Does Manual Therapy Provide Additional Benefit To Breathing Retraining In The Management Of Dysfunctional Breathing? A Randomised Controlled Trial

Purpose: Dysfunctional breathing (DB) is associated with an abnormal breathing pattern, unexplained breathlessness and significant patient morbidity. Treatment involves breathing retraining through respiratory physiotherapy. Recently, manual therapy (MT) has also been used, but no evidence exists to validate its use. This study sought to investigate whether MT produces additional benefit when compared with breathing retraining alone in patients with DB. Methods: Sixty subjects with primary DB were randomised into either breathing retraining (standard treatment; n¼30) or breathing retraining plus MT (intervention; n¼30) group. Both the groups received standardised respiratory physiotherapy, which included: DB education, breathing retraining, home regimen, and audio disc. Intervention group subjects additionally received MT following further assessment. Data from 57 subjects were analysed. Results: At baseline, standard treatment group subjects were statistically younger (41.7 + 13.5 versus 50.8 + 13.0 years; p¼0.001) with higher Nijmegen scores (38.6 + 9.5 versus 31.5 + 6.9; p¼0.001). However, no significant difference was found between the groups for primary outcome Nijmegen score (95% CI ( 1.1, 6.6) p¼0.162), or any secondary outcomes (Hospital Anxiety & Depression Score, spirometry or exercise tolerance). Conclusion: Breathing retraining is currently the mainstay of treatment for patients with DB. The results of this study suggest MT provides no additional benefit in this patient group.Juliana Burgess, Dr Robert Wilson, Royal Brompton & Harefield NHS Foundation Trust, and Dr Andy Jones fo

Perioperative characteristics, histologic diagnosis, complications, and outcomes of dogs undergoing percutaneous drainage, sclerotherapy or surgical management of intrarenal cystic lesions: 18 dogs (2004-2021)

BACKGROUND: Canine intrarenal cystic lesions (ICLs) are infrequently reported in the veterinary literature. Several treatment options have been described including cyst fenestration (partial nephrectomy/deroofing) +/- omentalization, sclerotherapy using alcohol as a sclerosing agent, percutaneous cyst drainage (PCD), and ureteronephrectomy. Information regarding presenting clinical signs, physical examination findings, histologic diagnosis and outcomes of dogs with ICLs treated by different methods is limited. Medical records of 11 institutions were retrospectively reviewed to identify dogs that underwent PCD, sclerotherapy, surgical deroofing +/- omentalization, or ureteronephrectomy for management of ICLs from 2004 to 2021. Six weeks postoperative/post-procedural follow-up was required. Cases suspected to represent malignancy on preoperative imaging were excluded. The study objective was to provide information regarding perioperative characteristics, complications, and outcomes of dogs undergoing treatment of ICLs. RESULTS: Eighteen dogs were included, with 24 ICLs treated. Ten had bilateral. There were 15 males and 3 females, with crossbreeds predominating. PCD, sclerotherapy, deroofing and ureteronephrectomy were performed in 5 (5 ICLs treated), 7 (11 ICLs), 6 (6), and 7 (7) dogs, respectively, with 5 dogs undergoing > 1 treatment. Seven dogs experienced 8 complications, with requirement for additional intervention commonest. PCD, sclerotherapy and deroofing resulted in ICL resolution in 0/5, 3/11 and 3/6 treated ICLs, respectively. Histopathology identified renal cysts (RCs) in 7/13 dogs with histopathology available and neoplasia in 6/13 (4 malignant, 2 benign). Of 5 dogs diagnosed histopathologically with neoplasia, cytology of cystic fluid failed to identify neoplastic cells. Among 7 dogs with histologically confirmed RCs, 4 had concurrent ICLs in ipsilateral/contralateral kidney, compared with 2/6 dogs with histologically confirmed neoplasia. CONCLUSIONS: Benign and neoplastic ICLs were approximately equally common and cystic fluid cytology failed to differentiate the 2. Among renal-sparing treatments, deroofing most commonly resulted in ICL resolution. Presence of concurrent ICLs in ipsilateral/contralateral kidney does not appear reliable in differentiating benign from malignant ICLs

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Ten-year mortality, disease progression, and treatment-related side effects in men with localised prostate cancer from the ProtecT randomised controlled trial according to treatment received

Background The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. Objective To report outcomes according to treatment received in men in randomised and treatment choice cohorts. Design, setting, and participants This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. Intervention Two cohorts included 1643 men who agreed to be randomised and 997 who declined randomisation and chose treatment. Outcome measurements and statistical analysis Analysis was carried out to assess mortality, metastasis and progression and health-related quality of life impacts on urinary, bowel, and sexual function using patient-reported outcome measures. Analysis was based on comparisons between groups defined by treatment received for both randomised and treatment choice cohorts in turn, with pooled estimates of intervention effect obtained using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. Results and limitations According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p = 0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p = 0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6 mo) and urinary incontinence (55% at 6 mo) after surgery, and of sexual dysfunction (88% at 6 mo) and bowel dysfunction (5% at 6 mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and changes in the protocol for AM during the lengthy follow-up required in trials of screen-detected PCa. Conclusions Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. Patient summary More than 95 out of every 100 men with low or intermediate risk localised prostate cancer do not die of prostate cancer within 10 yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are better after active monitoring, but the risks of spreading of prostate cancer are more common

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Functional and quality of life outcomes of localised prostate cancer treatments (prostate testing for cancer and treatment [ProtecT] study)

Objective To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. Patients and Methods Men aged 50–69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. Results Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. Conclusion Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes

Genetic improvement of hip-extended scores in 3 breeds of guide dogs using estimated breeding values: Notable progress but more improvement is needed.

Two hip quality phenotypes-a hip-extended score assigned by a board certified radiologist and the PennHIP distraction index-were analyzed to estimate genetic parameters and to calculate estimated breeding values used for selecting replacement breeders. Radiographs obtained at 12-18 months of age were available on 5,201 German Shepherd Dogs, 4,987 Labrador Retrievers and 2,308 Golden Retrievers. Obtained by fitting a two-trait model using Bayesian techniques, estimates of heritability for the hip-extended score were 0.76, 0.72, and 0.41 in German Shepherd Dogs, Labrador Retrievers, and Golden Retrievers, respectively, while estimated heritabilities for distraction index were 0.60, 0.66 and 0.59, respectively. Genetic correlations between the two hip quality measures were -0.28 in German Shepherd Dogs, -0.21 in Labrador Retrievers, and -0.29 in Golden Retrievers. Genetic selection for improved hip quality based upon the hip extended score phenotype began in 1980. Among first generation puppies, 34% of 273 German Shepherd Dogs, 55% of 323 Labrador Retrievers, and 43% of 51 Golden Retrievers had an Excellent hip extended score. After 8 generations of selection, mostly based on estimated breeding values derived from the hip extended score, over 93% of 695 German Shepherd Dogs, 94% of 528 Labrador Retrievers, and 87% of 116 Golden Retrievers received an Excellent hip extended score. With respect to PennHIP distraction index values among these same dogs, median values were at or above 0.30 for all 3 breeds meaning that half or more of dogs possessing the Excellent hip-extended-score phenotype remained susceptible to developing the osteoarthritis of canine hip dysplasia. Genetic improvement of the hip-extended-view phenotype to its desired biological endpoint left a surprising proportion of dogs expressing sufficient joint laxity to place them in an osteoarthritis at-risk state as they age. Only by directly applying selection pressure to reduce distraction index was marked reduction in joint laxity noted