Acupuncture in cancer care: recommendations for safe practice (peer-reviewed expert opinion).

BACKGROUND: Up-to-date recommendations for the safe practice of acupuncture in integrative oncology are overdue with new cancer treatments and an increase in survivors with late effects of disease; 17 years have elapsed since Filshie and Hester's 2006 guidelines. During 2022/2023 an expert panel assembled to produce updated recommendations aiming to facilitate safe and appropriate care by acupuncturists working with people with cancer. METHODS: A core development team comprising three integrative oncology professionals comprehensively updated pre-existing unpublished recommendations. Twelve invited international experts (senior acupuncturists with and without experience of working in oncology settings, oncologists, physicians and nurses trained in integrative oncology, researchers, academics, and professional body representatives) reviewed the recommendations. In multiple iterations, the core team harmonised comments for final ratification. To aid dissemination and uptake the panel represents national and international integrative oncology associations and major cancer treatment centres in Europe, USA, Australia, and the Middle East. RESULTS: These recommendations facilitate safe care by articulating contra-indications, cautions, and risks for patients both on and off treatment (surgery, SACT, radiotherapy). Situations where acupuncture may be contra-indicated or practices need adapting are identified. "Red and Amber Flags" highlight where urgent referral is essential. CONCLUSION: These are the first international, multidisciplinary peer-reviewed recommendations for safe acupuncture practice in integrative oncology. Concerns about safety remain a significant barrier to appropriate referral from oncology teams, to use by acupuncturists and to uptake by patients. Disseminating trustworthy, widely accessible guidance should facilitate informed, confident practice of acupuncture in and outside of oncology healthcare settings.

An accessory iliotibial band insertion: a unique anatomical variant.

The iliotibial band (ITB) is considered an important anterolateral knee joint stabiliser. Its exact anatomy remains unclear with inconsistency owing to relative paucity of detailed cadaveric studies. Multiple ITB distal insertional sites have been reported, the most common and well known being a direct attachment onto Gerdy's tubercle of the anterolateral tibia. We report a rare distal insertional site not previously documented. A 50-year-old man presented with anterior knee pain. MRI showed an accessory band deep to the ITB, partially blending in with its superficial fibres. It inserted onto the anterolateral tibial tuberosity, deep to the patellar tendon insertion and inferomedial to Gerdy's tubercle. This was asymptomatic but the patient did have an underlying median patella ridge osteochondral defect successfully treated with stem cell grafting, completely unrelated to the mentioned variant. This case highlights the importance of detecting rare anatomical variants which can potentially be a source of lateral knee pain.

Poikilodermatous plaque-like hemangioma: Case series of a newly defined entity.

BACKGROUND: We present a distinctive type of acquired vascular proliferation, for which we propose the name of poikilodermatous plaque-like hemangioma. OBJECTIVE: The aim of this study was to summarize the clinical and histopathologic features in a case series of poikilodermatous plaque-like hemangioma. METHODS: Sixteen cases were identified from the routine clinical and referral practices of the authors. Clinical characteristics, including demographic details and clinical morphology, were collated. The salient histopathologic features, including immunohistochemical staining results, were summarized. RESULTS: The lesions were usually solitary erythematous-to-violaceous poikilodermatous plaques on the lower extremities and pelvic girdle, with an indolent clinical course. Mean age of affected patients was 72 (range 58-80) years, and there was a male predominance. Histology comprised a distinctive band-like proliferation of vascular channels suggestive of postcapillary venules within the superficial dermis with a background of fibrosis, edema, and loss of elastic fibers. Despite the clinical atrophic appearance, acanthosis was a frequent finding. LIMITATIONS: Retrospective study. CONCLUSION: Poikilodermatous plaque-like hemangioma is a distinctive and previously undescribed vascular proliferation defined by a constellation of consistent and reproducible clinical and histologic features.

Understanding the measurement properties of the incremental shuttle walk test in patients with severe asthma.

BACKGROUND AND OBJECTIVE: We investigated the repeatability and validity of the incremental shuttle walk test (ISWT) distance compared to peak oxygen uptake (VO2pk ) during maximal incremental cycle ergometer (ICE) and treadmill (ITM) tests in adults with severe asthma. METHODS: Adults with severe asthma, Medical Research Council (MRC) dyspnoea ≥2, were recruited from specialists caring for patients with severe asthma. All participants performed three ISWT (familiarization and two subsequent tests on the same day), an ICE and an ITM in a randomized order, on separate days, to intolerance with expiratory gas analysis. RESULTS: A total of 50 patients (32 females, mean (SD), age: 54 (13) years, forced expiratory volume in 1 s (FEV1 ): 1.9 (0.8) L and body mass index (BMI): 32 (6) kg/m2 ) completed all five tests. The mean (SD) ISWT distance for each test was 400 (156), 418 (142) and 438 (157) m (P = 0.001), respectively. There was a strong correlation between the ISWT distance with VO2pk derived from ITM (r = 0.74, P < 0.001) and ICE (r = 0.75, P < 0.001). CONCLUSION: There was a small increase in the mean ISWT distance on sequential testing. In clinical practice, the coefficient of repeatability and heteroscedasticity need to be considered when assessing whether a true change has occurred within an individual patient. The ISWT has validity compared to VO2pk on both ICE and ITM, but they are not interchangeable.

Lung function decline and variable airway inflammatory pattern: longitudinal analysis of severe asthma.

BACKGROUND: Eosinophilic airway inflammation measured by using induced sputum is an important treatment stratification tool in patients with severe asthma. In addition, sputum eosinophilia has been shown to be associated with severe exacerbations and airflow limitation. OBJECTIVES: We sought to identify whether eosinophilic inflammation in sputum is associated with FEV1 decrease in patients with severe asthma and whether we could identify subgroups of decrease behavior based on the variation of eosinophilic airway inflammation over time. METHODS: Ninety-seven patients with severe asthma from the Glenfield Asthma Cohort were followed up with scheduled 3-month visits; the median duration of follow-up and number of visits was 6 years (interquartile range, 5.6-7.6 years) and 2.7 visits per year. Induced sputum was analyzed for eosinophilic inflammation at scheduled visits. Linear mixed-effects models were used to identify variables associated with lung function and overall decrease. In addition, using individual patients' mean and SD sputum eosinophil percentages over time, a 2-step cluster analysis was performed to identify patient clusters with different rates of decrease. RESULTS: FEV1 decrease was -25.7 mL/y in the overall population. Postbronchodilator FEV1 was also dependent on exacerbations, age of onset, height, age, sex, and log10 sputum eosinophil percentages (P < .001). Three decrease patient clusters were identified: (1) noneosinophilic with low variation (mean decrease, -14.0 mL/y), (2) eosinophilic with high variation (mean decrease, -40.9 mL/y), and (3) hypereosinophilic with low variation (mean decrease in lung function, -19.2 mL/y). CONCLUSION: The amplitude of sputum eosinophilia was associated with postbronchodilator FEV1 in asthmatic patients. In contrast, high variability rather than the amplitude at baseline or over time of sputum eosinophils was associated with accelerated FEV1 decrease.

Effectiveness of voriconazole in the treatment of Aspergillus fumigatus-associated asthma (EVITA3 study).

BACKGROUND: IgE sensitization to Aspergillus fumigatus and a positive sputum fungal culture result are common in patients with refractory asthma. It is not clear whether these patients would benefit from antifungal treatment. OBJECTIVES: We sought to determine whether a 3-month course of voriconazole improved asthma-related outcomes in patients with asthma who are IgE sensitized to A fumigatus. METHODS: Asthmatic patients who were IgE sensitized to A fumigatus with a history of at least 2 severe exacerbations in the previous 12 months were treated for 3 months with 200 mg of voriconazole twice daily, followed by observation for 9 months, in a double-blind, placebo-controlled, randomized design. Primary outcomes were improvement in quality of life at the end of the treatment period and a reduction in the number of severe exacerbations over the 12 months of the study. RESULTS: Sixty-five patients were randomized. Fifty-nine patients started treatment (32 receiving voriconazole and 27 receiving placebo) and were included in an intention-to-treat analysis. Fifty-six patients took the full 3 months of medication. Between the voriconazole and placebo groups, there were no significant differences in the number of severe exacerbations (1.16 vs 1.41 per patient per year, respectively; mean difference, 0.25; 95% CI, 0.19-0.31), quality of life (change in Asthma Quality of Life Questionnaire score, 0.68 vs 0.88; mean difference between groups, 0.2; 95% CI, -0.05 to -0.11), or any of our secondary outcome measures. CONCLUSION: We were unable to show a beneficial effect of 3 months of treatment with voriconazole in patients with moderate-to-severe asthma who were IgE sensitized to A fumigatus on either the rate of severe exacerbations, quality of life, or other markers of asthma control.

Elevated sputum interleukin-5 and submucosal eosinophilia in obese individuals with severe asthma.

RATIONALE: The relationship between airway inflammation and obesity in severe asthma is poorly understood. OBJECTIVES: We sought to determine the relationship between sputum mediator profiles and the distribution of eosinophilic inflammation and obesity in people with severe asthma. METHODS: Clinical parameters and eight mediators in sputum were assessed in 131 subjects with severe asthma from a single center categorized into lean, overweight, and obese groups defined by their body mass index. In an independent group of people with severe asthma (n = 45) and healthy control subjects (n = 19) eosinophilic inflammation was enumerated in bronchial submucosa, blood, and sputum and related to their body mass index. MEASUREMENTS AND MAIN RESULTS: Sputum IL-5 geometric mean (95% confidence interval) (pg/ml) was elevated in the obese (1.8 [1.2-2.6]) compared with overweight (1.1 [0.8-1.3]; P = 0.025) and lean (0.9 [0.6-1.2]; P = 0.018) subjects with asthma and was correlated with body mass index (r = 0.29; P < 0.001). There was no relationship among body mass index, the sputum cell count, or other sputum mediators. In the bronchoscopy group the submucosal eosinophil number in the subjects with asthma was correlated with body mass index (Spearman rank correlation, rs = 0.38; P = 0.013) and the median (interquartile range) number of submucosal eosinophils was increased in obese (19.4 [11.8-31.2]) (cells per square millimeter) versus lean subjects (8.2 [5.4-14.6]) (P = 0.006). There was no significant association between sputum or peripheral blood eosinophil counts and body mass index. CONCLUSIONS: Sputum IL-5 and submucosal eosinophils, but not sputum eosinophils, are elevated in obese people with severe asthma. Whether specific antieosinophilic therapy is beneficial, or improved diet and lifestyle in obese asthma has antiinflammatory effects beyond weight reduction, requires further study.

Structural basis for the phosphatase activity of polynucleotide kinase/phosphatase on single- and double-stranded DNA substrates.

Polynucleotide kinase/phosphatase (PNKP) is a critical mammalian DNA repair enzyme that generates 5'-phosphate and 3'-hydroxyl groups at damaged DNA termini that are required for subsequent processing by DNA ligases and polymerases. The PNKP phosphatase domain recognizes 3'-phosphate termini within DNA nicks, gaps, or at double- or single-strand breaks. Here we present a mechanistic rationale for the recognition of damaged DNA termini by the PNKP phosphatase domain. The crystal structures of PNKP bound to single-stranded DNA substrates reveals a narrow active site cleft that accommodates a single-stranded substrate in a sequence-independent manner. Biochemical studies suggest that the terminal base pairs of double-stranded substrates near the 3'-phosphate are destabilized by PNKP to allow substrate access to the active site. A positively charged surface distinct from the active site specifically facilitates interactions with double-stranded substrates, providing a complex DNA binding surface that enables the recognition of diverse substrates.

Autologous bone marrow derived mesenchymal stem cells are safe for the treatment of Achilles tendinopathy.

Achilles tendinopathy is a disabling condition that affects more than 50% of runners. Pre-clinical studies in a large animal model of naturally-occurring tendinopathy similar to human Achilles tendinopathy has shown benefits of autologous bone marrow-derived mesenchymal stem cell (MSC) implantation. However, MSCs are advanced therapies medicinal products (ATMPs), with strict regulatory requirements. Guided by the regulator we carried out a first in man study to assess the safety and efficacy of autologous MSC injection in human patients with non-insertional Achilles tendinopathy. Ten patients, mean age 47 with mid-portion Achilles tendon pain and swelling for more than 6 months, underwent autologous cultured cell injections (median 12.2 × 106, range 5-19 × 106 cells) into their Achilles tendon. At 24 weeks follow-up, no serious adverse reactions or important medical events were observed. MOXFQ, EQ-5D-5L, and VISA-A scores improved clinically at 12 and 24 weeks. VAS pain improved increasingly at 6, 12 and 24 weeks. MOXFQ Pain and VISA-A Scores improved > 12 points from baseline to 24 weeks in 8 patients. Maximum anteroposterior tendon thickness as measured by greyscale US decreased by mean 0.8 mm at 24 weeks. This phase IIa study demonstrated the safety of autologous MSC injection for non-insertional Achilles tendinopathy and provides proof-of-concept of the technique in patients, all of whom had previously failed conservative treatments for chronic disease and leads the way for a larger randomised controlled trial.

Enabling Adults With Severe Asthma to Exercise: A Qualitative Examination of the Challenges for Patients and Health Care Professionals.

BACKGROUND: Adults living with severe asthma have lower physical activity levels, particularly high-intensity physical activity, compared with their healthy peers. Physical inactivity is associated with increased morbidity and mortality. OBJECTIVE: To understand patient and health care professional attitudes toward exercise and physical activity to inform future strategies for the improvement of healthy lifestyle behaviors, including exercise. METHODS: Participants recruited from a specialist difficult asthma service were interviewed individually, and health care professionals (HCPs) from primary care, secondary care, and a tertiary center were invited to attend focus groups. Interviews and focus groups were transcribed verbatim. We performed thematic analysis on interviews and focus groups separately, followed by an adapted framework analysis to analyze datasets together. RESULTS: Twenty-nine people with severe asthma participated in a semi-structured interview. A total of 51 HCPs took part in eight focus groups across the East Midlands, United Kingdom. Final analysis resulted in three major themes: barriers to exercise and exercise counseling - in which patients and HCPs identified disease and non-disease factors affecting those living with severe asthma; attitudes toward HCP support for exercise - highlighting education needs for HCPs and preference for supervised exercise programs; and areas for system improvement in supporting patients and HCPs - challenges exist across health sectors that limit patient support are described. CONCLUSIONS: Patients identified the important role of HCPs in supporting and advising on lifestyle change. Despite a preference for supervised exercise programs, both patient and HCP barriers existed. To meet patients' varied support needs, improved integration of services is required and HCP skills need extending.

Mepolizumab and exacerbations of refractory eosinophilic asthma.

BACKGROUND: Exacerbations of asthma are associated with substantial morbidity and mortality and with considerable use of health care resources. Preventing exacerbations remains an important goal of therapy. There is evidence that eosinophilic inflammation of the airway is associated with the risk of exacerbations. METHODS: We conducted a randomized, double-blind, placebo-controlled, parallel-group study of 61 subjects who had refractory eosinophilic asthma and a history of recurrent severe exacerbations. Subjects received infusions of either mepolizumab, an anti-interleukin-5 monoclonal antibody (29 subjects), or placebo (32) at monthly intervals for 1 year. The primary outcome measure was the number of severe exacerbations per subject during the 50-week treatment phase. Secondary outcomes included a change in asthma symptoms, scores on the Asthma Quality of Life Questionnaire (AQLQ, in which scores range from 1 to 7, with lower values indicating more severe impairment and a change of 0.5 unit considered to be clinically important), forced expiratory volume in 1 second (FEV(1)) after use of a bronchodilator, airway hyperresponsiveness, and eosinophil counts in the blood and sputum. RESULTS: Mepolizumab was associated with significantly fewer severe exacerbations than placebo over the course of 50 weeks (2.0 vs. 3.4 mean exacerbations per subject; relative risk, 0.57; 95% confidence interval [CI], 0.32 to 0.92; P=0.02) and with a significant improvement in the score on the AQLQ (mean increase from baseline, 0.55 vs. 0.19; mean difference between groups, 0.35; 95% CI, 0.08 to 0.62; P=0.02). Mepolizumab significantly lowered eosinophil counts in the blood (P<0.001) and sputum (P=0.002). There were no significant differences between the groups with respect to symptoms, FEV(1) after bronchodilator use, or airway hyperresponsiveness. The only serious adverse events reported were hospitalizations for acute severe asthma. CONCLUSIONS: Mepolizumab therapy reduces exacerbations and improves AQLQ scores in patients with refractory eosinophilic asthma. The results of our study suggest that eosinophils have a role as important effector cells in the pathogenesis of severe exacerbations of asthma in this patient population. (Current Controlled Trials number, ISRCTN75169762.)

The relationship between clinical outcomes and medication adherence in difficult-to-control asthma.

Medication non-adherence and the clinical implications in difficult-to-control asthma were audited. Prescription issue data from 115 patients identified sub-optimal adherence (<80%) in 65% of patients on inhaled corticosteroids (ICS) or combined ICS/long-acting ß2 agonist (LABA). In those using separate ICS and LABA, adherence to LABA (50%) was significantly better than to ICS (14.3%). Patients with sub-optimal ICS adherence had reduced FEV(1) and higher sputum eosinophil counts. Adherence ratio was an independent predictor of previous ventilation for acute severe asthma (p=0.008). The majority of patients with difficult-to-control asthma are non-adherent with their asthma medication. Non-adherence is correlated with poor clinical outcomes.

Where do sexually active female London students go to access healthcare? Evidence from the POPI (Prevention of Pelvic Infection) chlamydia screening trial.

BACKGROUND: Little is known about where sexually active female students access healthcare. OBJECTIVES: Using data from the Prevention of Pelvic Infection (POPI) cohort, the authors aimed to: Describe where sexually active female students aged ≤ 27 years reported accessing healthcare. Investigate the association between numbers of sexual partners during 12 months of follow-up and healthcare usage, health-related quality of life (EQ-5D) and demographic and behavioural characteristics. METHODS: Participants provided vaginal swabs and completed questionnaires on sexual health and quality of life at baseline and at a 12-month follow-up. The follow-up questionnaire also asked about healthcare attendances during the previous 12 months. Mann-Whitney tests were used to relate healthcare seeking behaviour and other characteristics to reported numbers of partners during follow-up. RESULTS: Of 1865 women included in the analysis, 79% paid at least one visit to their general practice during follow-up, 23% attended an accident and emergency/walk-in clinic, 21% a family planning clinic and 14% a genitourinary medicine clinic. As the number of sexual partners increased (0-1, 2-3, 4+), women were more likely to have visited a genitourinary medicine clinic (10%, 16%, 30%, p<0.001) or accident and emergency/walk-in clinic (21%, 26%, 29%, p<0.002). Women with more sexual partners were also more likely to smoke, use condoms, be aged <16 years at sexual debut, have bacterial vaginosis, chlamydia or gonorrhoea at baseline and to have lower EQ5-D scores. CONCLUSION: This is the first UK study of healthcare attendance in multiethnic female students recruited outside healthcare settings. The high attendance in general practice may represent a valuable opportunity for screening for sexually transmitted infections.

Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers.

RATIONALE: Exacerbations of chronic obstructive pulmonary disease (COPD) are heterogeneous with respect to inflammation and etiology. OBJECTIVES: Investigate biomarker expression in COPD exacerbations to identify biologic clusters and determine biomarkers that recognize clinical COPD exacerbation phenotypes, namely those associated with bacteria, viruses, or eosinophilic airway inflammation. METHODS: Patients with COPD were observed for 1 year at stable and exacerbation visits. Biomarkers were measured in sputum and serum. Viruses and selected bacteria were assessed in sputum by polymerase chain reaction and routine diagnostic bacterial culture. Biologic phenotypes were explored using unbiased cluster analysis and biomarkers that differentiated clinical exacerbation phenotypes were investigated. MEASUREMENTS AND MAIN RESULTS: A total of 145 patients (101 men and 44 women) entered the study. A total of 182 exacerbations were captured from 86 patients. Four distinct biologic exacerbation clusters were identified. These were bacterial-, viral-, or eosinophilic-predominant, and a fourth associated with limited changes in the inflammatory profile termed "pauciinflammatory." Of all exacerbations, 55%, 29%, and 28% were associated with bacteria, virus, or a sputum eosinophilia. The biomarkers that best identified these clinical phenotypes were sputum IL-1ß, 0.89 (area under receiver operating characteristic curve) (95% confidence interval [CI], 0.83­0.95); serum CXCL10, 0.83 (95% CI, 0.70­0.96); and percentage peripheral eosinophils, 0.85 (95% CI, 0.78­0.93), respectively. CONCLUSIONS: The heterogeneity of the biologic response of COPD exacerbations can be defined. Sputum IL-1ß, serum CXCL10, and peripheral eosinophils are biomarkers of bacteria-, virus-, or eosinophil-associated exacerbations of COPD. Whether phenotype-specific biomarkers can be applied to direct therapy warrants further investigation.

A cross-sectional study of patterns of airway dysfunction, symptoms and morbidity in primary care asthma.

BACKGROUND: Most patients with asthma are managed exclusively in primary care. Little is known about the patterns of airway dysfunction in these patients and how these relate to other aspects of the disease. AIMS: We set out to assess this in a cross-sectional study of 262 patients. METHODS: Symptoms, spirometry, airway responsiveness, reversibility, and airway inflammation were all assessed. Exacerbations requiring oral corticosteroids in the preceding year were enumerated. RESULTS: Patients had heterogeneous patterns of airway dysfunction. Those with a post-bronchodilator forced expiratory volume in 1 sec/ forced vital capacity ratio of <0.7 had more exacerbations in the previous year (2.2 vs. 0.8; mean difference 1.4; 95% CI 0.4 to 2.4; p=0.007). Patients with normal results had less inflammation (proportion with a sputum eosinophil count of >1.9%, 20% vs. 48%, χ²=14.8, df=3; p<0.001) and fewer exacerbations (0.5 vs. 1.4; mean difference -0.9; 95% CI -1.4 to -0.4; p=0.001) but similar symptom scores (6.2 vs. 6.9; p=0.2) compared with patients with any abnormality. CONCLUSIONS: Patients with a diagnosis of asthma have mixed patterns of physiological impairment; many have no airflow obstruction or airway hyper-responsiveness. The physiological characterisation of asthma is not related to symptoms and is of little value in predicting exacerbations or eosinophilic airway inflammation.

Does body mass index influence the outcomes of a Waking-based pulmonary rehabilitation programme in COPD?

Body mass index (BMI) is an important prognostic measure in chronic obstructive pulmonary disease (COPD). However, its effects on pulmonary rehabilitation (PR) are unknown. This study aimed to evaluate the effectiveness of a walking-based PR programme across the BMI range and the impact of BMI on exercise performance and health status. A total of 601 patients with COPD completed a PR programme. The effects of BMI on exercise capacity (incremental and endurance shuttle walk tests (ISWT and ESWT)) and health status (chronic respiratory questionnaire (CRQ)) before and after PR were evaluated. 16% of patients were underweight, with 53% overweight or obese. At baseline, the obese had worse ISWT (-54 m ± 14 m; p = 0.001) despite a higher predicted forced expiratory volume in 1 s (7.4m ± 1.6%; p < 0.001). Patients in all BMI categories made clinically important improvements in ISWT distance: BMI <21, 62 m; 21-25, 59 m; 25-30, 59 m; >30, 65 m (p = < 0.001). All four domains of the CRQ increased above the level of clinical significance for all BMI categories (all p < 0.001). The majority of patients with COPD were overweight associated with a lower walking capacity. A walking-based PR programme was comparably effective across the BMI spectrum. Patients with COPD should be referred for standard PR, independent of BMI.

Impact of BRCA1 BRCT domain missense substitutions on phosphopeptide recognition.

The BRCA1 BRCT domain binds pSer-x-x-Phe motifs in partner proteins to regulate the cellular response to DNA damage. Approximately 120 distinct missense variants have been identified in the BRCA1 BRCT through breast cancer screening, and several of these have been linked to an increased cancer risk. Here we probe the structures and peptide-binding activities of variants that affect the BRCA1 BRCT phosphopeptide-binding groove. The results obtained from the G1656D and T1700A variants illustrate the role of Ser1655 in pSer recognition. Mutations at Arg1699 (R1699W and R1699Q) significantly reduce peptide binding through loss of contacts to the main chain of the Phe(+3) residue and, in the case of R1699W, to a destabilization of the BRCT fold. The R1835P and E1836K variants do not dramatically reduce peptide binding, in spite of the fact that these mutations significantly alter the structure of the walls of the Phe(+3) pocket.