Gene therapy with AAV9-SGPL1 in an animal model of lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung that leads rapidly to respiratory failure. Novel approaches to treatment are urgently needed. The bioactive lipid sphingosine-1-phosphate (S1P) is increased in IPF lungs and promotes proinflammatory and profibrotic TGF-ß signaling. Hence, decreasing lung S1P represents a potential therapeutic strategy for IPF. S1P is degraded by the intracellular enzyme S1P lyase (SPL). Here we find that a knock-in mouse with a missense SPL mutation mimicking human disease resulted in reduced SPL activity, increased S1P, increased TGF-ß signaling, increased lung fibrosis, and higher mortality after injury compared to wild type (WT). We then tested adeno-associated virus 9 (AAV9)-mediated overexpression of human SGPL1 (AAV-SPL) in mice as a therapeutic modality. Intravenous treatment with AAV-SPL augmented lung SPL activity, attenuated S1P levels within the lungs, and decreased injury-induced fibrosis compared to controls treated with saline or only AAV. We confirmed that AAV-SPL treatment led to higher expression of SPL in the epithelial and fibroblast compartments during bleomycin-induced lung injury. Additionally, AAV-SPL decreased expression of the profibrotic cytokines TNFα and IL1ß as well as markers of fibroblast activation, such as fibronectin (Fn1), Tgfb1, Acta2, and collagen genes in the lung. Taken together, our results provide proof of concept for the use of AAV-SPL as a therapeutic strategy for the treatment of IPF. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Enhancing self-care education amongst medical students: a systematic scoping review.

BACKGROUND: Reports of emotional, existential and moral distress amongst medical students witnessing death and suffering of patients during their clinical postings have raised awareness on the need for better psycho-emotional support during medical school. Furthermore, the stress experienced by medical students stemming from the rigours of their academic curriculum underlines the need for greater awareness on mental health issues and better self-care practices across medical training. With such programmes lacking in most medical schools, we propose a systematic scoping review (SSR) to map and address our research question, "what is known about self-care education interventions amongst medical students?". METHODS: We adopted the Systematic Evidence-Based Approach to guide a systematic scoping review (SSR in SEBA) of relevant articles published between 1st January 2000 and 30th June 2023 in PubMed, Embase, PsycINFO, ERIC, Google Scholar, and Scopus databases. The included articles were independently and concurrently thematically and content analysed, with complementary categories and themes combined using the Jigsaw Approach. The domains created from the Funnelling Process framed the discussion. RESULTS: A total of 6128 abstracts were identified, 429 full-text articles evaluated, and 147 articles included. The 6 domains identified were definition, topics, pedagogy, influences, outcomes and assessment. Most interventions were promising, though peer-led mindfulness-based interventions showed most promise in enhancing engagement, positively impacting personal wellbeing, and improving patient care. Overall, however, self-care education was poorly recognized, adopted and integrated into curricula. CONCLUSION: Greater dedicated time and conducive practice environments within medical school curricula is required to enhance medical student wellbeing. Host organizations must ensure faculty are appropriately selected to instil the importance of self-care, be trained to assess and personalize self-care interventions and provide longitudinal assessment and support. Further study into assessing self-care capabilities is required.

Mixed invasive ductal lobular carcinoma is clinically and pathologically more similar to invasive lobular than ductal carcinoma.

BACKGROUND: Mixed invasive ductal lobular carcinoma (mDLC) remains a poorly understood subtype of breast cancer composed of coexisting ductal and lobular components. METHODS: We sought to describe clinicopathologic characteristics and determine whether mDLC is clinically more similar to invasive ductal carcinoma (IDC) or invasive lobular carcinoma (ILC), using data from patients seen at the University of Pittsburgh Medical Center. RESULTS: We observed a higher concordance in clinicopathologic characteristics between mDLC and ILC, compared to IDC. There is a trend for higher rates of successful breast-conserving surgery after neoadjuvant chemotherapy in patients with mDLC compared to patients with ILC, in which it is known to be lower than in those with IDC. Metastatic patterns of mDLC demonstrate a propensity to develop in sites characteristic of both IDC and ILC. A meta-analysis evaluating mDLC showed shared features with both ILC and IDC with significantly more ER-positive and fewer high grades in mDLC compared to IDC, although mDLCs were significantly smaller and included fewer late-stage tumours compared to ILC. CONCLUSIONS: These findings support clinicopathologic characteristics of mDLC driven by individual ductal vs lobular components and given the dominance of lobular pathology, mDLC features are often more similar to ILC than IDC. This study exemplifies the complexity of mixed disease.

Web-based physical activity promotion in young people with CF: a randomised controlled trial.

BACKGROUND: Physical activity levels are known to decline following hospitalisation for people with cystic fibrosis (pwCF). However, optimal physical activity promotion strategies are unclear. This study investigated the effect of a web-based application (ActivOnline) in promoting physical activity in young pwCF. METHODS: Multicentre randomised controlled trial with assessor blinding and qualitative evaluation. People with CF (12-35 years) admitted to hospital for a respiratory cause were eligible and randomised to the 12-week ActivOnline intervention (AO) or usual care (UC). The primary outcome was change in device-based time spent in moderate-to-vigorous physical activity (MVPA) from baseline to post-intervention. Follow-up was at 6 months from hospital discharge when qualitative evaluation was undertaken. RESULTS: 107 participants were randomised to AO (n=52) or UC (n=55). Sixty-three participants (59%) contributed to the intention-to-treat analysis. Mean (SD) age was 21 (6) years (n=46, <18 years). At baseline, physical activity levels were high in both groups (AO 102 (52) vs UC 127 (73) min/day). There was no statistically significant difference in MVPA between groups at either timepoint (post-intervention mean difference (95% CI) -14 mins (-45 to 16)). Uptake of the intervention was low with only 40% (n=21) of participants accessing the web application. CONCLUSION: A web-based application, including individualised goal setting, real-time feedback and motivation for behavioural change, was no better than usual care at promoting physical activity in young pwCF following hospital discharge. High levels of baseline physical activity levels in both groups, and limited engagement with the intervention, suggest alternative strategies may be necessary to identify and support young pwCF who would benefit from enhanced physical activity. TRIAL REGISTRATION NUMBER: ACTRN12617001009303, 13 July 13 2017.

Single-institution outcomes after excision of benign phyllodes tumors: low recurrence risk even with positive margins.

PURPOSE: Benign phyllodes tumors (BPT) are rare breast neoplasms with clinical behavior that poses low recurrence risk. Guidelines regarding appropriate margins recommend surgical excision to negative margins, sometimes requiring re-excision surgery. Contemporary experience suggests that re-excision in the face of positive margins may not be needed. METHODS: This is a retrospective review of a single-institution experience with BPT from 2010 to 2019 with 102 patients. Demographics, outcomes and follow-up were analyzed. RESULTS: The median age was 37 years. 95% had a pre-operative biopsy and only 6% were confirmed BPT before surgery.56% had positive margins and were more likely to be younger and have a pre-operative diagnosis of fibroadenoma. The median follow-up was 33 months. Between the positive and negative margin groups, recurrence rates were not significantly different (p = 0.87). CONCLUSION: Positive margins on excision of BPT poses a low recurrence risk and re-excision surgery is not necessary.

Patient and Health Care Professional Perspectives on Addressing Obesity in ESKD.

RATIONALE & OBJECTIVE: Obesity is common among patients with end-stage kidney disease (ESKD) and is a pervasive barrier to kidney transplantation. Patient perspectives about barriers to weight loss and patient and health care professionals' viewpoints about optimal obesity management in ESKD are needed. STUDY DESIGN: Qualitative study using a descriptive phenomenological approach to understand ESKD patients' lived experiences with obesity and weight loss and patients' and health professionals' perceptions about optimal obesity care for ESKD patients. SETTING & PARTICIPANTS: Between October 2020 and December 2021, we conducted 90-minute semistructured interviews with 40 ESKD patients with obesity (body mass index [BMI] ≥30kg/m2) and 60-minute interviews with 20 ESKD health care professionals. ANALYTICAL APPROACH: Deductive and inductive thematic analysis of interviews. RESULTS: Among patients with ESKD, the median age was 55 (IQR, 46-63) years, median BMI was 39.5 (IQR, 35.3-41.6) kg/m2, and median dialysis vintage was 5 (IQR, 3-8) years; 58% were female, and 46% were non-Hispanic White. Among health care professionals, 50% were renal dietitians, 20% were nephrologists, and the remainder were transplant professionals (surgeons, nephrologists, and dietitians). ESKD patients described unique weight loss challenges, including (1) conflicting tenets of "kidney-friendly" versus popular diets, (2) fatigue due to dialysis that affects dietary choices, and (3) perceived pressure and unrealistic expectations from health professionals to lose weight for kidney transplantation. Professionals and patients described a lack of transparent and honest communication about obesity and unclear roles and responsibilities for obesity counseling. LIMITATIONS: Lack of caregiver perspectives and potential lack of transferability to overall dialysis population given overrepresentation of patients with severe obesity and previous weight loss surgery. CONCLUSIONS: Obesity interventions for ESKD patients should be tailored to meet the unique challenges reported by patients with ESKD. Clarifying ESKD health professionals' roles and responsibilities for obesity care would help to ensure that patients have consistent and effective support to manage obesity. PLAIN-LANGUAGE SUMMARY: Adults with coexisting obesity and end-stage kidney disease (ESKD) are often required to lose weight for kidney transplantation. Yet there is little knowledge about barriers to healthy weight loss in this population. In this study, we conducted interviews with 40 ESKD patients with coexisting obesity and 20 ESKD health care professionals to learn about opportunities to improve obesity-related health care in ESKD. Patients reported that fatigue and dialysis affected dietary choices, and fluid and food restrictions hampered weight loss. Professionals described a lack of training, comfort, and time to address obesity. Patients and professionals reported a lack of open communication about obesity management. Improving obesity-related education and clinical communication should be prioritized to improve care for patients with ESKD and obesity.

Exercise-based rehabilitation programmes for pulmonary hypertension.

BACKGROUND: Individuals with pulmonary hypertension (PH) have reduced exercise capacity and quality of life. Despite initial concerns that exercise training may worsen symptoms in this group, several studies have reported improvements in functional capacity and well-being following exercise-based rehabilitation. OBJECTIVES: To evaluate the benefits and harms of exercise-based rehabilitation for people with PH compared with usual care or no exercise-based rehabilitation. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 28 June 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in people with PH comparing supervised exercise-based rehabilitation programmes with usual care or no exercise-based rehabilitation. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. exercise capacity, 2. serious adverse events during the intervention period and 3. health-related quality of life (HRQoL). Our secondary outcomes were 4. cardiopulmonary haemodynamics, 5. Functional Class, 6. clinical worsening during follow-up, 7. mortality and 8. changes in B-type natriuretic peptide. We used GRADE to assess certainty of evidence. MAIN RESULTS: We included eight new studies in the current review, which now includes 14 RCTs. We extracted data from 11 studies. The studies had low- to moderate-certainty evidence with evidence downgraded due to inconsistencies in the data and performance bias. The total number of participants in meta-analyses comparing exercise-based rehabilitation to control groups was 462. The mean age of the participants in the 14 RCTs ranged from 35 to 68 years. Most participants were women and classified as Group I pulmonary arterial hypertension (PAH). Study durations ranged from 3 to 25 weeks. Exercise-based programmes included both inpatient- and outpatient-based rehabilitation that incorporated both upper and lower limb exercise. The mean six-minute walk distance following exercise-based rehabilitation was 48.52 metres higher than control (95% confidence interval (CI) 33.42 to 63.62; I² = 72%; 11 studies, 418 participants; low-certainty evidence), the mean peak oxygen uptake was 2.07 mL/kg/min higher than control (95% CI 1.57 to 2.57; I² = 67%; 7 studies, 314 participants; low-certainty evidence) and the mean peak power was 9.69 W higher than control (95% CI 5.52 to 13.85; I² = 71%; 5 studies, 226 participants; low-certainty evidence). Three studies reported five serious adverse events; however, exercise-based rehabilitation was not associated with an increased risk of serious adverse event (risk difference 0, 95% CI -0.03 to 0.03; I² = 0%; 11 studies, 439 participants; moderate-certainty evidence). The mean change in HRQoL for the 36-item Short Form (SF-36) Physical Component Score was 3.98 points higher (95% CI 1.89 to 6.07; I² = 38%; 5 studies, 187 participants; moderate-certainty evidence) and for the SF-36 Mental Component Score was 3.60 points higher (95% CI 1.21 to 5.98 points; I² = 0%; 5 RCTs, 186 participants; moderate-certainty evidence). There were similar effects in the subgroup analyses for participants with Group 1 PH versus studies of groups with mixed PH. Two studies reported mean reduction in mean pulmonary arterial pressure following exercise-based rehabilitation (mean reduction: 9.29 mmHg, 95% CI -12.96 to -5.61; I² = 0%; 2 studies, 133 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: In people with PH, supervised exercise-based rehabilitation may result in a large increase in exercise capacity. Changes in exercise capacity remain heterogeneous and cannot be explained by subgroup analysis. It is likely that exercise-based rehabilitation increases HRQoL and is probably not associated with an increased risk of a serious adverse events. Exercise training may result in a large reduction in mean pulmonary arterial pressure. Overall, we assessed the certainty of the evidence to be low for exercise capacity and mean pulmonary arterial pressure, and moderate for HRQoL and adverse events. Future RCTs are needed to inform the application of exercise-based rehabilitation across the spectrum of people with PH, including those with chronic thromboembolic PH, PH with left-sided heart disease and those with more severe disease.

AAV-SPL 2.0, a Modified Adeno-Associated Virus Gene Therapy Agent for the Treatment of Sphingosine Phosphate Lyase Insufficiency Syndrome.

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is an inborn error of metabolism caused by inactivating mutations in SGPL1, the gene encoding sphingosine-1-phosphate lyase (SPL), an essential enzyme needed to degrade sphingolipids. SPLIS features include glomerulosclerosis, adrenal insufficiency, neurological defects, ichthyosis, and immune deficiency. Currently, there is no cure for SPLIS, and severely affected patients often die in the first years of life. We reported that adeno-associated virus (AAV) 9-mediated SGPL1 gene therapy (AAV-SPL) given to newborn Sgpl1 knockout mice that model SPLIS and die in the first few weeks of life prolonged their survival to 4.5 months and prevented or delayed the onset of SPLIS phenotypes. In this study, we tested the efficacy of a modified AAV-SPL, which we call AAV-SPL 2.0, in which the original cytomegalovirus (CMV) promoter driving the transgene is replaced with the synthetic "CAG" promoter used in several clinically approved gene therapy agents. AAV-SPL 2.0 infection of human embryonic kidney (HEK) cells led to 30% higher SPL expression and enzyme activity compared to AAV-SPL. Newborn Sgpl1 knockout mice receiving AAV-SPL 2.0 survived ≥ 5 months and showed normal neurodevelopment, 85% of normal weight gain over the first four months, and delayed onset of proteinuria. Over time, treated mice developed nephrosis and glomerulosclerosis, which likely resulted in their demise. Our overall findings show that AAV-SPL 2.0 performs equal to or better than AAV-SPL. However, improved kidney targeting may be necessary to achieve maximally optimized gene therapy as a potentially lifesaving SPLIS treatment.

A historical delve into neurotrauma-focused critical care.

Neurocritical care is a multidisciplinary field managing patients with a wide range of aliments. Specifically, neurotrauma is a rapidly growing field with increasing demands. The history of how neurotrauma management came to its current form has not been extensively explored before. Our review delves into the history, timeline, and noteworthy pioneers of neurotrauma-focused neurocritical care. We explore the historical development during early times, the 18th-20th centuries, and modern times, as well as warfare- and sports-related concussions. Research is ever growing in this budding field, with several promising innovations on the horizon.

Recessive Rare Variants in Deoxyhypusine Synthase, an Enzyme Involved in the Synthesis of Hypusine, Are Associated with a Neurodevelopmental Disorder.

Hypusine is formed post-translationally from lysine and is found in a single cellular protein, eukaryotic translation initiation factor-5A (eIF5A), and its homolog eIF5A2. Biosynthesis of hypusine is a two-step reaction involving the enzymes deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase (DOHH). eIF5A is highly conserved throughout eukaryotic evolution and plays a role in mRNA translation, cellular proliferation, cellular differentiation, and inflammation. DHPS is also highly conserved and is essential for life, as Dhps-null mice are embryonic lethal. Using exome sequencing, we identified rare biallelic, recurrent, predicted likely pathogenic variants in DHPS segregating with disease in five affected individuals from four unrelated families. These individuals have similar neurodevelopmental features that include global developmental delay and seizures. Two of four affected females have short stature. All five affected individuals share a recurrent missense variant (c.518A>G [p.Asn173Ser]) in trans with a likely gene disrupting variant (c.1014+1G>A, c.912_917delTTACAT [p.Tyr305_Ile306del], or c.1A>G [p.Met1?]). cDNA studies demonstrated that the c.1014+1G>A variant causes aberrant splicing. Recombinant DHPS enzyme harboring either the p.Asn173Ser or p.Tyr305_Ile306del variant showed reduced (20%) or absent in vitro activity, respectively. We co-transfected constructs overexpressing HA-tagged DHPS (wild-type or mutant) and GFP-tagged eIF5A into HEK293T cells to determine the effect of these variants on hypusine biosynthesis and observed that the p.Tyr305_Ile306del and p.Asn173Ser variants resulted in reduced hypusination of eIF5A compared to wild-type DHPS enzyme. Our data suggest that rare biallelic variants in DHPS result in reduced enzyme activity that limits the hypusination of eIF5A and are associated with a neurodevelopmental disorder.

Managing behavioural and developmental paediatric conditions in rural outpatient clinics: An insight to the challenge ahead.

AIM: The aim of this study is to characterise the nature and caseload of general paediatric outpatient clinics in rural Queensland and to compare the findings with national data. METHODS: A retrospective clinical audit of medical records in paediatric clinics at two rural hospitals was undertaken over a 6-month period. Data extracted included demographics, diagnostic category and onward referral outcomes. The same diagnostic categories were used as the national Children Attending Paediatricians Study (CAPS) to facilitate comparison. RESULTS: A total of 346 records were reviewed, 56 (16.2%) documented Aboriginal and Torres Strait Islander descent. Compared to national data, significantly more children with behavioural/developmental diagnoses were seen in the rural clinics (CAPS 33.8%; rural 59.2%; P < 0.001). In contrast, children presenting with medical conditions (CAPS 48.2%; rural 28.6%; P < 0.001) and mixed medical/developmental conditions (CAPS 17.9%; rural 12.1%; P = 0.006) were seen less frequently in the rural clinics. Referral rates from the rural sites were lower than the rates reported by CAPS for children with behavioural/developmental diagnoses (CAPS 35.9%, rural 24.9%; P = 0.002) and mixed diagnoses (CAPS 40.6%, rural 19.0%; P = 0.005), while there was no difference in referral rates for children with medical diagnoses (CAPS 16.1%, rural 18.2%; P = 0.575). CONCLUSIONS: Rural paediatricians' caseloads are dominated by developmental/behavioural conditions, however children with these conditions are less likely to be referred to allied health and psychology services. The reasons for lower referral rates and specific pressures upon rural health services need to be investigated in future studies to provide better health services for rural children.

Top 10 research priorities for people living with pulmonary fibrosis, their caregivers, healthcare professionals and researchers.

INTRODUCTION: People with pulmonary fibrosis (PF) experience a high symptom burden, reduced quality of life and a shortened lifespan. Treatment options are limited and little is known about what patients, caregivers and healthcare professionals (HCPs)/researchers consider as the most important research priorities. This study aimed to identify the top 10 research priorities for PF across all stakeholders. METHODS: Participants included people with PF, caregivers and HCPs/researchers involved with PF. The research priority setting exercise involved three stages: (1) identifying priorities using an open-ended questionnaire and thematic analysis, (2) development of specific research questions at a face-to-face workshop, and (3) online ranking of research questions to identify the top 10 research priorities using nominal group ranking method. RESULTS: 196 participants completed stage 1 generating 560 questions and 14 research themes were identified. Stage 2 involved 32 participants and generated 53 indicative questions from which 39 were used for the final ranking. Stage 3 was completed by 270 participants. The top ranked priorities focussed on medications to reverse scarring in the lungs (ranked 1st), improving lung function (ranked 2nd, 6th and 8th), interventions aimed at alleviating symptoms (ranked 5th and 7th), prevention of PF (ranked 3rd and 4th) and the best exercise programme for PF (ranked 10th). There was good consensus among patients/carers and HCPs/researchers on the top 10 priorities, however, causes of acute exacerbations and early diagnosis for improving survival, was ranked higher by HCPs/researchers. CONCLUSION: Interventions for preserving lung health and alleviation of symptom burden were top research priorities for PF stakeholders.

Cutting Instruments to Cut Costs: A Simple Initiative with Breast Surgical Operating Room Trays that Resulted in Substantial Savings.

BACKGROUND: A substantial expense in surgical care is incurred in the operating room (OR). We evaluated the financial impact of a systematic reduction in instrument tray contents on charges for breast surgery procedures. METHODS: A catalog of OR trays historically used for breast procedures (excisional biopsy, segmental and total mastectomy with or without axillary staging) was reviewed by four dedicated breast surgeons and downsized to a single tray accommodating all surgeon preferences. A matched-case comparison was performed pre- and post-downsizing. Cost analysis for salary and benefits (S&B) and unit supply cost (USC) pre- and post-downsizing were carried out. Instrument number, OR tray weights, set-up, and breakdown times were also compared. RESULTS: Post-downsizing, OR tray counts were reduced from 132 to 67 instruments (49%) and tray weight decreased from 30 to 20 pounds (33%). Scrub technician set-up and breakdown times were shorter by 22% and 25%, respectively. Comparing 449 matched cases (239 pre- and 210 post-downsizing), S&B and USC post-downsizing were decreased collectively for all procedures (p < 0.0001). With an average variance of S&B and USC (pre- to post-intervention) of $354, and an annualized case load of 813 operations, this could translate into S&B and USC savings of $287,802 per year. CONCLUSION: Simply downsizing OR breast trays resulted in decreased combined S&B and USC per procedure, leading to a substantial cost savings for the healthcare system. This measure aligns with a value and quality-based approach to patient care and could be easily replicated across institutions and specialties.

Association of Tumor Molecular Subtype and Stage with Breast and Axillary Pathologic Complete Response After Neoadjuvant Chemotherapy for Breast Cancer.

BACKGROUND: Axillary pathologic complete response (pCR) confers higher overall and recurrence-free survival than residual axillary disease. Although breast pCR (ypT0) is associated with a pathologically negative axilla (ypN0) in human epidermal growth factor receptor 2-positive (HER2+) and triple-negative breast cancer (TNBC), how clinical T (cT) and N (cN) staging are associated with ypN0 in other tumor subtypes is incompletely understood. METHODS: A single-institution cancer registry was retrospectively reviewed for patients receiving neoadjuvant chemotherapy (NAC) followed by surgery from 2010 to 2018. Fisher's exact tests compared proportion of breast and axillary pCR by tumor subtype (hormone receptor [HR]-positive /HER2-,HR+/HER2+,HR-/HER2+,HR-/HER2-). Logistic regression determined factors associated with ypN0. Sensitivity analyses determined how cN status affected ypN status by tumor subtype. RESULTS: The study enrolled 1348 patients. The median age was 54 years (interquartile range [IQR], 44-63 years), and 55% of the patients (n = 736) were postmenopausal. The tumor subtypes were HR+/HER2- (12%, n = 155), HR+/HER2+ (48%, n = 653), HR-/HER2+ (25%, n = 343), and TNBC (15%, n = 197). In the study, cT included T0 (1%, n = 18), T1 (20%, n = 272), T2 (53%, n = 713), T3 (17%, n = 230), and T4 (9%, n = 111), and cN included cN0 (51%, n = 687), cN1 (41%, n = 549), cN2 (5%, n = 61), and cN3 (3%, n = 43). Breast pCR and ypN0 occurred most in the HER2+ and TNBC subtypes. A negative association was found between ypN0 and age at diagnosis (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.97-0.99; p < 0.001), cT4 stage (OR, 0.29; 95% CI, 0.09-0.91; p = 0.034), and HR+ subtypes (HR+/HER2-: OR, 0.54; 95% CI, 0.31-0.94; p = 0.028; HR+/HER2+: OR, 0.60; 95% CI, 0.39-0.93; p = 0.024). The HR-/HER2+ subtype was associated with ypN0 (OR, 1.70; 95% CI, 1.05-2.73; p = 0.030), and cN2/cN3 was negatively associated with ypN0 in HR+/HER2+ disease (OR, 0.26; 95% CI, 0.11-0.61; p = 0.002), HR-/HER2+ disease (OR, 0.42; 95% CI, 0.22-0.77; p = 0.005), and TNBC (OR, 0.11; 95% CI, 0.03-0.40; p = 0.001). CONCLUSION: Tumor subtype, clinical stage, and age at diagnosis may be important in consideration of de-escalation of axillary staging.

Acceptability of 3D-printed breast models and their impact on the decisional conflict of breast cancer patients: A feasibility study.

PURPOSE: To evaluate the acceptability and impact of 3D-printed breast models (3D-BMs) on treatment-related decisional conflict (DC) of breast cancer patients. METHODS: Patients with breast cancer were accrued in a prospective institutional review board-approved trial. All patients underwent contrast-enhanced breast magnetic resonance imaging (MRI). A personalized 3D-BM was derived from MRI. DC was evaluated pre- and post-3D-BM review. 3D-BM acceptability was assessed post-3D-BM review. RESULTS: DC surveys before and after 3D-BM review and 3D-BM acceptability surveys were completed by 25 patients. 3D-BM were generated in two patients with bilateral breast cancer. The mean patient age was 48.8 years (28-72). The tumor stage was Tis (7), 1 (8), 2 (8), and 3 (4). The nodal staging was 0 (19), 1 (7), and 3 (1). Tumors were unifocal (15), multifocal (8), or multicentric (4). Patients underwent mastectomy (13) and segmental mastectomy (14) with (20) or without (7) oncoplastic intervention. Neoadjuvant therapy was given to seven patients. Patients rated the acceptability of the 3D-BM as good/excellent in understanding their condition (24/24), understanding disease size (25/25), 3D-BM detail (22/25), understanding their surgical options (24/25), encouraging to ask questions (23/25), 3D-BM size (24/25), and impartial to surgical options (17/24). There was a significant reduction in the overall DC post-3D-BM review, indicating patients became more assured of their treatment choice (p = 0.002). Reduction post-3D-BM review was also observed in the uncertainty (p = 0.012), feeling informed about options (p = 0.005), clarity about values (p = 0.032), and effective (p = 0.002) Decisional Conflict Scale subscales. CONCLUSIONS: 3D-BMs are an acceptable tool to decrease DC in breast cancer patients.

Peer Connect Service for people with pulmonary fibrosis in Australia: Participants' experiences and process evaluation.

BACKGROUND AND OBJECTIVE: People living with pulmonary fibrosis (PF) report unmet needs for information and support. Lung Foundation Australia (LFA) have developed the Peer Connect Service to facilitate telephone support for people with PF across Australia. This project documented the experiences of participants and the resources required to support the service. METHODS: Consenting participants took part in semi-structured interviews by telephone. Primary peers (peers who agreed to initiate contact) and secondary peers (eligible patients who sought a peer match) were interviewed. Thematic analysis was undertaken by two independent researchers. Data were collected on the number of matches and contacts required to establish each match. RESULTS: Interviews were conducted with 32 participants (16 primary peers, 15 secondary peers and 1 who was both), aged from 53 to 89 years with 56% being male. Major themes included the value of shared experiences, providing mutual support and the importance of shared personal characteristics (e.g. gender and hobbies) in allowing information and emotional support needs to be met. Participants saw face-to-face contact with peers as highly desirable whilst acknowledging the practical difficulties. Primary peers were cognizant that their role was not to provide medical advice but to listen and share experiences. In the 12-month period, 60 peer matches were made, each match requiring a minimum of seven staff contacts. CONCLUSION: The Peer Connect Service provides a unique opportunity for people with PF to share experiences and offer mutual support. This telephone matching model may be useful in providing peer support for individuals with rare diseases who are geographically dispersed.

Rapid Quantification and Validation of Biomarker Scopoletin in Paederia foetida by qNMR and UV-Vis for Herbal Preparation.

Scopoletin has previously been reported as a biomarker for the standardization of Paederia foetida twigs. This study is the first report on the determination and quantification of scopoletin using quantitative nuclear magnetic resonance (qNMR) in the different extracts of Paederia foetida twigs. The validated qNMR method showed a good linearity (r2 = 0.9999), limit of detection (LOD) (0.009 mg/mL), and quantification (LOQ) (0.029 mg/mL), together with high stability (relative standard deviation (RSD) = 0.022%), high precision (RSD < 1%), and good recovery (94.08-108.45%). The quantification results of scopoletin concentration in chloroform extract using qNMR and microplate ultraviolet-visible (UV-vis) spectrophotometer was almost comparable. Therefore, the qNMR method is deemed accurate and reliable for quality control of Paederia foetida and other medicinal plants without extensive sample preparation.

Cytotoxic Activity of Christia vespertilionis Root and Leaf Extracts and Fractions against Breast Cancer Cell Lines.

Christia vespertilionis, commonly known as 'Daun Rerama', has recently garnered attention from numerous sources in Malaysia as an alternative treatment. Its herbal decoction was believed to show anti-inflammatory and anti-cancer effects. The present study investigated the cytotoxicity of the extract of root and leaf of C. vespertilionis. The plant parts were successively extracted using the solvent maceration method. The most active extract was further fractionated to afford F1-F8. The cytotoxic effects were determined using MTT assay against human breast carcinoma cell lines (MCF-7 and MDA-MB-231). The total phenolic content (TPC) of the extracts were determined. The antioxidant properties of the extract were also studied using DPPH and ß-carotene bleaching assays. The ethyl acetate root extract demonstrated selective cytotoxicity especially against MDA-MB-231 with the highest TPC and antioxidant properties compared to others (p < 0.05). The TPC and antioxidant results suggest the contribution of phenolic compounds toward its antioxidant strength leading to significant cytotoxicity. F3 showed potent cytotoxic effects while F4 showed better antioxidative strength compared to others (p < 0.05). Qualitative phytochemical screening of the most active fraction, F3, suggested the presence of flavonoids, coumarins and quinones to be responsible toward the cytotoxicity. The study showed the root extracts of C. vespertilionis to possess notable anti-breast cancer effects.

Home-based or remote exercise testing in chronic respiratory disease, during the COVID-19 pandemic and beyond: A rapid review.

OBJECTIVES: To identify exercise tests that are suitable for home-based or remote administration in people with chronic lung disease. METHODS: Rapid review of studies that reported home-based or remote administration of an exercise test in people with chronic lung disease, and studies reporting their clinimetric (measurement) properties. RESULTS: 84 studies were included. Tests used at home were the 6-minute walk test (6MWT, two studies), sit-to-stand tests (STS, five studies), Timed Up and Go (TUG, 4 studies) and step tests (two studies). Exercise tests administered remotely were the 6MWT (two studies) and step test (one study). Compared to centre-based testing the 6MWT distance was similar when performed outdoors but shorter when performed at home (two studies). The STS, TUG and step tests were feasible, reliable (intra-class correlation coefficients >0.80), valid (concurrent and known groups validity) and moderately responsive to pulmonary rehabilitation (medium effect sizes). These tests elicited less desaturation than the 6MWT, and validated methods to prescribe exercise were not reported. DISCUSSION: The STS, step and TUG tests can be performed at home, but do not accurately document desaturation with walking or allow exercise prescription. Patients at risk of desaturation should be prioritised for centre-based exercise testing when this is available.

Correction to: Sphingadienes show therapeutic efficacy in neuroblastoma in vitro and in vivo by targeting the AKT signaling pathway.

The authors would like to note an omission of disclosure in this paper. Author JDS is cofounder, equity-holder, and consultant of GILTRx Therapeutics.