Targeting Molecular Mechanisms of Obesity- and Type 2 Diabetes Mellitus-Induced Skeletal Muscle Atrophy with Nerve Growth Factor.

Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.

Beta-blockers or Placebo for Primary Prophylaxis (BOPPP) of oesophageal varices: study protocol for a randomised controlled trial.

BACKGROUND: Liver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD). METHODS/DESIGN: The BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival. DISCUSSION: The BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care. ETHICS AND DISSEMINATION: The trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation. TRIAL REGISTRATION: EUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.

Text messaging intervention to support patients with chronic pain during prescription opioid tapering: protocol for a double-blind randomised controlled trial.

INTRODUCTION: Increases in pain and interference with quality of life is a common concern among people with chronic non-cancer pain (CNCP) who are tapering opioid medications. Research indicates that access to social and psychological support for pain self-management may help people to reduce their opioid dose without increasing pain and interference. This study evaluates the efficacy of a text messaging intervention designed to provide people with CNCP with social and psychological support for pain self-management while tapering long-term opioid therapy (LTOT) under the guidance of their prescriber. METHODS AND ANALYSIS: A double-blind randomised controlled trial will be conducted. Patients with CNCP (n=74) who are tapering LTOT will be enrolled from across Australia. Participants will continue with their usual care while tapering LTOT under the supervision of their prescribing physician. They will randomly receive either a psychoeducational video and supportive text messaging (two Short Message Service (SMS) per day) for 12 weeks or the video only. The primary outcome is the pain intensity and interference assessed by the Pain, Enjoyment of Life and General Activity scale. Secondary outcomes include mood, self-efficacy, pain cognitions, opioid dose reduction, withdrawal symptoms, and acceptability, feasibility, and safety of the intervention. Participants will complete questionnaires at baseline and then every 4 weeks for 12 weeks and will be interviewed at week 12. This trial will provide evidence for the efficacy of a text messaging intervention to support patients with CNCP who are tapering LTOT. If proven to be efficacious and safe, this low-cost intervention can be implemented at scale. ETHICS AND DISSEMINATION: The study protocol was reviewed and approved by the Northern Sydney Local Health District (Australia). Study results will be published in peer-reviewed journals and presented at scientific and professional meetings. TRIAL REGISTRATION NUMBER: ACTRN12622001423707.

The voice characterisation checklist: psychometric properties of a brief clinical assessment of voices as social agents.

Aim: There is growing interest in tailoring psychological interventions for distressing voices and a need for reliable tools to assess phenomenological features which might influence treatment response. This study examines the reliability and internal consistency of the Voice Characterisation Checklist (VoCC), a novel 10-item tool which assesses degree of voice characterisation, identified as relevant to a new wave of relational approaches. Methods: The sample comprised participants experiencing distressing voices, recruited at baseline on the AVATAR2 trial between January 2021 and July 2022 (n = 170). Inter-rater reliability (IRR) and internal consistency analyses (Cronbach's alpha) were conducted. Results: The majority of participants reported some degree of voice personification (94%) with high endorsement of voices as distinct auditory experiences (87%) with basic attributes of gender and age (82%). While most identified a voice intention (75%) and personality (76%), attribution of mental states (35%) to the voice ('What are they thinking?') and a known historical relationship (36%) were less common. The internal consistency of the VoCC was acceptable (10 items, α = 0.71). IRR analysis indicated acceptable to excellent reliability at the item-level for 9/10 items and moderate agreement between raters' global (binary) classification of more vs. less highly characterised voices, κ = 0.549 (95% CI, 0.240-0.859), p < 0.05. Conclusion: The VoCC is a reliable and internally consistent tool for assessing voice characterisation and will be used to test whether voice characterisation moderates treatment outcome to AVATAR therapy. There is potential wider utility within clinical trials of other relational therapies as well as routine clinical practice.

Neurosarcoidosis, Coccidioidomycosis, or Both!

Purpose: To report a case of neurosarcoidosis (NS) who was initially diagnosed as Coccidioidomycosis immitis (CI) infection. Observations: A 57-year-old diabetic man presented with sudden painless diminution of vision, metamorphopsia, and color vision deficits in the left eye (OS) for one month. His vision was 20/20 in the right eye (OD) and 20/40 OS. Ophthalmic examination revealed left relative afferent pupillary defect, blurred optic nerve margin, creamy chorioretinal infiltration around the optic disc, and mild macular edema. OD examination was non-revealing. Chest CT scan with contrast showed calcified mediastinal lymph nodes, but biopsy of the lymph nodes was normal. Brain and orbit MRI demonstrated soft tissue abnormality with enhancement in left orbital apex with involvement of the extraocular muscles. CSF culture was negative, but complement fixation had positive titer of 1:2 for CI. The patient was diagnosed with CI meningitis, and antifungal therapy was initiated. Slight visual and symptomatic improvement was observed, which was not completely satisfactory. Biopsy of extraocular orbital muscle five months later revealed non-caseating granulomatous inflammation, leading to initiation of prednisone trial therapy. Nine months later, the patient was referred to a tertiary center owing to persistence of optic disc edema OS. PET CT was consistent with a diagnosis of sarcoidosis. Antifungal treatment was discontinued, and oral prednisone with methotrexate was initiated. Subsequently, methotrexate was replaced by infliximab to further manage ocular inflammation and neurologic symptoms which was effective. Vision was 20/20 OD and 20/30 OS at the most recent visit. Conclusion and Importance: Signs and symptoms of neurosarcoidosis and coccidioidomycosis can be similar and deceiving. The index case underscores importance of considering appropriate differential diagnoses in patients with similar symptoms and signs who may respond to preliminary designated treatment but not to the optimal extent. Considering such possibility could assist clinicians in managing the patients timely and efficiently.

Effect of Pupil Size on Fixed-Luminance Flicker Full-Field Electroretinogram Magnitude.

Purpose: Diopsys® NOVA fixed-luminance flicker full-field electroretinogram (ffERG) device is a potential adjunct to conventional flicker ffERG testing for assessing cone cell function. Magnitude of measured electrical response is known to vary with pupil size in conventional ffERG testing. The index study characterizes the relationship between magnitude of measured electrical activity and pupil size, both pupil diameter and pupil area, for this device. Methods: Seventeen patients (34 eyes) with no known ocular diseases were enrolled in the study. Electrophysiologic function of cone cells was evaluated using fixed-luminance flicker ffERG before and after dilation. Linear regression models, with inter-eye correlations controlled as fixed-effects, were used to characterize the effect of pupil dilation on the magnitude of the measured responses. Results: Mean age of study patients was 33.5 (standard deviation 7.4 years), and 35.3% of the subjects were female. Mean value of electrical response magnitude was 10.07±2.79µV before dilation and 15.30±4.08µV after dilation. The correlations of ERG magnitude with pupil diameter and with pupil area were not significant for either dilated or undilated eyes considered separately but were highly significant (p<0.001) for dilated and undilated eyes considered in aggregate. ERG magnitude tended to increase by 1.08 µV for every 1 mm increase in pupillary diameter. Conclusion: An increase in pupil size, both pupil diameter and pupil area, is significantly associated with an increase in flicker ffERG magnitude recorded by the Diopsys device, suggesting that pupil size should be measured and considered when making clinical judgments based on the flicker ffERGs recorded by the device, and that pupil size-specific reference ranges could improve the clinical utility of the device.

Association of pain-related threat beliefs and disability with postural control and trunk motion in individuals with low back pain: a systematic review and meta-analysis.

PURPOSE: Low back pain (LBP) individuals with high levels of fear of pain might display changes in motor behavior, which leads to disability. This study aimed to systematically review the influence of pain-related threat beliefs or disability on trunk kinematic or postural control in LBP. METHOD: Eight electronic databases were searched from January 1990 to July 1, 2020. Meta-analysis using random-effect model was performed for 18 studies on the association between pain-related threat beliefs or disability and lumbar range of motion. Pearson r correlations were used as the effect size. RESULT: Negative correlations were observed between lumbar range of motion (ROM) and pain-related threat beliefs (r = - 0.31, p < 0.01, 95% CI: - 0.39, - 0.24) and disability (r = - 0.24, p < 0.01, 95% CI: - 0.40, - 0.21). Nonsignificant correlations were reported between pain-related threat beliefs and center of pressure parameters during static standing in 75% of the studies. In 33% of the studies, moderate negative correlations between disability and postural control were observed. CONCLUSION: Motor behaviors are influenced by several factors, and therefore, the relatively weak associations observed between reduced lumbar ROM with higher pain-related threat beliefs and perceived disability, and postural control with disability are to be expected. This could aid clinicians in the assessment and planning rehabilitation interventions. LEVEL OF EVIDENCE I: Diagnostic: individual cross-sectional studies with the consistently applied reference standard and blinding.

Psychometric properties of the Persian version of the pain anxiety symptom scale (PASS-20) in chronic non-specific neck pain patients.

OBJECTIVES: Pain-related anxiety has been linked to avoidance behaviour, maintenance of pain and disability. A valid and reliable tool is required to evaluate pain-related anxiety among Persian speaking adults with chronic non-specific neck pain (CNSNP). This study aimed to evaluate psychometric properties of the Persian pain anxiety symptom scale-20 (PASS-20) according to the consensus-based standards for the selection of health measurement instruments (COSMIN) checklist in Iranian adults with CNSNP. METHODS: 198 individuals with CNSNP completed the PASS-20. The factorial structure (confirmatory factor analysis (CFA), exploratory factor analysis (EFA)), test-retest reliability (intraclass correlation coefficient (ICC), standard error of measurement (SEM) and minimal detectable change (MDC)), internal consistency (Cronbach's alpha), and construct validity (convergent and known-group validity) were assessed. The correlation between PASS-20 with pain catastrophizing scale (PCS), Tampa Scale for Kinesiophobia (TSK), neck disability index (NDI), Beck Depression Inventory (BDI), visual analog scale (VAS) (Spearman's rank correlation) were examined. Known-group validity of PASS-20 was evaluated by comparing the difference between the PASS-20 scores of the known groups based on level of disability, pain intensity and gender using non-parametric tests. RESULTS: The CFA showed almost the best fit with the original version. The subscales and total score demonstrated good internal consistency (Cronbach's α: 0.70-0.92) and high test-retest reliability (ICC: 0.94-0.97). PASS-20 had significant moderate correlations with PCS, TSK, NDI, VAS and a significant low correlation with BDI. Regarding known-group validity, the total score of Persian PASS-20 was higher in CNSNP with higher levels of pain and disability and in the female gender. CONCLUSIONS: The Persian PASS-20 has acceptable psychometric properties in adults with CNSNP. The results of the factor analysis supported the four-factor structure comparable to the original version. ETHICAL COMMITTEE NUMBER: 921672004.

Pelvic floor muscle training in multiple sclerosis patients with lower urinary tract dysfunction: A systematic review and meta-analysis.

BACKGROUND: Pelvic floor muscle training (PFMT) is a conservative treatment program for the management of lower urinary tract dysfunction (LUTD). This systematic review aimed to investigate the overall effectiveness of PFMT on LUTD in people with multiple sclerosis (MS). METHODS: Seven databases (PubMed/Medline, Scopus, PEDro, WOS, CINAHL, Cochrane, and Embase) were searched between 1990 and July 2019. We investigated urine leakage as our primary outcome. The secondary outcomes were neurogenic bladder symptoms measured by the overactive bladder questionnaire (OAB-V8 questionnaire) and the power/endurance of pelvic floor muscles. RESULTS: Fifteen studies were identified as eligible. Both urine leakage (standardized mean difference (SMD) = 0.50, 95% CI [-0.78, -0.23], and neurogenic bladder symptoms, SMD = -2.24, 95% CI [-4.44, -0.03] significantly decreased by PFMT in people with MS. PFMT increased the overall endurance and power of pelvic floor muscles moderately and significantly, SMD = 1.25, 95% CI [0.69, 1.81], and SMD = 0.64, 95% CI [0.24, 1.05], respectively. CONCLUSIONS: Moderate to high-quality studies showed the overall efficacy of PFMT in decreasing urine leakage and neurogenic bladder symptoms and increasing endurance and power of pelvic floor muscles. MS patients with lower urinary tract symptoms could benefit from PFMT in the short term.

Psilocybin-assisted therapy for the treatment of resistant major depressive disorder (PsiDeR): protocol for a randomised, placebo-controlled feasibility trial.

INTRODUCTION: Psilocybin-assisted therapy may be a new treatment for major depressive disorder (MDD), with encouraging data from pilot trials. In this trial (short name: PsiDeR) we aimed to test the feasibility of a parallel-group, randomised, placebo-controlled design. The primary outcomes in this trial are measures of feasibility: recruitment rates, dropout rates and the variance of the primary outcome measure of depression. METHODS AND ANALYSIS: We are recruiting up to 60 participants at a single centre in London, UK who are unresponsive to, or intolerant of, at least two evidence-based treatments for MDD. Participants are randomised to receive a single dosing session of 25 mg psilocybin or a placebo. All participants receive a package of psychological therapy. The primary outcome measure for depression is the Montgomery Asberg Depression Rating Scale collected by blinded, independent raters. The primary endpoint is at 3 weeks, and the total follow-up is 6 weeks. With further informed consent, this study collects neuroimaging and omics data for mechanism and biomarker analyses and offers participants an open label extension consisting of a further, open label dose of 25 mg of psilocybin. ETHICS AND DISSEMINATION: All participants will be required to provide written informed consent. The trial has been authorised by the National Research Ethics Committee (20-LO/0206), Health Research Authority (252750) and Medicine's and Healthcare Products Regulatory Agency (CTA 14523/0284/001-0001) in the UK. Dissemination of results will occur via a peer-reviewed publication and other relevant media. TRIAL REGISTRATION NUMBERS: EUDRACT2018-003573-97; NCT04959253.

Investigating the effect of health transformation plan on the public hospitals performance indicators; a case study from Iran.

BACKGROUND: Health systems need constant changes and reforms in their structure to adapt to changing conditions and meet the needs of society. One of the fundamental changes in the health system of Iran is the health transformation plan (HTP), the effects of which must be examined from different aspects. Therefore, the purpose of this study is to investigate the effect of HTP on the performance indicators of public hospitals in Yazd city, Iran. METHODS: This cross-sectional study was carried out in all public hospitals in city of Yazd. Six performance indicators were examined monthly and in two time periods of 12 months before and 12 months after the implementation of Health Transformation Plan (HTP). The data was analyzed by SPSS software program version 22, using the paired T-test, and the Interrupted Time Series (ITS) model. FINDINGS: Findings showed that the performance indicators of the studied hospitals have improved after the implementation of the HTP. According to the ITS model, the implementation of HTP did not have a significant effect on the level and trend of the bed rotation distance, average length of stay and the ratio of surgical operations to bed indicators. However, it had a statistically significant effect on the level and trend of mortality and hospitalization rates. Moreover, the implementation of HTP had a significant effect on the level of the bed occupancy rate, but did not have a significant effect on the trend of this indicator. CONCLUSION: Based on the research findings, all the selected indicators changed to some extent after the implementation of HTP, which showed the effect of this plan on the performance of hospitals. However, not all indicators were statistically significant as the findings sub-section revealed.

Towards classification criteria for early-stage knee osteoarthritis: A population-based study to enrich for progressors.

OBJECTIVE: To facilitate a greater likelihood of favorable response to new disease-modifying therapies, recruitment of patients at an earlier stage of their disease into clinical trials may be an attractive strategy. Hence, there is a need to develop widely accepted classification criteria for early-stage knee osteoarthritis (OA). We have proposed a set of classification criteria for early-stage knee OA (2018 classification criteria) now being further refined. Here, we test the draft criteria for enrichment for clinical and structural progression. DESIGN: Performance of the 2018 classification criteria for early stage knee OA was tested using data from the Osteoarthritis Initiative (OAI). The OAI comprises data of 4796 men and women aged 45-79 years with or at risk for knee OA at baseline. Based on the 2018 classification criteria, a knee with Kellgren & Lawrence (K&L) grade of 0-I, two out of four Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales equal or less than 85, and presence of at least one of joint line tenderness or crepitus, was considered as early-stage knee OA. Knees with K&L grade 0-I that did not fulfill the 2018 criteria, were considered as controls. Logistic regression analysis was used to evaluate the predictive performance of the criteria set for structural as well as clinical progression. We further explored the discriminatory capability of criteria by including the average KOOS4 score, and relevant clinical examination findings such as the presence of effusion and/or Heberden's nodes. RESULTS: We identified 1315 (27%) knees from OAI fulfilling the 2018 early-stage knee OA classification criteria. The female to male ratio was higher in the early knee OA group compared to controls. The early-stage knee OA group were on average slightly younger and had higher body mass index vs controls (mean [SD] age: 59.2 [8.9] years vs. 60.2 [9.1] and mean [SD] BMI 28.3 [7.0] vs. 26.8 [6.0]). By applying the 2018 criteria, there was a substantial enrichment compared to controls at 48 and 96 months for both structural (OR=1.1-1.4, and AUC=0.72-0.74) and clinical progressors (OR=2.1-2.5, 95% and AUC=0.66). Expanding the clinical examination findings by including joint effusion and/or Heberden's nodes improved the enrichment for both structural and clinical progressors (OR=4.2, 95% confidence interval=3.2-5.5 and OR=3.3, 95% confidence interval=2.8-3.5, respectively). Replacing scoring of the 4 separate KOOS domains by a KOOS4 score performed comparably. CONCLUSIONS: The proposed 2018 early-stage knee OA classification criteria showed encouraging performance characteristics with regard to an enrichment for structural and clinical progression using longitudinal OAI data. Our results indicate that the addition of clinical findings improves the performance of previous criteria to define early-stage disease and risk for progression.

Quantification of human sperm concentration using machine learning-based spectrophotometry.

Spectrophotometry is an indirect non-invasive and quantitative method for specifying materials with unknown contents based on absorption behavior. This paper presents the first application of artificial neural network in spectrophotometry for quantification of human sperm concentration. A well-trained full spectrum neural network (FSNN) model is developed by examining the absorption response of sperm samples from 41 human subjects to different light spectra (wavelength from 390 to 1100 nm). It is shown that this FSNN accurately estimates sperm concentration based on the full absorption spectrum with over 93% prediction accuracy, and provides 100% agreement with clinical assessments in differentiating the samples of healthy donor from patient samples. We suggest the machine learning-based spectrophotometry approach with the trained FSNN model as a rapid, low-cost, and powerful technique to quantify sperm concentration. The performance of this technique is superior to available spectrophotometry methods currently used for semen analysis and will provide novel research and clinical opportunities for tackling male infertility.

Can Slow Deep Breathing Reduce Pain? An Experimental Study Exploring Mechanisms.

Slow deep breathing (SDB) is commonly employed in the management of pain, but the underlying mechanisms remain equivocal. This study sought to investigate effects of instructed breathing patterns on experimental heat pain and to explore possible mechanisms of action. In a within-subject experimental design, healthy volunteers (n = 48) performed 4 breathing patterns: 1) unpaced breathing, 2) paced breathing (PB) at the participant's spontaneous breathing frequency, 3) SDB at 6 breaths per minute with a high inspiration/expiration ratio (SDB-H), and 4) SDB at 6 breaths per minute with a low inspiration/expiration ratio (SDB-L). During presentation of each breathing pattern, participants received painful heat stimuli of 3 different temperatures and rated each stimulus on pain intensity. Respiration, heart rate, and blood pressure were recorded. Compared to unpaced breathing, participants reported less intense pain during each of the 3 instructed breathing patterns. Among the instructed breathing patterns, pain did not differ between PB and SDB-H, and SDB-L attenuated pain more than the PB and SDB-H patterns. The latter effect was paralleled by greater blood pressure variability and baroreflex effectiveness index during SDB-L. Cardiovascular changes did not mediate the observed effects of breathing patterns on pain. PERSPECTIVES: SDB is more efficacious to attenuate pain when breathing is paced at a slow rhythm with an expiration that is long relative to inspiration, but the underlying mechanisms remain to be elucidated.

Respiratory Hypoalgesia? The Effect of Slow Deep Breathing on Electrocutaneous, Thermal, and Mechanical Pain.

The aim of the study reported in this paper is to investigate the effect of slow-deep breathing (SDB) on self-reported pain, heart rate variability, and baroreflex sensitivity (BRS). These effects are examined in 3 separate experiments, each using a different phasic pain modality. For each experiment, different subjects were recruited. Eighty-three healthy female participants were instructed to breathe guided by a visual cue at a slow frequency (SDB: .1 Hz), and at a frequency close to the spontaneous breathing frequency (normal paced breathing, .2 Hz). Pain was induced during instructed breathing using electrocutaneous (experiment 1, n = 31), thermal (experiment 2, n = 28), or mechanical stimuli (experiment 3, n = 24). Participants were requested to rate the intensity of each painful stimulus (Numerical Rating Scale) and subjective level of pleasantness, arousal, and dominance (self-assessment manikin). During the experiment, R-R interval, blood pressure, tidal volume, and end-tidal CO2 were continuously measured. Results for self-reported pain, self-assessment manikin, and physiological measurements were consistent across the 3 experiments. Although SDB significantly increased baroreflex sensitivity and heart rate variability, self-reported pain did not differ between breathing conditions, regardless of pain modality. Other potential mechanisms or components should be considered such as behavioral modulators including relaxation and treatment expectation. PERSPECTIVE: Merely slowing down the breathing frequency to .1 Hz is not sufficient to induce hypoalgesia, despite the significant physiological effects associated with SDB compared to spontaneous breathing.

Gait stability of diabetic patients is altered with the rigid rocker shoes.

BACKGROUND: Rigid-rocker shoes may induce gait instability in diabetics, however, this is not clearly investigated. The present study investigates if rigid-rocker shoes influence diabetic gait stability. METHODS: Fourteen non-neuropathic and nine neuropathic diabetics, plus eleven healthy young-adults were recruited. Full-body kinematic data was captured during walking. Experimental conditions included barefoot and three rocker-shoe designs according to the rocker angle, apex angle and apex position (R10: 10°, 80°, 60%; R15: 15°, 95°, 52%; R20: 20°, 95°, 60%). Sagittal and frontal stability margin, plus fear of fall were main outcome measures. FINDINGS: Sagittal stability margin was not affected by health, however, was increased with R10 and R15 in non-neuropathic diabetics and healthy individuals (R2 = 0.16). Variability of sagittal stability margin was not altered in neuropathic diabetics, but was increased with R15 and R20 in healthy participants, with R15 in non-neuropathic diabetics (R2 = 0.12). Frontal stability margin (R2 = 0.46) and its variability (R2 = 0.39) were significantly increased in neuropathic and non-neuropathic diabetics compared to healthy individuals. Frontal stability margin was significantly higher with R15 in neuropathic diabetics, and with R20 in both non-neuropathic and healthy participants. Sagittal and frontal stability margin were strongly correlated with fear of fall in neuropathic diabetics. INTERPRETATIONS: R15 and R20 might challenge gait stability of diabetics cause them restrict centre of mass motion thereby imposing a tighter control over walking. However, neuropathic diabetics generally walk very cautious due to neuropathy and increased fear of fall. Frontal stability margin, highly affected by health and experimental condition, is a more sensitive indicator of gait stability.

CRB1-Related Leber Congenital Amaurosis: Reporting Novel Pathogenic Variants and a Brief Review on Mutations Spectrum

Background: LLeber congenital amaurosis (LCA) is a rare inherited retinal disease causing severe visual impairment in infancy. It has been reported that 9-15% of LCA cases have mutations in CRB1 gene. The complex of CRB1 protein with other associated proteins affects the determination of cell polarity, orientation, and morphogenesis of photoreceptors. Here, we report three novel pathogenic variants in CRB1 gene and then briefly review the types, prevalence, and correlation of reported mutations in CRB1 gene. Methods: Whole exome sequencing and targeted gene panel were employed. Then validation in the patient and segregation analysis in affected and unaffected members was performed. Results: Our detected novel pathogenic variants (p.Glu703*, c.2128+1G>A and p.Ser758SerfsX33) in CRB1 gene were validated by Sanger sequencing. Segregation analysis confirmed the inheritance pattern of the pathogenic variants. Conclusion: Our findings show that emerging the next-generation sequencing-based techniques is very efficient in identifying causative variants in disorders with locus heterogeneity.

Patient Assessment of Constipation Quality of Life Questionnaire: Translation, Cultural Adaptation, Reliability, and Validity of the Persian Version.

BACKGROUND: The Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire is the most validated and the most specific tool for measuring the quality of life of patients with constipation. Over 120 million people live in countries whose official language is Persian. There is no reported Persian version of the PAC-QOL questionnaire yet. The aim of this study was to translate and culturally adapt the PAC-QOL questionnaire and to assess its reliability and validity among Persian patients with chronic constipation. METHODS: Following the translation and cultural adaptation of the PAC-QOL questionnaire to Persian, 100 patients (mean±SD age=40.51±13.67) with constipation were recruited for validity measurement and 20 patients were re-examined for reliability. Content validity was assessed based on the opinions of an expert committee and the floor/ceiling effect. Construct validity was evaluated according to the hypothesis test. The SF-36 questionnaire was used for concurrent criterion validity, intra-class correlation coefficient for reliability, and Cronbach's alpha for internal consistency. RESULTS: The content validity of the PAC-QOL questionnaire was proven, and there was no floor/ceiling effect. Construct validity also was confirmed based on the hypothesis test. The overall Cronbach's alpha of the PAC-QOL questionnaire was 0.92 (range=0.72-0.92), and the overall intra-class correlation coefficient of the questionnaire was 0.88 (range=0.69-0.87). The correlation between the SF-36 and PAC-QOL questionnaires was moderate. CONCLUSION: The Persian version of the PAC-QOL questionnaire demonstrated good validity and reliability properties in chronic constipation. Accordingly, Persian researchers and clinicians can benefit from this questionnaire in further research and assessment of treatment outcomes.