated for acute myeloid leukemia (AML) have generated considerable interest and may have the potential to influence practice. We performed a retrospective cross-sectional study performed from September to November 2019 to determine 1) demographic and subgroup characteristics of patients with newly diagnosed cases of acute myeloid leukemia, 2) FDA data on drugs indicated for AML approved from 1969 through November 2019, 3) measures of response from drug labels, and 4) published reports documenting the response for drugs approved before the 1979 Labeling Act. We used publicly available data from the Food and Drug Administration (FDA), the American Cancer Society, the Leukemia and Lymphoma Society, and the U.S. Census Bureau. According to our estimation methods, cytarabine infused continuously for 7 days, with three short boluses of anthracycline over Days 1-3, the standard of care known as "7 + 3", continues to have the largest population benefit. The maximum cost per course of treatment for an average regimen is enasidenib for salvage therapy, estimated to be around $120,131. The minimum cost was $1,662.50 for standard 7 + 3 chemotherapy. The mean and median cost for all AML treatments was $43,784.26 and $35,083.70, respectively. While it is true that the number of available therapies approved by the FDA has increased dramatically, it is not yet clear how large of a clinical benefit we can expect to see from these new lines of therapies.

Improving Timeliness of Lung Cancer Diagnosis and Staging Investigations Through Implementation of Standardized Triage Pathways.

PURPOSE: Timely care for patients with lung cancer (LC) is associated with improved clinical outcomes. In Southeastern Ontario, Canada, we identified delays in the diagnostic process for patients undergoing evaluation for suspected LC through a rapid assessment clinic. We developed improvement initiatives with an aim of reducing the time from referral to diagnosis. METHODS: A Standardized Triage Process (STP) was implemented for patients referred with suspected LC, including routine interdisciplinary triage, standardized pathways with preordered staging tests, and a new Small Nodule Clinic. We retrospectively analyzed all patients referred pre-STP (January to April 2018) and prospectively for improvement (May 2018 to March 2019). Process measures included STP compliance and time to completion of staging investigations (positron emission tomography [PET] and computed tomography/magnetic resonance imaging of brain). Data are reported as means; significance was determined by special-cause variation using Statistical Process Control charts; unpaired t tests were compared between groups. RESULTS: We reviewed 833 referrals (207 baseline and 626 post-STP). STP compliance improved monthly to 99.4%. Post-STP, time from referral to PET decreased (from 38.5 to 15.7 days), time from referral to brain imaging decreased (from 33.4 to 13.1 days), and time from referral to diagnosis decreased (from 38.0 to 22.7 days), all demonstrating special-cause variation. Patients completing preordered staging tests experienced significantly faster care than those without preordered tests, including time to PET (23.0 v 35.9 days), computed tomography/magnetic resonance imaging of brain (16.2 v 29.9 days), and diagnosis (39.9 v 28.1 days), all P < .001. CONCLUSION: An STP significantly improved timeliness of diagnosis and staging for patients with suspected LC undergoing evaluation in a rapid assessment clinic.

Shifting, overlapping and expanding use of "precision oncology" terminology: a retrospective literature analysis.

IMPORTANCE: The terms "personalized oncology" and "precision oncology" have increased in usage and have generated considerable traction in terms of public attention and research funding. To our knowledge, no prior study has as thoroughly documented the use of the "precision oncology" terminology over the last decade. OBJECTIVE: To determine how the use of the terms "personalized oncology" and "precision oncology" have changed over time. DESIGN: A retrospective literature analysis using two databases (PubMed and Scopus) over 10 years was performed. Manuscripts using either term "personalized oncology" or "precision oncology" were collected. Manuscripts published in 2011, 2013, 2015, 2017 and through 30 June 2019 were pulled for text analysis. Common reasons for exclusion were if the search term appeared in the institution name only, the search term appeared only in keyword or publication title, or the search term was used to justify the relevance or application of research with no clear definition. SETTING: Manuscripts published and catalogued in PubMed or Scopus. RESULTS: In our study, we analysed 399 unique manuscripts published over the last decade. Over time, the terminology has shifted from "personalized oncology" to "precision oncology". Targeted therapy, molecular biomarker-guided tumour profiling and next generation sequencing (ie, "omics-guided tumor profiling") are the three most common definitions of the term. While these definitions are somewhat overlapping in concept, over the decade we observed an increase in the number of distinct interpretations of "precision oncology", ranging from structural biology to clinical practice. CONCLUSIONS AND RELEVANCE: We have observed that the phrase "precision oncology" is shifting, overlapping and expanding in definition. This all-encompassing approach to defining "precision oncology" ironically renders the term imprecise. Our analysis highlights the inherent challenges in defining novel movements in medicine.

Facilitative effects of environmental enrichment for cocaine relapse prevention are dependent on extinction training context and involve increased TrkB signaling in dorsal hippocampus and ventromedial prefrontal cortex.

Cocaine-cue extinction training combined with brief interventions of environmental enrichment (EE) was shown previously to facilitate extinction and attenuate reacquisition of cocaine self-administration in rats. It is unknown whether or not the usefulness of this approach would be undermined if extinction training took place in a novel rather than familiar context. Drawing on previous studies involving pharmacological interventions, we hypothesized that the facilitative effects of EE for cocaine relapse prevention would be independent of the context used for extinction training. Rats trained to self-administer cocaine underwent cocaine-cue extinction training in either the familiar self-administration context or a novel context, with or without EE. Rats then were tested for reacquisition of cocaine self-administration in the familiar context. Target brain regions were lysed and probed for memory-related changes in receptors for glutamate and BDNF by western blotting. Contrary to our hypothesis, the facilitative effects of EE for cocaine relapse prevention were dependent on the context used for extinction training. While EE facilitated extinction regardless of context used, it inhibited cocaine relapse only after extinction training in the familiar context. EE was associated with increased GluA2 in nucleus accumbens, TrkB in dorsal hippocampus and activated TrkB in ventromedial prefrontal cortex. Of these, the changes in dorsal hippocampus and ventromedial prefrontal cortex mirrored outcomes of the cocaine relapse tests in that these changes were specific to rats receiving EE plus extinction training in the familiar context. These findings support a role for hippocampal-prefrontal BDNF-TrkB signaling in extinction-based relapse prevention strategies involving EE.

Morphological and Molecular Defects in Human Three-Dimensional Retinal Organoid Model of X-Linked Juvenile Retinoschisis.

X-linked juvenile retinoschisis (XLRS), linked to mutations in the RS1 gene, is a degenerative retinopathy with a retinal splitting phenotype. We generated human induced pluripotent stem cells (hiPSCs) from patients to study XLRS in a 3D retinal organoid in vitro differentiation system. This model recapitulates key features of XLRS including retinal splitting, defective retinoschisin production, outer-segment defects, abnormal paxillin turnover, and impaired ER-Golgi transportation. RS1 mutation also affects the development of photoreceptor sensory cilia and results in altered expression of other retinopathy-associated genes. CRISPR/Cas9 correction of the disease-associated C625T mutation normalizes the splitting phenotype, outer-segment defects, paxillin dynamics, ciliary marker expression, and transcriptome profiles. Likewise, mutating RS1 in control hiPSCs produces the disease-associated phenotypes. Finally, we show that the C625T mutation can be repaired precisely and efficiently using a base-editing approach. Taken together, our data establish 3D organoids as a valid disease model.

Estimation of Study Time Reduction Using Surrogate End Points Rather Than Overall Survival in Oncology Clinical Trials.

Importance: Surrogate end points in oncology trade the advantage of reducing the time needed to conduct clinical trials for the disadvantage of greater uncertainty regarding the treatment effect on patient-centered end points, such as overall survival (OS) and quality of life. Objective: To quantify the amount of time saved through the acceptance of surrogate end points, including response rate (RR) and progression-free survival (PFS). Design, Setting, and Participants: This retrospective study of US Food and Drug Administration (FDA) oncology approvals and their drug registration trials based on actual publication analyzed the original and updated clinical trials data that led to FDA-approved drug indications in oncology from 2006 to 2017 by using existing publications, conference abstracts, and package inserts from the FDA. Data related to cancer type, line of therapy (first-line, second-line, and third- or later-line treatment of advanced or metastatic disease), FDA approval type, end point basis for approval (RR, PFS, or OS/quality of life), sample size, accrual rate, and drug RR were extracted by March 23, 2018. All data were analyzed by July 13, 2018. Main Outcomes and Measures: The main outcome was the study duration needed to complete the primary end point analysis used for each drug indication approval. This was estimated from reported enrollment dates, analysis cutoff dates, time to response, median duration of response, median PFS, and median OS. Results: In total, 188 distinct indications among 107 cancer drugs were identified. The RR was more often used for FDA approval in subsequent lines of therapy (17 of 71 drug indications [24%] in first-line therapy vs 34 of 77 drug indications [44%] in second-line therapy vs 19 of 24 drug indications [79%] in third- or later-line therapy, P < .001). Study duration for PFS (median, 31 [range, 10-104] months) was similar to that for OS (median, 33 [range, 12-117] months; P = .31), whereas study duration for RR (median, 25 [range, 11-54] months) was shorter than that for OS (P = .001). In multivariate analysis, compared with using OS, use of PFS as the end point was associated with study durations that were shorter by a mean of 11 months (95% CI, 5-17 months), and the use of RR as the end point was associated with study durations that were shorter by a mean of 19 months (95% CI, 13-25 months). Conclusions and Relevance: From the findings of this study, an estimated 11 months appeared to be needed (ie, approximately 12% longer in the drug development cycle) to assess the OS benefit of a cancer drug. This study's findings suggest that this must be weighed against the downside of increased uncertainty of clinical benefit arising from using surrogate end points.

Using CRISPR-Cas9 to Generate Gene-Corrected Autologous iPSCs for the Treatment of Inherited Retinal Degeneration.

Patient-derived induced pluripotent stem cells (iPSCs) hold great promise for autologous cell replacement. However, for many inherited diseases, treatment will likely require genetic repair pre-transplantation. Genome editing technologies are useful for this application. The purpose of this study was to develop CRISPR-Cas9-mediated genome editing strategies to target and correct the three most common types of disease-causing variants in patient-derived iPSCs: (1) exonic, (2) deep intronic, and (3) dominant gain of function. We developed a homology-directed repair strategy targeting a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) and demonstrated restoration of the retinal transcript and protein in patient cells. We generated a CRISPR-Cas9-mediated non-homologous end joining (NHEJ) approach to excise a major contributor to Leber congenital amaurosis, the IVS26 cryptic-splice mutation in CEP290, and demonstrated correction of the transcript and protein in patient iPSCs. Lastly, we designed allele-specific CRISPR guides that selectively target the mutant Pro23His rhodopsin (RHO) allele, which, following delivery to both patient iPSCs in vitro and pig retina in vivo, created a frameshift and premature stop that would prevent transcription of the disease-causing variant. The strategies developed in this study will prove useful for correcting a wide range of genetic variants in genes that cause inherited retinal degeneration.

Frequency and Duration of Adrenal Suppression Following Glucocorticoid Therapy in Children With Rheumatic Diseases.

OBJECTIVE: Adrenal suppression (AS), a glucocorticoid (GC) side effect with potentially significant morbidity, is poorly understood. The purpose of our study was to determine frequency, duration, and predictors of AS following a gradual taper of GC in children with rheumatic conditions. METHODS: A prospective, observational cohort study was conducted. All patients ages ≤16 years ready to discontinue GC after >4 weeks of therapy were included. Morning cortisol was tested 4 weeks after GC taper to physiologic doses and then repeatedly until normalization. GCs were subsequently discontinued and a low-dose adrenocorticotropic hormone stimulation test was performed. RESULTS: The study was completed by 31 of 39 patients. The median age was 12.9 years and median duration of GC therapy was 39.6 weeks. Seventeen patients (54.8%) had AS. Of the patients with AS, 50% showed recovery by 7 months. Two patients had persistent AS at 12 months and 1 patient at 2 years. A higher maximum GC dose was a significant predictor for the development of AS. CONCLUSION: More than 50% of our patients had AS after GC discontinuation, despite a gradual taper of GC. Stress steroids should be considered in children treated with long-term GC, even after steroid discontinuation, to prevent possible adrenal crisis.