The changing epidemiology of pulmonary infection in children and adolescents with cystic fibrosis: an 18-year experience.

The impact of evolving treatment regimens, airway clearance strategies, and antibiotic combinations on the incidence and prevalence of respiratory infection in cystic fibrosis (CF) in children and adolescents remains unclear. The incidence, prevalence, and prescription trends from 2002 to 2019 with 18,339 airway samples were analysed. Staphylococcus aureus [- 3.86% (95% CI - 5.28-2.43)] showed the largest annual decline in incidence, followed by Haemophilus influenzae [- 3.46% (95% CI - 4.95-1.96)] and Pseudomonas aeruginosa [- 2.80%95% CI (- 4.26-1.34)]. Non-tuberculous mycobacteria and Burkholderia cepacia showed a non-significant increase in incidence. A similar pattern of change in prevalence was observed. No change in trend was observed in infants < 2 years of age. The mean age of the first isolation of S. aureus (p < 0.001), P. aeruginosa (p < 0.001), H. influenza (p < 0.001), Serratia marcescens (p = 0.006) and Aspergillus fumigatus (p = 0.02) have increased. Nebulised amikacin (+ 3.09 ± 2.24 prescription/year, p = 0.003) and colistin (+ 1.95 ± 0.3 prescriptions/year, p = 0.032) were increasingly prescribed, while tobramycin (- 8.46 ± 4.7 prescriptions/year, p < 0.001) showed a decrease in prescription. Dornase alfa and hypertonic saline nebulisation prescription increased by 16.74 ± 4.1 prescriptions/year and 24 ± 4.6 prescriptions/year (p < 0.001). There is a shift in CF among respiratory pathogens and prescriptions which reflects the evolution of cystic fibrosis treatment strategies over time.

Research interests of family physicians applying for research training.

BACKGROUND: There is an ongoing need for research to support the practice of high quality family medicine. The Family Medicine Discovers Rapid Cycle Scientific Discovery and Innovation (FMD RapSDI) program is designed to build capacity for family medicine scientific discovery and innovation in the United States. Our objective was to describe the applicants and research questions submitted to the RapSDI program in 2019 and 2020. METHODS: Descriptive analysis for applicant characteristics and rapid qualitative analysis using principles of grounded theory and content analysis to examine the research questions and associated themes. We examined differences by year of application submission and the applicant's career stage. RESULTS: Sixty-five family physicians submitted 70 applications to the RapSDI program; 45 in 2019 and 25 in 2020. 41% of applicants were in practice for five years or less (n = 27), 18% (n = 12) were in in practice 6-10 years, and 40% (n = 26) were ≥ 11 years in practice. With significant diversity in questions, the most common themes were studies of new innovations (n = 20, 28%), interventions to reduce cost (n = 20, 28%), improving screening or diagnosis (n = 19, 27%), ways to address mental or behavioral health (n = 18, 26%), and improving care for vulnerable populations (n = 18, 26%). CONCLUSION: Applicants proposed a range of research questions and described why family medicine is optimally suited to address the questions. Applicants had a desire to develop knowledge to help other family physicians, their patients, and their communities. Findings from this study can help inform other family medicine research capacity building initiatives.

Single-arm, open-labelled, safety and tolerability of intrabronchial and nebulised bacteriophage treatment in children with cystic fibrosis and Pseudomonas aeruginosa.

INTRODUCTION: Cystic fibrosis (CF) is a multisystem condition that is complicated by recurrent pulmonary infections requiring aggressive antibiotic treatment. This predisposes the patient to complications such as sensorineural hearing loss, renal impairment, hypersensitivity and the development of antibiotic resistance. Pseudomonas aeruginosa is one of the more common organisms which cause recurrent infections and result in greater morbidity and mortality in people living with CF. Bacteriophages have been identified as a potential alternative or adjunct to antibiotics. We hypothesise that bacteriophage therapy is a safe and well-tolerated treatment in children with CF infected with P. aeruginosa infection in their airways. METHODS: This single-arm, open-labelled, non-randomised trial will run for a maximum period of 36 months with up to 10 participants. Adolescents (≥12 years and <18 years of age) who continue to shed P.aeruginosa (within 3 months of enrolment) despite undergoing eradication therapy previously, will be considered for this trial. Non-genetically modified bacteriophages that have demonstrated obligate lytic activity against each of the study participants' P. aeruginosa strains will be selected and prepared according to a combination of established protocols (isolation, purification, sterility testing and packaging) to achieve close to good manufacturing practice recommendations. The selected bacteriophage will be administered endo-bronchially first under direct vision, followed by two times a day nebulisation for 7 days in addition to standard CF treatment (intravenous antibiotics, physiotherapy to be completed as inpatient for 10-14 days). Safety and tolerability will be defined as the absence of (1) fever above 38.5°C occurring within 1 hour of the administration of the nebulised bacteriophage, (2) a 10% decline in spirometry (forced expiratory volume in 1 s %) measured preadministration and postadministration of the first dose of nebulised bacteriophage. Clinical reviews including repeat sputum cultures and spirometry will be performed at 3, 6, 9 and 12 months following bacteriophage treatment. ETHICS AND DISSEMINATION: Our clinical trial is conducted in accordance with (1) good clinical practice, (2) Australian legislation, (3) National Health and Medical Research Council guidelines for the ethical conduct of research. TRIAL REGISTRATION NUMBER: Australia and New Zealand Clinical Trial Registry (ACTRN12622000767707).

Transition to adult care in cystic fibrosis: The challenges and the structure.

In developed countries, it is projected that there will be a 70% increase in the number of adults living with Cystic Fibrosis (CF) between 2010 and 2025. This shift in demographics highlights the importance of high-quality transition programmes with developmentally appropriate integrated health care services as the individual moves through adolescence to adulthood. Adolescents living with CF face additional and unique challenges that may have long-term impacts on their health, quality of life and life-expectancy. CF specific issues around socially challenging symptoms, body image, reproductive health and treatment burden differentiate people with CF from their peers and require clinicians to identify and address these issues during the transition process. This review provides an overview of the health, developmental and psychosocial challenges faced by individuals with CF, their guardians and health care teams considering the fundamental components and tools that are required to build a transition programme that can be tailored to suit individual CF clinics.

Elevated risk thresholds predict endocrine risk-reducing medication use in the Athena screening registry.

Risk-reducing endocrine therapy use, though the benefit is validated, is extremely low. The FDA has approved tamoxifen and raloxifene for a 5-year Breast Cancer Risk Assessment Tool (BCRAT) risk ≥ 1.67%. We examined the threshold at which high-risk women are likely to be using endocrine risk-reducing therapies among Athena Breast Health Network participants from 2011-2018. We identified high-risk women by a 5-year BCRAT risk ≥ 1.67% and those in the top 10% and 2.5% risk thresholds by age. We estimated the odds ratio (OR) of current medication use based on these thresholds using logistic regression. One thousand two hundred and one (1.2%) of 104,223 total participants used medication. Of the 33,082 participants with 5-year BCRAT risk ≥ 1.67%, 772 (2.3%) used medication. Of 2445 in the top 2.5% threshold, 209 (8.6%) used medication. Participants whose 5-year risk exceeded 1.67% were more likely to use medication than those whose risk was below this threshold, OR 3.94 (95% CI = 3.50-4.43). The top 2.5% was most strongly associated with medication usage, OR 9.50 (8.13-11.09) compared to the bottom 97.5%. Women exceeding a 5-year BCRAT ≥ 1.67% had modest medication use. We demonstrate that women in the top 2.5% have higher odds of medication use than those in the bottom 97.5% and compared to a risk of 1.67%. The top 2.5% threshold would more effectively target medication use and is being tested prospectively in a randomized control clinical trial.

Factors That Influence Use of a Patient Portal by Health Professionals.

Patient portals are websites or apps that provide patients with tools to manage healthcare appointments, access their health records, and communicate with clinicians. Patient portals have been demonstrated to be beneficial for improving communication between patients/carers and their healthcare team in a range of health settings. However, there is limited research on the barriers and enablers for implementing patient portals from the perspective of health professionals and healthcare teams, particularly in a paediatric setting. This study aimed to understand healthcare teams' experiences of using a patient portal and, using the Unified Theory of Acceptance and Use of Technology (UTAUT) framework, explore the barriers and enablers to ongoing use. Participants were 11 health professionals participating in the pilot of a patient portal for patients/carers in paediatric care. Data were collected using semi-structured interviews. Analysis of the interview data identified nine themes about implementing a patient portal in paediatric care, all of which aligned with the four constructs of the UTAUT. This study identified that barriers and enablers of the uptake of a patient portal by health professionals in a paediatric context aligned with the UTAUT framework. Value for the patient, improved workflow, and adequate technical and implementation support were highlighted by participants.

Analysis of human leukocyte antigen allele polymorphism in patients with non alcoholic fatty liver disease.

The human leukocyte antigen (HLA) genes may play a role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and its progressive form, non-alcoholic steatohepatitis (NASH). The aim of this study was to assess the association of HLA class I and II alleles with NASH and its histological features.Deoxyribonucleic acid (DNA) was extracted from 140 subjects (85 biopsy-proven NAFLD and 55 controls) and genotyped for HLA (-A, -B, -C, -DR1, -DR3, -DQ, and -DP). Liver biopsies were assessed for presence of NASH, degree of fibrosis and inflammation. Multivariate analysis was performed to assess associations between HLA genes and different histologic features of NAFLD.Our data for HLA class I showed that HLA-C*4 was associated with lower risk for histologic NASH and HLA-C*6 was protective against portal fibrosis. Conversely, HLA-B*27 was associated with high-grade hepatic steatosis, while HLA-A*31 was associated with increased risk for advanced fibrosis. Among HLA class II alleles, HLA-DQA1*01 was associated with lower risk for NASH while HLA-DRB1*03 was associated with increased risk for NASH.Our findings indicate that HLA class I and II gene polymorphism may be associated with susceptibility to NASH, fibrosis and other pathologic features and may be involved in the pathogenesis of NAFLD.

Cost-effectiveness of soluble beta-glucan gel in hard-to-heal wounds: an evaluation.

OBJECTIVE: To evaluate the cost-effectiveness of a soluble beta-glucan-containing gel as short-term adjunct therapy in the treatment of hard-to-heal wounds in a UK community health-care setting. METHODS: A comparative clinical evaluation involving consecutive patients treated for up to eight weeks with a beta-glucan-containing gel as adjunct to standard care. This was compared with consecutive patients as retrospective controls, and using the same standard care protocol from a year previously. The inclusion criteria was wounds that were slow-healing or stalled (<40% healing in four weeks). RESULTS: A total of 300 patients took part. Complete follow-up at 24 weeks was available for 144 patients in the beta-glucan group, and 136 patients in the standard care group. At 24 weeks, the beta-glucan group had a 96% healing rate compared with 75% in the standard care group (p<0.001). The improvement in healing was associated with a reduction in the mean number of weeks of treatment per patient (7.2 and 10.7 for beta-glucan and standard care, respectively), and a reduction in the mean cost of treatment (£576 versus £685 for beta-glucan and standard care, respectively). Treatment costs included nursing time, prescription medications and dressings. In a subset of ulcer wounds (50% of the full sample), at 24 weeks the beta-glucan group had a 92% healing rate compared with 46% in the standard care group (p<0.001). Mean weeks of treatment were 10.4 versus 17.6, leading to a reduction in treatment cost of £388 per patient (£1227 versus £839) over 24 weeks. CONCLUSION: The results of this evaluation suggest that short-term use of the beta-glucan gel as an adjunct to standard care on slow-healing wounds can shorten healing times and reduce NHS costs.

Innovations in Ventricular Assist Devices for End-Stage Heart Failure.

The number of patients with end-stage heart failure (HF) continues to increase over time, but there has been little change in the availability of organs for cardiac transplantation, intensifying the demand for left ventricular assist devices (LVADs) as a bridge to transplantation. There is also a growing number of patients with end-stage HF who are not transplant candidates but may be eligible for long-term support with an LVAD, known as destination therapy. Due to this increasing demand, LVAD technology has evolved, resulting in transformative improvements in outcomes. Additionally, with growing clinical experience patient management continues to be refined, leading to iterative improvements in outcomes. With outcomes continuing to improve, the potential benefit from LVAD therapy is being considered for patients earlier in their course of advanced HF. We review recent changes in technology, patient management, and implant decision making in LVAD therapy.

A clinical observation evaluation of bioactive soluble beta-glucan gel compared with standard care.

OBJECTIVE: Clinicians across all health-care settings are challenged daily by wounds that are slow or static in healing due to time constraints, reduced resources and the negative impact upon the patient's quality of life (QoL). Community settings are particularly challenging due to the varied environments, patient social, psychological and financial constraints, and multi-clinician wound care monitoring. The aim of this clinical evaluation is to clinically evaluate bioactive soluble beta-glucan gel (BSBG) on those wounds that have stalled at four weeks as an adjunct to normal standards of care. METHOD: A clinical observational evaluation was undertaken within a large community setting, reviewing patients who self-presented with stalled healing/chronic wounds, and the effects upon adding a BSBG gel twice a week for eight weeks as part of their set standard care. Formulary cleansing and dressing products were continued and results monitored by a designated clinician. All data was collected as part of the patient's normal wound review routine in relation to primary outcome of wound reduction with secondary outcomes relating to pain reduction, slough and necrosis reduction, exudate reduction and adverse events. RESULTS: At six months, analysis of data demonstrated >2-times a higher rate of healing in chronic wounds with eight weeks' initial treatment and >4-times a higher rate of healing over six months in those patients with ulceration (PU, VLU, DFU). A reduction of per patient care cost saving was achieved across the treatment group compared with the standard care retrospective group. CONCLUSION: The administration of a wound healing gel within a moderate size cohort of patients presenting with chronic wounds resulted in improved wound reduction and significant cost savings.

Hemoglobin spray as adjunct therapy in complex wounds: Meta-analysis versus standard care alone in pooled data by wound type across three retrospective cohort controlled evaluations.

OBJECTIVES: Low tissue oxygenation is a predictor of healing outcomes in complex wounds. Adjunct hemoglobin to aid oxygen diffusion has been demonstrated to achieve superior healing outcomes; however, the relative healing benefit across different wound types and evaluations has not yet been estimated. This article does this for the first time. METHODS: Data were pooled from previously published real world controlled evaluations, three retrospective cohort controlled studies of a variety of wounds within standard care across hospital and primary care in the North of England in patients with diabetic foot ulcers (n = 40), chronic wounds (n = 100), and sloughy wounds (n = 200). Wounds were equally distributed between adjunct hemoglobin and control and the hemoglobin spray was used as per instructions for use and applied twice weekly, mostly for the duration of the wounds in all three evaluations. Wound healing over 26 weeks was the primary outcome in each of the evaluations, with additional healing and quality of life indicators including pain, wound size, slough coverage, wound exudate levels, adverse events, and dressing regimen used, over time. Each wound type with 10 or more patients in both the standard care alone and adjunctive hemoglobin groups (n = 257/73% of patients) was evaluated. RESULTS: Cox proportional hazards log-rank regressions demonstrated significantly higher weekly chance of healing in each wound type (ß, 95% range, sample, p): trauma 1.55 (1.23-1.96, n = 110, p < 0.001), diabetic foot ulcers 2.39 (1.52-3.75, n = 60, p = 0.01), venous leg ulcers 4.98 (1.69-14.7, n = 33, p = 0.04), burns 1.82 (1.11-2.99, n = 30, p = 0.02), and post-surgical wounds 2.75 (1.53-4.96, n = 24, p = 0.001). Results on additional healing indicators were consistent with the main findings. Notably, controlling for ischemia in diabetic foot ulcers resulted in an increased ß of 5.68 (2.33-13.86, n = 29, p < 0.001). CONCLUSION: Adjunct hemoglobin spray, when implemented within standard care, is likely to achieve substantial healing benefits to patients, in particular for diabetic foot ulcers, venous leg ulcers, and post-surgical wounds.

Assessment of clinical effectiveness of haemoglobin spray as adjunctive therapy in the treatment of sloughy wounds.

OBJECTIVE: To assess use of an adjunctive topical haemoglobin spray in the treatment of sloughy wounds. METHOD: In addition to a standard wound care regimen, consecutive patients with sloughy wounds self-administered haemoglobin spray treatment twice a week until the wound was healed. All patients were followed-up for 26 weeks. Results were compared with a retrospective cohort of 100 consecutive patients, treated during the same period the previous year with standard wound care alone. Data were collected on wound characteristics including percentage of slough, exudate levels, wound pain, and wound size. RESULTS: After 26 weeks, 94/100 patients (94%) treated with haemoglobin spray were completely healed compared with 63/100 control patients (63%). Positive results were evident as early as week one with 52% mean wound size reduction using the heamoglobin spray versus 11% in the retrospective control (p<0.001). At baseline, mean slough coverage was higher in the haemoglobin group, 58% versus 44% in the control group (p<0.001). By week four, mean slough coverage was 1% in the haemoglobin versus 29% in the control group (p<0.001). Reductions in exudate and pain levels (p<0.001) were also observed. CONCLUSION: Overall, results of this evaluation showed the addition of adjunctive haemoglobin spray to standard wound care treatment achieved positive clinical outcomes for patients self-managing complicated sloughy wounds, by supporting reduction of wound exudate and slough within the complex multifaceted process of wound healing.

13C-Mixed Triglyceride Breath Test and Fecal Elastase as an Indirect Pancreatic Function Test in Cystic Fibrosis Infants.

BACKGROUND: The 'gold standard' test for the indirect determination of pancreatic function status in infants with cystic fibrosis (CF), the 72-hour fecal fat excretion test, is likely to become obsolete in the near future. Alternative indirect pancreatic function tests with sufficient sensitivity and specificity to determine pancreatic phenotype need further evaluation in CF infants. OBJECTIVE: Evaluation of the clinical utility of both the noninvasive, nonradioactive C-mixed triglyceride (MTG) breath test and fecal elastase-1 (FE1) in comparison with the 72-hour fecal fat assessment in infants with CF. METHODS: C-MTG breath test and the monoclonal and polyclonal FE1 assessment in stool was compared with the 72-hour fecal fat assessment in 24 infants with CF. Oral pancreatic enzyme substitution (PERT; if already commenced) was stopped before the tests. RESULTS: Sensitivity rates between 82% and 100% for CF patients with pancreatic insufficiency assessed by both the C-MTG breath test and the FE1 tests proved to be high and promising. The C-MTG breath test (31%-38%) as well as both FE1 tests assessed by the monoclonal (46%-54%) and the polyclonal (45%) ELISA kits, however, showed unacceptably low-sensitivity rates for the detection of pancreatic-sufficient CF patients in the present study. CONCLUSIONS: The C-MTG breath test with nondispersive infrared spectroscopy (NDIRS) technique, as well as both FE1 tests, are not alternatives to the fecal fat balance test for the evaluation of pancreatic function in CF infants during the first year of life.

Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review.

Heart transplantation has become a standard therapy option for advanced heart failure. The translation of heart transplantation from innovative experiments to long-term clinical success has married prescient insights with discipline and organization in the domains of surgical techniques, organ preservation, immunosuppression, organ donation and transplantation logistics, infection control, and long-term graft surveillance. This review explores the key milestones of the past 50 years of heart transplantation and discusses current challenges and promising innovations on the clinical horizon.

Patient-Reported Outcomes Following Treatment of Chronic Hepatitis C Virus Infection With Sofosbuvir and Velpatasvir, With or Without Voxilaprevir.

BACKGROUND & AIMS: Chronic infection with hepatitis C virus (HCV) has many hepatic and extrahepatic manifestations, measured by patient-reported outcomes (PROs). We measured changes in PROs during HCV treatment with recently developed pangenotypic regimens and from a sustained virologic response 12 weeks after treatment ended (SVR12). METHODS: We collected PRO data from 2 multi-center, blinded, international phase 3 trials of sofosbuvir, velpatasvir, and voxilaprevir, from 748 patients previously treated with direct-acting antivirals for chronic infection with HCV of any genotype (59% HCV genotype 1, 43% with compensated cirrhosis) (POLARIS-1 and POLARIS-4). The combination of sofosbuvir, velpatasvir, and voxilaprevir was given to 445 patients, the combination of sofosbuvir and velpatasvir to 151 patients, and placebo to 152 patients. Patients completed the SF-36, FACIT-F, CLDQ-HCV, and WPAI:SHP questionnaires at baseline, during treatment, and during the follow-up period. RESULTS: There was no difference in baseline clinical or demographic features or PRO scores among the groups (all P > .05). The group that received the combination of sofosbuvir, velpatasvir, and voxilaprevir had more gastrointestinal symptoms than the groups that received sofosbuvir and velpatasvir or placebo (P = .0001). An SVR12 was achieved by 90.1% of patients who received sofosbuvir and velpatasvir vs 96.9% of patients who received sofosbuvir, velpatasvir, and voxilaprevir (P = .0008). After 12 weeks of treatment, some PRO scores improved in both treatment groups (by 2.5 or by 9.1 points, on a 0-100 scale; P < .05) but not in the placebo group. All increases in PRO scores were sustained or increased after treatment ended (an increase of up to 11.1 points at 12 weeks after treatment and an increase of up to 16.6 points at 24 weeks after treatment ended) (P < .05 for all but 2 PROs). There were no differences in PROs between the sofosbuvir and velpatasvir group vs the sofosbuvir, velpatasvir, and voxilaprevir group (all P > .05). In multivariate analysis, after adjustment for clinical and demographic factors and baseline PRO scores, receiving treatment was associated with higher PROs scores than receiving placebo (beta as high as 5.1) (P < .05). CONCLUSIONS: In an analysis of data from 2 phase 3 clinical trials of patients with chronic HCV infection of any genotype, we found the combination of sofosbuvir, velpatasvir, with or without voxilaprevir, to increase PRO scores compared with placebo. These findings indicate the comprehensive benefit of these regimens during treatment and after SVR.