Clinical outcomes and frequency of persistent infection among immunosuppressed patients treated with bebtelovimab for COVID-19 infection at an ambulatory cancer center.

BACKGROUND: There are limited data on clinical outcomes associated with the use of bebtelovimab for the treatment of coronavirus disease 2019 (COVID-19) among cancer patients. We aimed to define the clinical characteristics and outcomes among patients receiving bebtelovimab as part of the COVID-19 therapeutics program at our cancer center. METHODS: This is a retrospective cohort study of immunosuppressed adult patients who received bebtelovimab at Fred Hutchinson Cancer Center between March 2022, and November 2022. We reviewed medical records to capture the date of the first positive COVID-19 test, clinical characteristics, outcomes, and follow-up COVID-19 testing for 60 days after the first positive. Persistent infection was defined as a positive test beyond day 30; these patients were reviewed beyond day 60. RESULTS: Among 93 patients who received bebtelovimab, 64 (69%) had hematologic malignancy. Sixty-nine (74%) patients received bebtelovimab within 2 days after diagnosis. Two (2%) patients were hospitalized, none required ICU care, and one patient died on day 52; although it is unknown if death was directly related to COVID-19. Ten (11%) patients had persistent COVID-19 infection; of these, four received additional COVID-19 therapy with either nirmatrelvir/ritonavir or remdesivir, and five out of six patients with sequencing data available had spike protein mutations associated with bebtelovimab resistance. CONCLUSION: A coordinated systems-based approach led to prompt initiation of bebtelovimab within two days of testing positive in most patients. We observed few hospitalizations or deaths. Persistent infection was noted in 11% of patients with four requiring additional therapies, highlighting a need for novel strategies to manage immunosuppressed patients.

Hearing aid utilization in Ontario - a population based study.

BACKGROUND: Hearing loss is one of the most common sensory impairments and hearing aids are the most common unmet assistive device need among individuals with a disability. The benefits of hearing interventions are well-documented as they are known to deter the sequalae of hearing loss including social isolation, poor mental health, falls and cognitive decline. Identifying trends in hearing aid users can provide valuable information for improving access to hearing loss interventions. METHODS: Data were retrieved from ICES databases that were used to generate a cohort of 372,448 individuals in Ontario, Canada, who first claimed hearing aids between April 2007 and March 2018 through the Assistive Devices Program. RESULTS: The data indicated that the frequency distribution of hearing aids has steadily inclined since 2007. The mean age of hearing aid users was 70.25 ± 14.70 years and higher neighbourhood income quintile was associated with greater hearing aid use (p < 0.001). Most first claims occurred after visiting primary care physicians (70.60%) compared with otolaryngology (13.39%). An examination of clinical comorbidities revealed hypertension (63.41%), and diabetes (24.93%) to be the most common. Regression analysis demonstrated a positive associated between age and most comorbidities. Furthermore, higher neighbourhood income quintiles were associated with a reduced risk of having the examined comorbidities. CONCLUSIONS: This study examines patient demographics and clinical comorbidities in a cohort of hearing aid users in Ontario. The results identify associations between demographics and comorbidities that provide information relevant for improving access to hearing interventions and clinical decision-making in primary care.Implications for RehabilitationScreening for hearing loss (using an audiogram) in elderly individuals that manage multiple comorbidities, and any patient with significant risk factors for hearing loss (e.g., noise exposure history, prior ototoxic medications, prior head injury, history of ear surgery, family history of hearing loss) will identify deficits and direct appropriate hearing interventions.Improving access to care in low-income communities should include community-based education around expectation management and communication strategies to reinforce proper use and care of hearing devices.Geographic proximity to hearing testing facilities and hearing aid dispensaries is a significant barrier to hearing rehabilitation strategies.

Approach to hearing loss.

OBJECTIVE: To provide family physicians with a practical evidence-based approach to the management of patients with hearing loss. SOURCES OF INFORMATION: MEDLINE and PubMed databases were searched for English-language hearing loss research, review articles, and guidelines published between 1980 and 2020. Most of the retrieved articles provided level II or III evidence. MAIN MESSAGE: Hearing loss is one of the most common sensory impairments worldwide and causes great detriment to a patient's overall well-being by affecting physical health, finances, social inclusion, and mental health. A robust clinical assessment of hearing loss includes a history and physical examination that effectively characterizes the deficit as conductive, sensorineural, or mixed. Patients presenting with red flags (such as sudden unilateral sensorineural hearing loss) must be urgently referred to otolaryngology-head and neck surgery or immediately assessed in the emergency department. Many nonurgent presentations of hearing loss will also require referral for further audiological assessment, diagnosis, and management. CONCLUSION: As primary care providers, family physicians are well equipped to manage the psychological concerns associated with hearing loss and to reinforce conservative treatment strategies. Frequently, referral or urgent workup, including imaging, is necessary to confirm a patient's diagnosis and initiate management in order to prevent further complications.

Aborder la perte auditive.

OBJECTIF: Fournir aux médecins de famille une approche pratique et fondée sur des données probantes pour la prise en charge de la perte auditive. SOURCES D'INFORMATION: Une recherche dans les bases de données MEDLINE et PubMed a relevé les revues de synthèse, recherches et lignes directrices publiées en anglais de 1980 à 2020. Les données probantes étaient de niveau II ou III dans la plupart des articles relevés. MESSAGE PRINCIPAL: La perte auditive est l'une des déficiences sensorielles les plus fréquentes dans le monde, et elle est grandement préjudiciable au bien-être général du patient, affectant sa santé physique, ses finances, son inclusion sociale et sa santé mentale. Une solide évaluation clinique de la perte auditive comprend une anamnèse et un examen physique qui caractérisent efficacement la perte auditive comme étant de transmission, neurosensorielle ou mixte. Les patients qui présentent des signes alarmants (comme une perte auditive neurosensorielle unilatérale soudaine) doivent être aiguillés d'urgence en oto-rhino-laryngologie et chirurgie cervico-faciale ou être évalués immédiatement au service des urgences. Beaucoup de cas non urgents de perte auditive nécessitent également une évaluation audiologique plus poussée, un diagnostic et la prise en charge. CONCLUSION: À titre de fournisseurs de soins de première ligne, les médecins de famille sont bien placés pour gérer les préoccupations psychologiques liées à la perte auditive et pour renforcer les stratégies thérapeutiques prudentes. Il est fréquemment nécessaire d'aiguiller le patient ou d'effectuer un bilan urgent, dont l'imagerie, pour confirmer le diagnostic et instaurer la prise en charge afin de prévenir d'autres complications.

Association of tympanostomy tubes with future assistive hearing devices-a population based study.

BACKGROUND: Ear (tympanostomy) tube (TT) placement is a common ambulatory surgery in children. Despite the commonality of this treatment, the long-term effects are unknown. The objective of this study was to determine the rate of permanent hearing loss, as measured by use of a rehabilitative hearing device. METHODS: A retrospective comprehensive population-based cohort study was performed, evaluating all hospitals in the Canadian province of Ontario. Three cohorts of children were constructed: TT - at least one ear tube procedure (n = 193,880), No-TT -recurrent visits to a physician for middle ear disease, did not undergo ear tubes (n = 203,283), and Control - an age/sex matched group who had not undergone ear tubes and who didn't have repeat physician visits for middle ear disease (n = 961,168). The main outcome measures were risk and odds ratio (OR) of rehabilitative hearing devices. RESULTS: The TT cohort had a higher risk of obtaining a hearing aid (OR 4.53 vs. No-TT, p < 0.001; OR 10.81 vs. Control, p < 0.001), an FM system (OR 3.84 vs. No-TT, p < 0.001; OR 15.13 vs. Control, p < 0.001), and an implanted bone conduction device (OR 5.08 vs. No-TT, p < 0.001; OR 15.67 vs. Control, p < 0.001). CONCLUSIONS: An association between ear tube placement and long-term need for a rehabilitative hearing device was found. This association warrants future prospective research in this area.

Cancer overturned: Endometrioma mimicking granulosa cell tumor and the importance of FOXL2 analysis.

BACKGROUND: Various ovarian neoplasms may show histological findings that are morphologically indistinguishable from adult granulosa cell tumor (AGCT). CASE PRESENTATION: A 36 year-old women presented with left lower extremity pain and numbness. Ultrasound revealed a 10 cm left adnexal mass treated with ovarian cystectomy. Histopathology revealed endometriotic cyst with intramural granulosa cell tumor. She underwent a laparoscopic left salpingo-oophorectomy and omental biopsy by Gynecologic Oncology. Pathologic review of residual ovarian abnormality prompted a molecular analysis. FOXL2 gene mutation was absent supporting the diagnosis of benign endometrioma. CONCLUSIONS: A somatic missense mutation in the FOXL2 gene is a sensitive molecular marker for AGCT. Mutation analysis can help distinguish malignant from benign pathology to provide appropriate treatment and disease surveillance.

Management of disseminated intravascular coagulation in a patient with hepatic angiosarcoma: A case report.

RATIONALE: Hepatic angiosarcoma is a rare endothelial cell tumor that may lead to concurrent consumptive coagulopathies including disseminated intravascular coagulation (DIC). This report details a multifaceted approach to managing DIC in a patient with advanced-stage hepatic angiosarcoma, which continued to progress after a brief response to taxane-based chemotherapy. PATIENT CONCERNS: A 55-year-old man with a recent history of hemorrhoids and hemarthroses presented with acute rectal bleeding. He was found to have concurrent hepatomegaly, abnormal liver function tests, anemia, thrombocytopenia, and coagulopathy. DIAGNOSES: DIC in the setting of hepatic angiosarcoma. INTERVENTIONS: The patient's acute bleeding in the setting of DIC was controlled with a combination of antifibrinolytic agents to prevent clot breakdown, heparin products to prevent deposition of new clot, and romiplostim to increase platelet production. His angiosarcoma was treated with various combinations of chemotherapy, including taxane-based chemotherapy, doxorubicin, and pazopanib. OUTCOMES: The patient's DIC and acute bleeding on initial presentation improved following treatment with unfractionated heparin and low-molecular weight heparin maintenance therapy. It is unclear if the chemotherapy to treat the hepatic angiosarcoma played a significant role in the improvement of DIC. LESSONS: Laboratory measurement of prothrombin fragment 1.2, a byproduct of prothrombin conversion to thrombin, proved to be a useful way to monitor this patient's DIC over time.

Audiometric Testing Guideline Adherence in Children Undergoing Tympanostomy Tubes: A Population-Based Study.

Objective Tympanostomy tube (TT) insertion is the most common ambulatory surgery performed on children. American Academy of Otolaryngology-Head and Neck Surgery Founda-tion (AAO-HNSF) Clinical Practice Guidelines (CPGs) recommend hearing testing for all pediatric TT candidates. The aim of this study was to assess audiometric testing in this population. Study Design Retrospective population-based cohort study. Setting All hospitals in the Canadian province of Ontario. Subjects and Methods All patients 12 years of age and younger who underwent at least 1 TT procedure between January 1993 and June 2016. The primary outcomes were the percentage of patients who underwent a hearing test within 1 year before and/or 1 year after surgery. Results A total of 316,599 bilateral TT procedures were performed during the study period (1993 to 2016). Presurgical hearing tests increased from 55.7% to 74.9%, and postsurgical hearing tests increased from 42.2% to 68.9%. Younger surgeons demonstrated a greater adherence to the CPGs (relative risk [RR], 1.22; 95% CI, 1.08-1.38; P = .001). Remarkably, there was not a spike in preoperative hearing tests following the introduction of the CPGs in 2013 (RR, 1.12; 95% CI, 0.85-1.47; P = .432). Presurgical hearing testing ranged from 26.1% to 83.5% across health regions. Conclusion In this cohort of children who underwent TT placement, the trends of preoperative and postoperative audiometric testing are increasing but are still lower than recommended by the CPGs, despite a tripling of practicing audiologists. This study describes the current state of testing in Ontario and highlights issues of access to audiology services, possible parent preferences, and the importance of ongoing continuing medical education for all health care practitioners.

Ligament shortening compared to vaginal colpopexy at the time of hysterectomy for pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: The performance of a colpopexy at the time of hysterectomy for pelvic organ prolapse is a potential indicator of surgical quality. However, vaginal colpopexy has not been directly compared with the classic technique of ligament shortening and reattachment. We sought to test the null hypothesis that there is no difference in prolapse recurrence between the techniques. METHODS: We performed a retrospective chart review of 330 vaginal hysterectomies performed for prolapse, comparing symptomatic and/or anatomic recurrence rates between patients having a vaginal colpopexy (uterosacral ligament suspension or sacrospinous ligament suspension) and those having ligament shortening and reattachment. Clinically relevant variables significantly associated with recurrence in a univariate analysis were used to create a multivariable logistic regression model to predict recurrence. RESULTS: With a mean follow-up of 20 months, there was no significant difference between symptomatic and/or anatomic recurrence rates: 19.4 % of patients (41 of 211) having colpopexy vs. 11.8 % of patients (14 of 119) having ligament shortening (p = 0.07). Baseline prolapse stage was higher in patients having colpopexy (median 3, IQR 2 - 5) than in those having ligament shortening (median 2, IQR 1 - 3; p ≤ 0.0001). In the multivariable logistic regression analysis, the procedure performed was not associated with recurrence (OR 1.57, 95 % CI 0.79 - 3.12). A baseline prolapse of 4 cm or greater was associated with recurrence (OR 2.63, 95 % CI 1.32 - 5.22), as was the time since hysterectomy (OR 1.02 per month, 95 % CI 1.01 - 1.04). CONCLUSIONS: When compared with vaginal colpopexy, selective use of the ligament shortening technique at the time of vaginal hysterectomy was associated with similar rates of prolapse recurrence. Preoperative prolapse size was the factor most strongly associated with recurrence.

Mutant Calreticulin Requires Both Its Mutant C-terminus and the Thrombopoietin Receptor for Oncogenic Transformation.

UNLABELLED: Somatic mutations in calreticulin (CALR) are present in approximately 40% of patients with myeloproliferative neoplasms (MPN), but the mechanism by which mutant CALR is oncogenic remains unclear. Here, we demonstrate that expression of mutant CALR alone is sufficient to engender MPN in mice and recapitulates the disease phenotype of patients with CALR-mutant MPN. We further show that the thrombopoietin receptor MPL is required for mutant CALR-driven transformation through JAK-STAT pathway activation, thus rendering mutant CALR-transformed hematopoietic cells sensitive to JAK2 inhibition. Finally, we demonstrate that the oncogenicity of mutant CALR is dependent on the positive electrostatic charge of the C-terminus of the mutant protein, which is necessary for physical interaction between mutant CALR and MPL. Together, our findings elucidate a novel paradigm of cancer pathogenesis and reveal how CALR mutations induce MPN. SIGNIFICANCE: The mechanism by which CALR mutations induce MPN remains unknown. In this report, we show that the positive charge of the CALR mutant C-terminus is necessary to transform hematopoietic cells by enabling binding between mutant CALR and the thrombopoietin receptor MPL.

Distinct effects of concomitant Jak2V617F expression and Tet2 loss in mice promote disease progression in myeloproliferative neoplasms.

Signaling mutations (eg, JAK2V617F) and mutations in genes involved in epigenetic regulation (eg, TET2) are the most common cooccurring classes of mutations in myeloproliferative neoplasms (MPNs). Clinical correlative studies have demonstrated that TET2 mutations are enriched in more advanced phases of MPNs such as myelofibrosis and leukemic transformation, suggesting that they may cooperate with JAK2V617F to promote disease progression. To dissect the effects of concomitant Jak2V617F expression and Tet2 loss within distinct hematopoietic compartments in vivo, we generated Jak2V617F/Tet2 compound mutant genetic mice. We found that the combination of Jak2V617F expression and Tet2 loss resulted in a more florid MPN phenotype than that seen with either allele alone. Concordant with this, we found that Tet2 deletion conferred a strong functional competitive advantage to Jak2V617F-mutant hematopoietic stem cells (HSCs). Transcriptional profiling revealed that both Jak2V617F expression and Tet2 loss were associated with distinct and nonoverlapping gene expression signatures within the HSC compartment. In aggregate, our findings indicate that Tet2 loss drives clonal dominance in HSCs, and Jak2V617F expression causes expansion of downstream precursor cell populations, resulting in disease progression through combinatorial effects. This work provides insight into the functional consequences of JAK2V617F-TET2 comutation in MPNs, particularly as it pertains to HSCs.