Attenuated androgen discontinuation in patients with hereditary angioedema: a commented case series

Background Hereditary angioedema (HAE) is characterized by potentially severe and life-threatening attacks of localized swelling. Prophylactic therapies are available, including attenuated androgens. Efficacy of attenuated androgens has not been assessed in large, randomized, placebo-controlled trials and can be associated with frequent, and sometimes severe, side effects. As better tolerated targeted therapies become available, attenuated androgen withdrawal is increasingly considered by physicians and their patients with HAE. Attenuated androgens withdrawal has not been systematically studied in HAE, although examination of other disorders indicates that attenuated androgen withdrawal may result in mood disturbances and flu-like symptoms. Standardized protocols for attenuated androgen discontinuation that continue to provide control of attacks while limiting potential attenuated androgen withdrawal symptoms are not established as the outcomes of different withdrawal strategies have not been compared. We aim to describe the challenges of attenuated androgen discontinuation in patients with HAE and how these may continue into the post-androgen period. Case presentation We present a retrospective case series of 10 patients with confirmed type I HAE who have discontinued prophylactic treatment with attenuated androgens. The most common reason for attenuated androgen discontinuation was side effects. Attenuated androgens were either immediately withdrawn, tapered and/or overlapped with another treatment. The major challenge of discontinuation was the management of an increased frequency and severity of HAE attacks in some patients. Conclusions Healthcare teams need to undertake careful planning and monitoring after attenuated androgens discontinuation, and modify treatment strategies if HAE control is destabilized with an increased number of attacks. Discontinuation of attenuated androgens is definitively an option in an evolving HAE treatment landscape, and outcomes can be favourable with additional patient support and education.

Comprehensive Multi-cohort Transcriptional Meta-analysis of Muscle Diseases Identifies a Signature of Disease Severity

Muscle diseases share common pathological features suggesting common underlying mechanisms. We hypothesized there is a common set of genes dysregulated across muscle diseases compared to healthy muscle and that these genes correlate with severity of muscle disease. We performed meta-analysis of transcriptional profiles of muscle biopsies from human muscle diseases and healthy controls. Studies obtained from public microarray repositories fulfilling quality criteria were divided into six categories: i) Immobility, ii) inflammatory myopathies, iii) ICU acquired weakness (ICUAW), iv) congenital muscle diseases, v) chronic systemic diseases, vi) motor neuron disease. Patient cohorts were separated in discovery and validation cohorts retaining roughly equal proportions of samples for the disease categories. To remove bias towards a specific muscle disease category we repeated the meta-analysis five times by removing data sets corresponding to one muscle disease class at a time in a “leave-one-disease-out” analysis. We used 636 muscle tissue samples from 30 independent cohorts to identify a 52 gene signature (36 up-regulated and 16 down-regulated genes). We validated the discriminatory power of this signature in 657 muscle biopsies from 12 additional patient cohorts encompassing five categories of muscle diseases with an area under the receiver operating characteristic curve of 0.91, 83% sensitivity, and 85.3% specificity. The expression score of the gene signature inversely correlated with quadriceps muscle mass (r =-0.50, p-value = 0.011) in ICUAW and shoulder abduction strength (r=-0.77, p-value = 0.014) in amyotrophic lateral sclerosis (ALS). The signature also positively correlated with histologic assessment of muscle atrophy in ALS (r=0.88, p-value=1.62x10−3) and fibrosis in muscular dystrophy (Jonckheere trend test p-value = 4.45 x 10−9). Our results identify a conserved transcriptional signature associated with clinical and histologic muscle disease severity. Several genes in this conserved signature have not been previously associated with muscle disease severity.

STEPS – a patient centric and low-cost solution to ensure standards of TB care to patients reaching private sector in India

Background More than half of the TB patients in India seek care from the private sector. Two decades of attempts by the National TB Program to improve collaboration between the public and private sectors have not worked except in a few innovative pilots. The System for TB Elimination in Private Sector (STEPS) evolved in 2019 as a solution to ensure standards of TB care to every patient reaching the private sector. We formally evaluated the STEPS to judge the success of the model in achieving its outcomes and to inform decisions about scaling up of the model to other parts of the country. Methods An evaluation team was constituted involving all relevant stakeholders. A logic framework for the STEPS model was developed. The evaluation focused on (i) processes - whether the activities are taking place as intended and (ii) proximal outcomes - improvements in quality of care and strengthening of TB surveillance system. We (i) visited 30 randomly selected STEPS centres for assessing infrastructure and process using a checklist, (ii) validated the patient data with management information system of National TB Elimination Program (NTEP) by telephonic interview of 57 TB patients (iii) analysed the quality of patient care indicators over 3 years from the management information system (iv) conducted in-depth interviews (IDI) with 33 beneficiaries and stakeholders to understand their satisfaction and perceived benefits of STEPS and (v) performed cost analysis for the intervention from the perspective of NTEP, private hospital and patients. Results Evaluation revealed that STEPS is an acceptable model to all stakeholders. IDIs revealed that all patients were satisfied about the services received. Data in management information system of NTEP were consistent with the hospital records and with the information provided by the patient. Quality of TB care indicators for patients diagnosed in private hospitals showed improvements over years as proportion of TB patients notified from private sector with a microbiological confirmation of diagnosis improved from 25% in 2018 to 38% in 2020 and the documented treatment success rate increased from 33% (2018 cohort) to 88% (2019 cohort). Total additional programmatic cost (deducting cost for patient entitlements) per additional patient with successful treatment outcome was estimated to be 67 USD. Total additional expense/business loss for implementing STEPS for the hospital diagnosing 100 TB patients in a year was estimated to be 573 USD while additional minimum returns for the hospital was estimated to be 1145 USD. Conclusion Evaluation confirmed that STEPS is a low cost and patient-centric strategy. STEPS successfully addressed the gaps in the quality of care for patients seeking care in the private sector and ensured that services are aligned with the standards of TB care. STEPS could be scaled up to similar settings.

Integrating Domain Knowledge into Deep Learning for Skin Lesion Risk Prioritization to Assist Teledermatology Referral

Teledermatology has developed rapidly in recent years and is nowadays an essential tool for early diagnosis. In this work, we aim to improve existing Teledermatology processes for skin lesion diagnosis by developing a deep learning approach for risk prioritization with a dataset of retrospective data from referral requests of the Portuguese National Health System. Given the high complexity of this task, we propose a new prioritization pipeline guided and inspired by domain knowledge. We explored automatic lesion segmentation and tested different learning schemes, namely hierarchical classification and curriculum learning approaches, optionally including additional patient metadata. The final priority level prediction can then be obtained by combining predicted diagnosis and a baseline priority level accounting for explicit expert knowledge. In both the differential diagnosis and prioritization branches, lesion segmentation with 30% tolerance for contextual information was shown to improve classification when compared with a flat baseline model trained on original images; furthermore, the addition of patient information was not beneficial for most experiments. Curriculum learning delivered better results than a flat or hierarchical approach. The combination of diagnosis information and a knowledge map, created in collaboration with dermatologists, together with the priority achieved interesting results (best macro F1 of 43.93% for a validated test set), paving the way for new data-centric and knowledge-driven approaches.

Treatment of FRI after intramedullary nailing of tibia fractures: assessment of nail retention and nail removal

Objectives: Fracture related infection (FRI) is a severe, potentially limb-threatening complication after fracture fixation. Dilemma exists with regard to removing or retaining implants while treating the infection. The purpose of this study was to compare primary bone union and infection clearance in patients who had an infection following intramedullary nailing of the tibia treated either by retaining the implant or by removing the implant. Methods: Patients from two level-I trauma centers were identified through billing registries and retrospectively reviewed between January 2013 and December 2020. We identified 44 patients who had a diagnosis of FRI within 90 days of their initial fixation and returned to the OR for operative treatment of the infection. The incidences of both primary union and infection clearance were calculated for both groups and multiple parameters that may be associated with success or failure were assessed. Results: Four patients did not have complete records and were excluded. Of the remaining patients, 20 (50%) achieved infection clearance. Twenty-three (59%) patients achieved primary union whereas 16 (41%) had a primary outcome of either delayed union, nonunion, or amputation (one additional patient excluded as healing status unknown). Further analysis showed no significant difference (X2 (39) = 1.13, p < .29) in infection clearance between patients treated with nail retention (64%) versus nail removal (68%). No significant difference was seen in primary bone union (X2 (39) = 3.24, p < .07) with 36% of patients treated with nail retention and 68% of patients treated with nail removal reaching primary union; however, this does trend toward an association. Fewer surgeries performed for infection and complication after initial fixation was positively associated with infection clearance (p < .04, M=4.6, SD=2.13, df=39) and primary union (p < .001, M=4, SD=2, df=38). Conclusion: Infection clearance seems similarly possible with both nail retention and nail removal strategies, with fewer number of surgeries performed for infection and complication improving the likelihood of infection clearance and bone union. This may suggest that more severe FRI’s are less likely to unite and clear infection. Nail removal may play a role in increasing primary bone union; however, a larger sample size is needed for more definitive assessment.

Development of a core outcome set for the evaluation of interventions to enhance trial participation decisions on behalf of adults who lack capacity to consent: a mixed methods study (COnSiDER Study)

Background Trials involving adults who lack capacity to provide consent rely on proxy or surrogate decision-makers, usually a family member, to make decisions about participation. Interventions to enhance proxy decisions about trial participation are now being developed. However, a lack of standardised outcome measures limits evaluation of these interventions. The aim of this study was to establish an agreed standardised core outcome set (COS) for use when evaluating interventions to improve proxy decisions about trial participation. Methods We used established methods to develop the COS including a consensus study with key stakeholder groups comprising those who will use the COS in research (researchers and healthcare professionals) and patients or their representatives. Following a scoping review to identify candidate items, we used a modified two-round Delphi survey to achieve consensus on core outcomes, with equivocal items taken to a consensus meeting for discussion. The COS was finalised following an online consensus meeting in October 2020. Results A total of 28 UK stakeholders (5 researchers, 10 trialists, 3 patient/family representatives, 7 recruiters and 3 advisors/approvers) participated in the online Delphi survey to rank candidate items from the scoping review (n = 36) and additional items proposed by participants (n = 1). Items were broadly grouped into three categories: how family members make decisions, their experiences of making decisions, and the personal aspects that influence the decision. Following the Delphi survey, 27 items were included and ten items exhibited no consensus which required discussion at the consensus meeting. Sixteen participants attended the meeting, including additional patient/family representatives invited to increase representation from this key group (n = 2). We reached consensus for the inclusion of 28 outcome items, including one selected at the consensus meeting. Conclusions The study identified outcomes that should be measured as a minimum in all evaluations of interventions to enhance proxy decisions about trials. These relate to the process of decision-making, proxies’ experience of decision-making, and factors that influence decision-making such as understanding. Further work with people with impairing conditions and their families is needed to explore their views about the COS and to identify appropriate outcome measures and timing of measurement. Trial registration The study is registered on the COMET database (https://www.comet-initiative.org/Studies/Details/1409)

Patient outcomes and cost savings associated with hospital safe nurse staffing legislation: an observational study

ObjectiveTo evaluate variation in Illinois hospital nurse staffing ratios and to determine whether higher nurse workloads are associated with mortality and length of stay for patients, and cost outcomes for hospitals.DesignCross-sectional analysis of multiple data sources including a 2020 survey of nurses linked to patient outcomes data.Setting: 87 acute care hospitals in Illinois.Participants210 493 Medicare patients, 65 years and older, who were hospitalised in a study hospital. 1391 registered nurses employed in direct patient care on a medical–surgical unit in a study hospital.Main outcome measuresPrimary outcomes were 30-day mortality and length of stay. Deaths avoided and cost savings to hospitals were predicted based on results from regression estimates if hospitals were to have staffed at a 4:1 ratio during the study period. Cost savings were computed from reductions in lengths of stay using cost-to-charge ratios.ResultsPatient-to-nurse staffing ratios on medical-surgical units ranged from 4.2 to 7.6 (mean=5.4; SD=0.7). After adjusting for hospital and patient characteristics, the odds of 30-day mortality for each patient increased by 16% for each additional patient in the average nurse’s workload (95% CI 1.04 to 1.28; p=0.006). The odds of staying in the hospital a day longer at all intervals increased by 5% for each additional patient in the nurse’s workload (95% CI 1.00 to 1.09, p=0.041). If study hospitals staffed at a 4:1 ratio during the 1-year study period, more than 1595 deaths would have been avoided and hospitals would have collectively saved over $117 million.ConclusionsPatient-to-nurse staffing ratios vary considerably across Illinois hospitals. If nurses in Illinois hospital medical–surgical units cared for no more than four patients each, thousands of deaths could be avoided, and patients would experience shorter lengths of stay, resulting in cost-savings for hospitals.

Unpacking Data From Adult Day Centers in Order to Realize Their Untapped Potential in Dementia Care

Adult day centers (ADCs) in the United States represent a vital, but commonly overlooked, resource for dementia care among community-dwelling older adults. However, the severity of dementia in ADC users, their medical complexity, the supports offered to them, and health outcomes associated with adult day services among persons living with dementia is poorly understood. This is in part due to a lack of standardized data collection in this industry. In this symposium, we present the most current research on these issues, as well as strategies to improve data collection across ADCs to strengthen care. The symposium begins with analysis of data from the state of California that identifies patterns of chronic conditions in ADC users with dementia that are associated with emergency department visits and hospitalizations. We then examine data from the Centers for Disease Control, comparing dementia specialized ADCs and their participants to non-specializing ADCs. We compare the extent to which states with ADC programs require collection of patient centered reported outcomes on persons with dementia. Finally, we explore an innovative collaboration between researchers and community partners to simplify data collection in these centers. Our findings suggest that persons with dementia in ADCs are an extremely complex population and that some ADCs are better suited than others to meet their extensive needs. Additional patient-centered data collection can be supported with widely available software, and has the potential to demonstrate the effectiveness of ADCs, aid in program development, and help leverage funding opportunities.

Clinical and Immunological Features of Human BCL10 Deficiency

The CARD-BCL10-MALT1 (CBM) complex is critical for the proper assembly of human immune responses. The clinical and immunological consequences of deficiencies in some of its components such as CARD9, CARD11, and MALT1 have been elucidated in detail. However, the scarcity of BCL10 deficient patients has prevented gaining detailed knowledge about this genetic disease. Only two patients with BCL10 deficiency have been reported to date. Here we provide an in-depth description of an additional patient with autosomal recessive complete BCL10 deficiency caused by a nonsense mutation that leads to a loss of expression (K63X). Using mass cytometry coupled with unsupervised clustering and machine learning computational methods, we obtained a thorough characterization of the consequences of BCL10 deficiency in different populations of leukocytes. We showed that in addition to the near absence of memory B and T cells previously reported, this patient displays a reduction in NK, γδT, Tregs, and TFH cells. The patient had recurrent respiratory infections since early childhood, and showed a family history of lethal severe infectious diseases. Fortunately, hematopoietic stem-cell transplantation (HSCT) cured her. Overall, this report highlights the importance of early genetic diagnosis for the management of BCL10 deficient patients and HSCT as the recommended treatment to cure this disease.

Antibody Response after One and/or Two Doses of BNT162b2 Anti- Sars-Cov-2 mRNA Vaccine in Patients Treated By CAR T-Cells Therapy

Introduction: Data regarding the efficacy of anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) messenger RNA vaccines in immunocompromised hosts are scarce and no data yet appear to be available for patients with hematological malignancies who also received chimeric antigen receptor-T (CAR-T) cells therapy. Methods: The efficacy and safety of one and/or two injections of the BNT162b2 (Pfizer-BioNTech) vaccine was evaluated retrospectively in 23 CAR-T recipients in our Hematology Department, compared to a cohort of 25 healthy caregivers, vaccinated concomitantly between January 28 and May 31, 2021. None of these individuals had a previous clinical history of COVID-19. Results: Overall, the patients (14 males and 9 females) had a median age of 62 years old (range: 21-79) and had received CAR-T for high-grade lymphoma (n= 20) or acute lymphoblastic leukemia (n= 3). Eight and 3 had been respectively previously autografted or allografted and two were allografted after CAR-T. All patients were pretreated for lymphodepletion by fludarabine + cyclophosphamide before CAR-T infusion. The CAR-T provided were axicabtagene ciloleucel (Yescarta, Kite/Gilead, n=16, tisagenlecleucel (Kymriah, Novartis Pharma, n=5 and brexucabtagene autoleucel (KTE-X19, Tecartus, Kite/Gilead, n=1). One additional patient received allogeneic UCART19 (Servier). The median delay between CAR-T administration and the first vaccine (V1) was 401 days (d; range: 113-819). All patients but 2 were in complete remission at V1 and 3 were still on therapy (revlimid n=1, tafasitamab n=1, chemotherapy n=1). After V1, antibody response to the SARS-CoV-2 spike protein receptor-binding domain was tested by the Roche Elecsys® assay at a median time of 29 d (range: 16-32) in 19 patients and 23 d (range:18-32) in controls. At that time, only 4/23 patients (21%) but all controls (100%) had a positive anti-spike antibody response (p&lt;0.001). Among seropositive cases, median IgG titers were higher in controls (35.1 U/mL, range 2.2-&gt;250) than in patients (5.9 U/mL range 4.1-41.6, p=0.06). The highest IgG titer (&gt;250) was obtained in 2 controls. The median delay between V1 and the second vaccine (V2) was 28 d (range: 14-46) for patients and 23 d (range: 18-32) for controls. Among the 20 patients tested after V2, 17 had also been tested after V1 while 3 were tested only after V2. All controls were tested after V2. The second serology assay was performed at a median interval from V2 of 52 d (range: 21-99) for patients and 58 d (range: 32-71) for controls. This serology assay was positive in 6 patients (30%), while all controls (100%, p&lt;0.001) had again a positive response. Three out of these 6 patients (15% of all patients) achieved the highest IgG titer according to the serology assay used. Among the 4 patients with positive antibody titers after V1, 3 remained positive including one reaching the highest IgG titer. The fourth patient has not yet received V2. Median IgG titers could not be compared with controls because various methods of detection were used after V2. However, all controls tested again by Roche Elecsys® displayed the highest IgG titer (&gt;250) after V2. The two patients in relapse and treated by chemotherapy or tafasitamab did not develop antibodies after V2 conversely to the patient under maintenance by revlimid. The delay between CAR-T infusion and vaccine did not influence the antibody response nor did the rate of lymphopenia as almost all patients remained under a lymphocyte threshold of 1x10 9/L. Finally, with a median follow up from V1 of 77 d (range: 49-127) in patients and 81 d (range: 62-95) in controls, no COVID-19 infection has been documented in any of these participants. Conclusion: This study shows that the administration of two doses of BNT162b2 anti-SARS-CoV-2 messenger RNA vaccine provides a low rate of seroconversion (30%) in recipients of CAR-T therapy. This is likely related to the profound B-cell depletion induced by this treatment precisely targeting CD19+ cells. Investigation of the development of specific T-cell responses in these individuals could provide more information about the efficacy of vaccination in this context. Disclosures Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria.