The epidemiology, prognosis and management of carpal tunnel syndrome in primary care

Carpal tunnel syndrome (CTS) is a compression neuropathy of the median nerve. Patients may experience discomfort in the hand and wrist, altered sensation and functional deficit. The management of mild to moderate CTS involves local corticosteroid injection (CSI) and night splinting (NS). The aims of the studies presented in this thesis were to describe the epidemiology of CTS and to develop prognostic models to predict future likely outcomes in patients presenting with CTS in a primary care setting. Evidence for predictors of treatment effect (CSI or NS) were also explored. The estimated crude prevalence of patients presenting with CTS in UK primary care (using data from the Clinical Practice Research Datalink - CPRD) increased from 26.03 per 10,000 person years in 1993 (95% CI 25.10 to 27.00) to 36.08 per 10,000 person years (95% CI 35.45 to 36.72) in 2013. The proportion of patients having carpal tunnel release surgery (CTR) changed over the study period increasing from 19.35% in 1993 to a peak in 2009 at 29.32% and then decreasing to 27.3% in 2013. A systematic review of 16 cohort studies reporting on the course and prognosis of CTS showed that prolonged symptom duration, a positive Phalen’s test, and thenar wasting were associated with poor outcome over a follow-up period of between six months and 12 years. However, not all associations were statistically significant and many studies were deemed to be at increased risk of bias (particularly relating to study attrition, confounding, and/or statistical analysis or reporting), hence the overall judgement regarding their predictive value remained inconclusive. A CPRD cohort of 91,412 patients with CTS was developed. 20.24% of the cohort had a recorded episode of CTR within 3 years of diagnosis. A prognostic model predicting time to surgical intervention was developed using Cox regression and included age, obesity, alcohol use, smoking and having multi-site pain, an inflammatory condition or a neck symptoms (adjusting for region and deprivation). The predictive capability of the model was limited, C statistic 0.59 (95% CI 0.58 to 0.59). Multivariable linear regression modelling using data from a randomised controlled trial (INSTINCTS) was used to develop a prognostic model predicting patient reported outcome at six months. The final model included the baseline Boston Carpal Tunnel Questionnaire score, the symptom severity score, and the absence of any other neck or upper limb symptom. The optimism-adjusted model calibrated poorly, overestimating the severity of outcome in patients with less severe observed CTS, and underestimating the severity of outcome in patients with more severe observed CTS. A second systematic review including four RCTs summarised evidence for predictors of treatment effect. The results from one trial indicated that the effect of CSI was larger in patients with more severe nerve conduction and baseline symptom scores. Exploratory analysis of a small set of a priori defined candidate predictors of treatment effect using INSTINCTS data suggested that at six months, CSI was less effective than NS in patients with unilateral symptoms compared to those with bilateral CTS. However, results need to be carefully interpreted given the lack of significant interaction, the possibility of a unit of analysis error and a very small sample size. In summary, patients with CTS presented in primary care with increasing frequency between 1993 and 2013. However, since around 2008, the proportion of patients receiving surgical treatment was observed to decrease, despite being considered clinically effective for most patients. Lower rates of surgery may be associated with changes in access to the procedure. This highlights the need for optimal management to be provided in primary care. Assuming the CPRD population to be representative, at least 20% of patients presenting with CTS did not respond well to their initial management in primary care. There is likely to be clinical benefit in identifying this group early in the course of their symptoms, and explore any differential treatment response, in order to better target treatment to the individual and identify those who are likely to require surgery. However, the prognostic models developed in this thesis performed poorly. It seems that the prediction of CTS is complex and potentially includes prognostic factors not measurable in CPRD or trial data. Similarly, no confirmatory evidence was found that could be used to match treatment options to individuals. Therefore, patients with CTS can be initially managed in primary care using current guidance and should be routinely followed up and referred for surgery if they fail to experience initial satisfactory improvement

Contribution of intestinal- and cereal-derived phytase activity on phytate degradation in young broilers

There is little consensus as to the capability of poultry to utilize dietary phytate without supplemental phytase. Therefore, an experiment was conducted to examine the extent to which endogenous phytase of intestinal and cereal origin contributes to phytate degradation in birds aged 0 to 14 d posthatch. Ross 308 broilers (n = 720) were fed one of 4 experimental diets with differing dietary ingredient combinations and approximate total phytate levels of 10 g/kg, dietary phytase activity analyzed at 460 U/kg, dietary calcium (Ca) levels of 11 g/kg, and nonphytate-phosphorus (P) levels of 4 g/kg. Broiler performance, gizzard, duodenum, jejunum and ileum pH, Ca and P digestibility and solubility, amount of dietary phytate hydrolyzed in the gizzard, jejunum, and ileal digesta phytase activity were analyzed at d 4, 6, 8, 10, 12, and 14 posthatch. Intestinal endogenous phytase activity increased significantly (P < 0.001) between d 4 and 6, resulting in increased phytate hydrolysis in the gizzard (P = 0.003), jejunum (P < 0.001), and ileum (P < 0.001). Phytase activity and phytate hydrolysis continued to increase with age, with a greater phytase activity and associated increase in phytate hydrolysis and mineral utilization between d 10 and 12. Gizzard and jejunum Ca and P solubility and ileal Ca and P digestibility increased significantly (P < 0.001), and gastrointestinal pH decreased significantly (P < 0.001) between d 4 and 6. By d 14, phytase activity recovered in the ileum was approximately 45 U/kg. There were strong correlations between phytase activity measured in the ileum and phytate hydrolyzed in the gizzard (r = 0.905, P < 0.001), jejunum (r = 0.901, P = 0.023), and ileum (r = 0.938, P = 0.042). This study shows intestinal- and dietary-derived endogenous phytase activity is responsible for phytate-P hydrolysis in broilers

In vitro versus in situ evaluation of the effect of phytase supplementation on calcium and phosphorus solubility in soya bean and rapeseed meal broiler diets

1. In vitro assays provide a sensitive and economic tool to evaluate dietary effects, but have limitations. In this study, the effect of phytase supplementation on solubility, and presumed availability, of calcium (Ca) and phosphorus (P) in soybean meal (SBM) and rapeseed meal (RSM) based diets was evaluated both in situ and by a 2-step in vitro digestion assay that simulated the gastric and small intestine (SI) phases of digestion

Trends in the prevalence, incidence and surgical management of carpal tunnel syndrome between 1993 and 2013: an observational analysis of UK primary care records

OBJECTIVES: To describe the prevalence, incidence and surgical management of carpal tunnel syndrome (CTS), between 1993 and 2013, as recorded in the Clinical Practice Research Datalink (CPRD). DESIGN: We completed a series of cross-sectional epidemiological analyses to observe trends over time. SETTING: Primary care data collected between 1993 and 2013, stored in the CPRD. POPULATION: Individuals aged ≥18 years were selected. Prevalent and incident episodes of CTS and episodes of surgical intervention were identified using a list of preidentified Read codes. ANALYSIS: We defined incident episodes as those with no preceding diagnostic code for CTS in the past 2 years of data. Episodes of surgery were expressed as a percentage of the prevalent population during the same calendar year. Joinpoint regression was used to determine significant changes in the underlying trend. RESULTS: The prevalence of CTS increased over the study period, with a particular incline between 2000 and 2004 (annual percentage change 7.81). The female-to-male prevalence ratio reduced over time from 2.74 in 1993 to 1.93 in 2013. The median age of females and males with CTS were noted to increase from 49 and 53 years, respectively in 1993 to 54 and 59 years, respectively in 2013. Incidence was also noted to increase over time. After an initial increase between 1993 and 2007, the percentage of prevalent patients with a coded surgical episode began to decrease after 2007 to 27.41% in 2013 (annual percentage change -1.7). CONCLUSION: This study has demonstrated that the prevalence and incidence of CTS increased over the study period between 1993 and 2013. Rates of surgery for CTS also increased over the study period; however after 2007, the per cent of patients receiving surgery showed a statistically significant decline back to the rate seen in 2004

Predicting surgical intervention in patients presenting with carpal tunnel syndrome in primary care.

Purpose: Carpal tunnel syndrome (CTS) is a symptomatic compression neuropathy of the median nerve. This study investigated the value of candidate prognostic factors (PFs) in predicting carpal tunnel release surgery. Patients and methods: This is a retrospective cohort study set in the Clinical Practice Research Datalink. Patients ≥18 years presenting with an incident episode of CTS were identified between 1989 and 2013. Candidate PF's defined in coded electronic patient records were identified following literature review and consultation with clinicians. Time to first carpal tunnel release surgery was the primary end point. A manual backward stepwise selection procedure was used to obtain an optimal prediction model, which included all the significant PFs. Results: In total, 91,412 patients were included in the cohort. The following PFs were included in an optimal model (C-statistic: 0.588 [95% CI 0.584-0.592]) for predicting surgical intervention: geographical region; deprivation status; age hazard ratio (HR 1.02 per year, 95% CI 1.01-1.02); obesity (HR 1.23, 95% CI 1.19-1.27); alcohol drinker (HR 1.05, 95% CI 1.00-1.10); smoker (HR 1.06, 95% 1.03-1.10); inflammatory condition (HR 1.13, 95% CI 0.98-1.29); neck condition (HR 1.13, 95% CI 1.03-1.23); and multisite pain (HR 1.10, 95% CI 1.05-1.15). Although not included in the multivariable model, pregnancy (if gender female) within 1 year of the index consultation, reduced the risk of surgery (HR 0.24, 95% CI 0.21-0.28). Conclusion: This study shows that patients who are older and who have comorbidities including other pain conditions are more likely to have surgery, whereas patients presenting with CTS during or within a year of pregnancy are less likely to have surgery. This information can help to inform clinicians and patients about the likely outcome of treatment and to be aware of which patients may be less responsive to primary care interventions

Dementia and osteoporosis in a geriatric population: Is there a common link?

AIM To determine the existence of a common pathological link between dementia and osteoporosis through reviewing the current evidence base. METHODS This paper reviews the current literature on osteoporosis and dementia in order to ascertain evidence of a common predisposing aetiology. A literature search of Ovid MEDLINE (1950 to June 2016) was conducted. The keywords “osteoporosis”, “osteoporotic fracture”, “dementia” and “Alzheimer’s disease” (AD) were used to determine the theoretical links with the most significant evidence base behind them. The key links were found to be vitamins D and K, calcium, thyroid disease, statins, alcohol and sex steroids. These subjects were then searched in combination with the previous terms and the resulting papers manually examined. Theoretical, in vitro and in vivo research were all used to inform this review which focuses on the most well developed theoretical common causes for dementia (predominantly Alzheimer’s type) and osteoporosis. RESULTS Dementia and osteoporosis are multifaceted disease processes with similar epidemiology and a marked increase in prevalence in elderly populations. The existence of a common link between the two has been suggested despite a lack of clear pathological overlap in our current understanding. Research to date has tended to be fragmented and relatively weak in nature with multiple confounding factors reflecting the difficulties of in vivo experimentation in the population of interest. Despite exploration of various possible mechanisms in search for a link between the two pathologies, this paper found that it is possible that these associations are coincidental due to the nature of the evidence available. One finding in this review is that prior investigation into common aetiologies has found raised amyloid beta peptide levels in osteoporotic bone tissue, with a hypothesis that amyloid beta disorders are systemic disorders resulting in differing tissue manifestations. However, our findings were that the most compelling evidence of a common yet independent aetiology lies in the APOE4 allele, which is a well-established risk for AD but also carries an independent association with fracture risk. The mechanism behind this is thought to be the reduced plasma vitamin K levels in individuals exhibiting the APOE4 allele which may be amplified by the nutritional deficiencies associated with dementia, which are known to include vitamins K and D. The vitamin theory postulates that malnutrition and reduced exposure to sunlight in patients with AD leads to vitamin deficiencies. CONCLUSION Robust evidence remains to be produced regarding potential links and regarding the exact aetiology of these diseases and remains relevant given the burden of dementia and osteoporosis in our ageing population. Future research into amyloid beta, APOE4 and vitamins K and D as the most promising aetiological links should be welcomed

G-Protein coupled receptors: structure and function in drug discovery

The G-protein coupled receptors (GPCRs) superfamily comprise similar proteins arranged into families or classes thus making it one of the largest in the mammalian genome. GPCRs take part in many vital physiological functions making them targets for numerous novel drugs. GPCRs share some distinctive features, such as the seven transmembrane domains, they also differ in the number of conserved residues in their transmembrane domain. Here we provide an introductory and accessible review detailing the computational advances in GPCR pharmacology and drug discovery. An overview is provided on family A-C GPCRs; their structural differences, GPCR signalling, allosteric binding and cooperativity. The dielectric constant (relative permittivity) of proteins is also discussed in the context of site-specific environmental effects

The clinical and cost-effectiveness of corticosteroid injection versus night splints for carpal tunnel syndrome (INSTINCTS trial): an open-label, parallel group, randomised controlled trial

Background To our knowledge, the comparative effectiveness of commonly used conservative treatments for carpal tunnel syndrome has not been evaluated previously in primary care. We aimed to compare the clinical and cost-effectiveness of night splints with a corticosteroid injection with regards to reducing symptoms and improving hand function in patients with mild or moderate carpal tunnel syndrome. Methods We did this randomised, open-label, pragmatic trial in adults (≥18 years) with mild or moderate carpal tunnel syndrome recruited from 25 primary and community musculoskeletal clinics and services. Patients with a new episode of idiopathic mild or moderate carpal tunnel syndrome of at least 6 weeks' duration were eligible. We randomly assigned (1:1) patients (permutated blocks of two and four by site) with an online web or third party telephone service to receive either a single injection of 20 mg methylprednisolone acetate (from 40 mg/mL) or a night-resting splint to be worn for 6 weeks. Patients and clinicians could not be masked to the intervention. The primary outcome was the overall score of the Boston Carpal Tunnel Questionnaire (BCTQ) at 6 weeks. We used intention-to-treat analysis, with multiple imputation for missing data, which was concealed to treatment group allocation. The trial is registered with the European Clinical Trials Database, number 2013-001435-48, and ClinicalTrial.gov, number NCT02038452. Findings Between April 17, 2014, and Dec 31, 2016, 234 participants were randomly assigned (118 to the night splint group and 116 to the corticosteroid injection group), of whom 212 (91%) completed the BCTQ at 6 weeks. The BCTQ score was significantly better at 6 weeks in the corticosteroid injection group (mean 2·02 [SD 0·81]) than the night splint group (2·29 [0·75]; adjusted mean difference −0·32; 95% CI −0·48 to −0·16; p=0·0001). No adverse events were reported. Interpretation A single corticosteroid injection shows superior clinical effectiveness at 6 weeks compared with night-resting splints, making it the treatment of choice for rapid symptom response in mild or moderate carpal tunnel syndrome presenting in primary care

Diabetes as a risk factor for the onset of frozen shoulder: a systematic review and meta-analysis.

OBJECTIVE: Summarise longitudinal observational studies to determine whether diabetes (types 1 and 2) is a risk factor for frozen shoulder. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, Embase, AMED, PsycINFO, Web of Science Core Collection, CINAHL, Epistemonikos, Trip, PEDro, OpenGrey and The Grey Literature Report were searched on January 2019 and updated in June 2021. Reference screening and emailing professional contacts were also used. ELIGIBILITY CRITERIA: Longitudinal observational studies that estimated the association between diabetes and developing frozen shoulder. DATA EXTRACTION AND SYNTHESIS: Data extraction was completed by one reviewer and independently checked by another using a predefined extraction sheet. Risk of bias was judged using the Quality In Prognosis Studies tool. For studies providing sufficient data, random-effects meta-analysis was used to derive summary estimates of the association between diabetes and the onset of frozen shoulder. RESULTS: A meta-analysis of six case-control studies including 5388 people estimated the odds of developing frozen shoulder for people with diabetes to be 3.69 (95% CI 2.99 to 4.56) times the odds for people without diabetes. Two cohort studies were identified, both suggesting diabetes was associated with frozen shoulder, with HRs of 1.32 (95% CI 1.22 to 1.42) and 1.67 (95% CI 1.46 to 1.91). Risk of bias was judged as high in seven studies and moderate in one study. CONCLUSION: People with diabetes are more likely to develop frozen shoulder. Risk of unmeasured confounding was the main limitation of this systematic review. High-quality studies are needed to confirm the strength of, and understand reasons for, the association. PROSPERO REGISTRATION NUMBER: CRD42019122963

Diabetes as a Prognostic Factor in Frozen Shoulder: A Systematic Review.

Objective: To summarize evidence from longitudinal observational studies to determine whether diabetes (types 1 and 2) is associated with the course of symptoms in people with frozen shoulder. Data Sources: A systematic literature search of 11 bibliographic databases (published through June 2021), reference screening, and emailing professional contacts. Study Selection: Studies were selected if they had a longitudinal observational design that included people diagnosed with frozen shoulder at baseline and compared outcomes at follow-up (>2wk) among those with and without diabetes at baseline. Data Extraction: Data extraction was completed by 1 reviewer using a predefined extraction sheet and was checked by another reviewer. Two reviewers independently judged risk of bias using the Quality in Prognostic Factor Studies tool. Data Synthesis: A narrative synthesis, including inspection of forest plots and use of the prognostic factor Grading of Recommendations, Assessment, Development and Evaluations framework. Twenty-eight studies satisfied the inclusion criteria. Seven studies were judged to be at a moderate risk of bias and 21 at a high risk of bias. Diabetes was associated with worse multidimensional clinical scores (moderate certainty in evidence), worse pain (low certainty in evidence), and worse range of motion (very low certainty in evidence). Conclusions: This review provides preliminary evidence to suggest that people with diabetes may experience worse outcomes from frozen shoulder than those without diabetes. If high-quality studies can confirm the findings of this review, then clinicians should monitor patients with frozen shoulder with diabetes more closely and offer further treatment if pain or lack of function persists long-term