Citations

Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in C9ORF72 , play a critical role in C9ORF72 -related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR–induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD.

Importance Laser-assisted drug delivery (LADD) is used for various medical and cosmetic applications. However, there is insufficient evidence-based guidance to assist clinicians performing LADD. Objective To develop recommendations for the safe and effective use of LADD. Evidence Review A systematic literature review of Cochrane Central Register of Controlled Trials, Embase, and MEDLINE was conducted in December 2019 to identify publications reporting research on LADD. A multidisciplinary panel was convened to draft recommendations informed by the systematic review; they were refined through 2 rounds of Delphi survey, 2 consensus meetings, and iterative review by all panelists until unanimous consensus was achieved. Findings Of the 48 published studies of ablative fractional LADD that met inclusion criteria, 4 were cosmetic studies; 21, oncologic; and 23, medical (not cosmetic/oncologic), and 6 publications of nonablative fractional LADD were included at the request of the expert panel, producing a total of 54 studies. Thirty-four studies (63.0%) were deemed to have low risk of bias, 17 studies (31.5%) had moderate risk, and 3 (5.5%) had serious risk. The key findings that informed the guidelines developed by the expert panel were as follows: LADD is safe in adults and adolescents (≥12 years) with all Fitzpatrick skin types and in patients with immunosuppression; it is an effective treatment for actinic keratosis, cutaneous squamous cell carcinoma in situ, actinic cheilitis, hypertrophic scars, and keloids; it is useful for epidermal and dermal analgesia; drug delivery may be increased through the application of heat, pressure, or occlusion, or by using an aqueous drug solution; laser settings should be selected to ensure that channel diameter is greater than the delivered molecule; antibiotic prophylaxis is not recommended, except with impaired wound healing; antiviral prophylaxis is recommended when treating the face and genitalia; and antifungal prophylaxis is not recommended. The guideline’s 15 recommendations address 5 areas of LADD use: (I) indications and contraindications; (II) parameters to report; (III) optimization of drug delivery; (IV) safety considerations; and (V) prophylaxis for bacterial, viral, and fungal infections. Conclusions and Relevance This systematic review and Delphi consensus approach culminated in an evidence-based clinical practice guideline for safe and effective use of LADD in a variety of applications. Future research will further improve our understanding of this novel treatment technique.

Patients scheduling or checking in for medical appointments often share with frontline employees’ details of their stories, including their worries, prior negative experiences, and hopes. These interactions require employees to not only complete their task, but also to be mindfully present, picking up on important social cues and showing appropriate emotional congruence and empathic understanding. Based on a review of recorded patient calls, a gap was identified in the communication skills of desk and scheduling staff at this large academic medical center, and a sustained training program was created to fill this gap. The training is centered on an evolving set of theoretical principles and skills that have come to be known as the Experience Model of Communication (XMOC). We wanted to understand if training in XMOC, a set of skills essential for healthcare providers, would also be beneficial for frontline staff. The training was evaluated with pre/post surveys, listening sessions, an annual evaluation, and quarterly tracking of patient experience scores, and findings suggest that the training content has had a positive impact. We continue to build and evaluate the training program to identify and refine the elements that make up XMOC and the most effective ways to transfer that learning to the staff who benefit. Experience Framework This article is associated with the Staff & Provider Engagement lens of The Beryl Institute Experience Framework (https://www.theberylinstitute.org/ExperienceFramework). Access other PXJ articles related to this lens. Access other resources related to this lens.

Objective Develop an online estimator that accurately predicts bronchopulmonary dysplasia (BPD) severity or death using readily-available demographic and clinical data. Design Retrospective analysis of data entered into a prospective registry. Setting Infants cared for at centres of the United States Neonatal Research Network between 2011 and 2017. Patients Infants 501–1250 g birth weight and 23 0/7–28 6/7 weeks’ gestation. Interventions None. Main outcome measures Separate multinomial regression models for postnatal days 1, 3, 7, 14 and 28 were developed to estimate the individual probabilities of death or BPD severity (no BPD, grade 1 BPD, grade 2 BPD, grade 3 BPD) defined according to the mode of respiratory support administered at 36 weeks’ postmenstrual age. Results Among 9181 included infants, birth weight was most predictive of death or BPD severity on postnatal day 1, while mode of respiratory support was the most predictive factor on days 3, 7, 14 and 28. The predictive accuracy of the models increased at each time period from postnatal day 1 (C-statistic: 0.674) to postnatal day 28 (C-statistic 0.741). We used these results to develop a web-based model that provides predicted estimates for BPD by postnatal day. Conclusion The probability of BPD or death in extremely preterm infants can be estimated with reasonable accuracy using a limited amount of readily available clinical information. This tool may aid clinical prognostication, future research, and center-specific quality improvement surrounding BPD prevention. Trial registration number NCT00063063

Objectives/HypothesisThis study defines essential data elements to be recorded during an aerodigestive “triple endoscopy” to form the foundation of a standardized multicenter registry and to clearly define measurement of each consensus item.Study DesignModified Delphi process.MethodsModified Delphi consensus with six survey rounds. Twenty‐four expert pediatric otolaryngology, pulmonology, and gastroenterology aerodigestive clinicians from eight large academic pediatric aerodigestive programs formed the Delphi panel. After achieving consensus through the Delphi process, outside validation was performed at 2019 national Aerodigestive Society conference. Consensus, near‐consensus, or exclusion was obtained for each proposed data element. Concordance was then measured between expert panel conclusions and validation group conclusions.ResultsOverall response rate was 94.4%. 73/167 proposed items reached consensus in six domains (flexible bronchoscopy, bronchoalveolar lavage, microdirect laryngoscopy and bronchoscopy, esophagogastroduodenoscopy with biopsies, and esophageal impedance and pH probe). Measurement of all items was defined; classification/grading systems were selected for 11 items. Validation group endorsed importance of 82/167 data items; compared to expert consensus, overall, inclusion, and exclusion concordance rates were 94.5%, 98.7%, and 90.9%.ConclusionTriple endoscopy is a central component of aerodigestive care. This study identifies and defines data elements to be recorded for all triple endoscopy procedures. The list is of usable length, and clear definitions were created for all items, with explicit classification/grading systems selected for 11 items. Face validity was confirmed with an independent multispecialty sample of aerodigestive providers. This consensus provides the foundation for a triple endoscopy registry but also is immediately applicable to standardize clinical documentation in aerodigestive care.Level of Evidence5 Laryngoscope, 132:2251–2258, 2022

Abstract Background Starting in November 2020, the US Food and Drug Administration (FDA) has issued Emergency Use Authorizations (EUAs) for multiple novel virus-neutralizing monoclonal antibody therapies, including bamlanivimab monotherapy (now revoked), bamlanivimab and etesivimab, casirivimab and imdevimab (REGEN-COV), and sotrovimab, for treatment or postexposure prophylaxis of Coronavirus disease 2019 (COVID-19) in adolescents (≥12 years of age) and adults with certain high-risk conditions. Previous guidance is now updated based on new evidence and clinical experience. Methods A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacotherapy, and pediatric critical care medicine from 18 geographically diverse US institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on a review of the best available evidence and expert opinion. Results The course of COVID-19 in children and adolescents is typically mild, though more severe disease is occasionally observed. Evidence supporting risk stratification is incomplete. Randomized controlled trials have demonstrated the benefit of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-specific monoclonal antibody therapies in adults, but data on safety and efficacy in children or adolescents are limited. Potential harms associated with infusion reactions or anaphylaxis are reportedly low in adults. Conclusions Based on evidence available as of August 31, 2021, the panel suggests a risk-based approach to administration of SARS-CoV-2 monoclonal antibody therapy. Therapy is suggested for the treatment of mild to moderate COVID-19 in adolescents (≥12 years of age) at the highest risk of progression to hospitalization or severe disease. Therapeutic decision-making about those at moderate risk of severe disease should be individualized. Use as postexposure prophylaxis could be considered for those at the highest risk who have a high-risk exposure but are not yet diagnosed with COVID-19. Clinicians and health systems should ensure safe and timely implementation of these therapeutics that does not exacerbate existing healthcare disparities.

Small-molecule recruitment of an endogenous nuclease rescues pathologies associated with c9ALS/FTD in vivo by targeting an RNA repeat expansion.

PURPOSE The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated nonmetastatic Ewing sarcoma. METHODS Patients were randomly assigned to receive standard five-drug interval compressed chemotherapy (regimen A) for 17 cycles or experimental therapy with five cycles of VTC within the 17 cycles (regimen B). Patients were stratified by age at diagnosis (< 18 years and ≥18 years) and tumor site (pelvic bone, nonpelvic bone, and extraosseous). Tumor volume at diagnosis was categorized as < 200 mL or ≥ 200 mL. Local control occurred following six cycles. Histologic response was categorized as no viable or any viable tumor. Event-free survival (EFS) and overall survival (OS) were compared between randomized groups with stratified log-rank tests. RESULTS Of 642 enrolled patients, 309 eligible patients received standard and 320 received experimental therapy. The 5-year EFS and OS were 78% and 87%, respectively. There was no difference in survival outcomes between randomized groups (5-year EFS regimen A v regimen B, 78% v 79%; P = .192; 5-year OS 86% v 88%; P = .159). Age and primary site did not affect the risk of an EFS event. However, age ≥ 18 years was associated with an increased risk of death at 5 years (hazard ratio 1.84; 95% CI, 1.15 to 2.96; P = .009). The 5-year EFS rates for patients with pelvic, nonpelvic bone, and extraosseous primary tumors were 75%, 78%, and 85%, respectively. Tumor volume ≥ 200 mL was significantly associated with lower EFS. CONCLUSION While VTC added to five-drug interval compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma.

AbstractThe study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.