The transient receptor potential (subfamily M, member 8; TRPM8) is a nonselective cation channel localized in primary sensory neurons, and is a candidate for cold thermosensing, mediation of cold ...pain, and bladder overactivity. Studies with TRPM8 knockout mice and selective TRPM8 channel blockers demonstrate a lack of cold sensitivity and reduced cold pain in various rodent models. Furthermore, TRPM8 blockers significantly lower body temperature. We have identified a moderately potent (IC50 = 103 nM), selective TRPM8 antagonist, PF-05105679 (R)-3-(1-(4-fluorophenyl)ethyl)(quinolin-3-ylcarbonyl)aminomethylbenzoic acid. It demonstrated activity in vivo in the guinea pig bladder ice water and menthol challenge tests with an IC50 of 200 nM and reduced core body temperature in the rat (at concentrations >1219 nM). PF-05105679 was suitable for acute administration to humans and was evaluated for effects on core body temperature and experimentally induced cold pain, using the cold pressor test. Unbound plasma concentrations greater than the IC50 were achieved with 600- and 900-mg doses. The compound displayed a significant inhibition of pain in the cold pressor test, with efficacy equivalent to oxycodone (20 mg) at 1.5 hours postdose. No effect on core body temperature was observed. An unexpected adverse event (hot feeling) was reported, predominantly periorally, in 23 and 36% of volunteers (600- and 900-mg dose, respectively), which in two volunteers was nontolerable. In conclusion, this study supports a role for TRPM8 in acute cold pain signaling at doses that do not cause hypothermia.
Carpal tunnel decompression surgery to treat carpal tunnel syndrome is a common procedure, yet data on safety and effectiveness of the operation in the general population remain scarce. We aimed to ...estimate the incidence of reoperation and serious postoperative complications (requiring admission to hospital or further surgery) following carpal tunnel decompression in routine clinical practice and to identify the patient factors associated with these adverse outcomes.
We did a nationwide cohort analysis including all carpal tunnel decompression surgeries in patients aged 18 years or older, done in the National Health Service in England between April 1, 1998, and March 31, 2017, using the Hospital Episode Statistics dataset linked to mortality records. Patients were followed-up until death or until the end of the study (March 31, 2017). Primary outcomes were the overall incidence of carpal tunnel decompression reoperation and serious postoperative complications (surgical site infection or dehiscence, or neurovascular or tendon injury, requiring admission to hospital or further surgery) within 30 days and 90 days after surgery. Multivariable Cox regression analysis was used to identify factors influencing complications and reoperation, and the Fine and Gray method was used to adjust for the competing risk of mortality. This study is registered with ClinicalTrials.gov, NCT03573765.
855 832 carpal tunnel decompression surgeries were done between April 1, 1998, and March 31, 2017 (incidence rate 1·10 per 1000 person-years 95% CI 1·02–1·17). 29 288 procedures (3·42%) led to carpal tunnel decompression reoperation (incidence rate 3·18 per 1000 person-years 95% CI 3·12–3·23). Of the 855 832 initial surgeries, 620 procedures (0·070% 95% CI 0·067–0·078) led to a serious complication within 30 days after surgery, and 698 procedures (0·082% 0·076–0·088) within 90 days. Local complications within 90 days after surgery were associated with male sex (adjusted hazard ratio 2·32 95% CI 1·74–3·09) and age category 18–29 years (2·25 1·10–4·62). Male sex (adjusted subhazard ratio 1·09 95% CI 1·06–1·13), old age (>80 years vs 50–59 years: 1·09 1·03–1·15), and greater levels of comorbidity (Charlson score ≥5 vs 0: 1·25 1·19–1·32) and socioeconomic deprivation (most deprived 10% vs least deprived 10%: 1·18 1·10–1·27) were associated with increased reoperation risk.
To our knowledge, this is the largest national study on carpal tunnel decompression to date, providing strong evidence on serious postoperative complication and reoperation rates. Carpal tunnel decompression appears to be a safe operation in most patients, with an overall serious complication rate (requiring admission to hospital or further surgery) of less than 0·1%.
Versus Arthritis; Medical Research Council; Royal College of Surgeons of England and National Joint Registry research fellowship; University of Oxford; National Institute for Health Research; and National Institute for Health Research Biomedical Research Centre, Oxford.
ObjectivesTo determine the incidence of further procedures and serious adverse events (SAEs) requiring admission to hospital following elective surgery for base of thumb osteoarthritis (BTOA), and ...the patient factors associated with these outcomes.DesignPopulation based cohort study.SettingNational Health Service using the national Hospital Episode Statistics data set linked to mortality records over a 19-year period (01 April 1998–31 March 2017).Participants43 076 primary surgeries were followed longitudinally in secondary care until death or migration on 37 329 patients over 18 years of age.Main outcome measuresIncidence of further thumb base procedures (including revision surgery or intra-articular steroid injection) at any time postoperatively, and local wound complications and systemic events (myocardial infarction, stroke, respiratory tract infection, venous thromboembolic events, urinary tract infection or renal failure) within 30 and 90 days. To identify patient factors associated with outcome, Fine and Gray model regression analysis was used to adjust for the competing risk of mortality in addition to age, overall comorbidity and socioeconomic status.ResultsOver the 19 years, there was an increasing trend in surgeries undertaken. The rate of further thumb base procedures after any surgery was 1.39%; the lowest rates after simple trapeziectomy (1.12%), the highest rates after arthroplasty (3.84%) and arthrodesis (3.5%). When matched for age, comorbidity and socioeconomic status, those undergoing arthroplasty and arthrodesis were 2.5 times more likely to undergo a further procedure (subHR 2.51 (95% CI 1.81 to 3.48) and 2.55 (1.91 to 3.40)) than those undergoing simple trapeziectomy. Overall complication rates following surgery were 0.22% for serious local complications and 0.58% for systemic events within 90 days of surgery.ConclusionsThe number of patients proceeding to BTOA surgery has increased over the last 19 years, with a low rate of further thumb base procedures and SAEs after surgery overall registered. Arthrodesis and arthroplasty had a significantly higher revision rate.Trial registration numberNCT03573765.
Abstract
Objectives
Intra-articular steroid injection is commonly used to treat base of thumb osteoarthritis (BTOA), despite a lack of large-scale data on safety and effectiveness. We estimate the ...incidence of serious complications and further procedures following BTOA injection, including the risk of post-operative serious surgical site infection for subsequent operative intervention.
Methods
Hospital Episode Statistics data linked to mortality records from 1 April 1998 to 31 March 2017 were used to identify all BTOA injections undertaken in adults in the National Health Service secondary care in England. Patients were followed up longitudinally until death or 31 March 2017. A multivariable regression with a Fine and Gray model adjusting for the competing risk of mortality in addition to age, sex and socioeconomic deprivation was used to identify factors associated with progression to further procedure. Secondary outcomes included serious complications after injection and subsequent surgical site infection.
Results
A total of 19 120 primary injections were performed during the 19-year period in 18 356 patients. Of these 76.5% were female; mean age 62 years (s.d. 10.6); 50.48% underwent further procedure; 22.40% underwent surgery. Median time to further intervention was 412 days (IQR 110–1945). Female sex was associated with increased risk of proceeding to surgery. Serious complication rate following injection was 0.04% (0.01–0.08) within 90 days. Of those proceeding to surgery 0.16% (0.06–0.34) presented with a wound infection within 30 days and 90 days, compared with an overall post-operative wound infection rate of 0.03% (0.02–0.05).
Conclusions
Very low rates of serious complications were identified following BTOA injections performed in secondary care; only one in five patients proceeded to subsequent surgery.
Clinical trial registration
clinicaltrials.gov, https://www.clinicaltrials.gov, NCT03573765
Patients with overactive bladder often exhibit abnormal bladder contractions in response to intravesical cold saline (positive ice-water test). The molecular entity involved in cold sensation within ...the urinary bladder is unknown, but a potential candidate is the ion channel, transient receptor potential (melastatin)-8 (TRPM8). The objective of the present study was to investigate the role of TRPM8 in a bladder-cooling reflex evoked in anaesthetised guinea-pigs that is comparable to the positive ice-water test seen in patients. Guinea-pig TRPM8 was cloned from L6 dorsal root ganglia (DRG) and expressed in HEK293 cells. Functional agonist- and cold-induced Ca2+ influx and electrophysiology assays were performed in these cells, and for comparison in HEK293 cells expressing human TRPM8, using a novel TRPM8 antagonist, the S-enantiomer of 1-phenylethyl 4-(benzyloxy)-3-methoxybenzyl (2-aminoethyl) carbamate hydrochloride (PBMC). Potency data from these assays was used to calculate intravenous infusion protocols for targeted plasma concentrations of PBMC in studies on micturition reflexes evoked by intravesical infusion of menthol or cold saline in anaesthetised guinea-pigs. Tissue expression of TRPM8 in guinea-pig bladder, urethra and in dorsal root ganglia neurones traced from the bladder was also investigated. TRPM8 mRNA and protein were detected in L6 dorsal root ganglia, bladder urothelium and smooth muscle. PBMC antagonised in vitro activation of human and guinea-pig TRPM8 and reversed menthol and cold-induced facilitation of the micturition reflex at plasma concentrations consistent with in vitro potencies. The present data suggest that the bladder-cooling reflex in the guinea-pig involves TRPM8. The potential significance of TRPM8 in bladder disease states deserves future investigation.
We used UK Hand Registry data to study two aspects of basal thumb osteoarthritis surgery: first, whether health-related quality of life improves after surgery. Second, whether results from trials ...comparing simple trapeziectomy and trapeziectomy with ligament reconstruction and tendon interposition are reproducible in routine clinical practice. Prospectively collected EQ5D index and Patient Evaluation Measure part 2 data were compared at baseline and at 3, 6, and 12 months postoperatively in 1456 patients (median age 67 years; 78% female). A mixed-effects regression model was also used to determine the postoperative trajectory of these variables. There was a significant improvement in the EQ5D index (median + 0.15; (interquartile range 0 to 0.40)) and Patient Evaluation Measure (–22; (–33 to –10)) by 1 year postoperatively and with no meaningful difference between the two techniques. This study demonstrates health state utility gains after basal thumb osteoarthritis surgery regardless of surgical techniques used.
Level of evidence: III
Defining the optimal, evidence-based management of flexor tendon injury remains challenging. Lack of consensus on which measures to use to assess the outcome of interventions is a key issue, ...especially with regard to patient-reported outcome measures (PROMs). This systematic review defines the landscape of outcome measurement in studies on interventions for flexor tendon injuries to guide future research.
A PRISMA-compliant systematic review was conducted using bespoke search strategies applied to MEDLINE, EMBASE, PsycINFO, CENTRAL, CINAHL and AMED. A protocol was developed and registered prospectively (CRD42020186780). We identified all studies describing adult patients undergoing interventions for acute hand flexor tendon injuries.
Of the 4844 studies, 114 studies met the final inclusion criteria for evaluating the outcomes of 8127 participants with 9071 injured digits. Studies included 24 randomised controlled trials, 19 cohort studies and 61 case series. Nine different PROMs were used in 24 studies (22%): three site-specific PROMs, one generic quality-of-life measure and four visual analogue scales. Clinician-reported outcome measures were used in 103 studies (96%), such as the range of motion reported in 102 studies (94%). Adverse outcomes were reported in 96 studies (89%), with the most frequently reported adverse outcomes being tendon rupture and infection. Re-operation was reported in 21 studies (19%). The most frequently reported health economic outcome measure was the length of work absence, reported in ten studies (9%).
There is variability in the use of outcome measures used to study interventions for flexor tendon injuries. An independent systematic review of the psychometric properties of the identified outcome measures and a specific multi-stakeholder consensus process may support optimal choice and standardisation for future studies.
This report summarises the presentations and activities of the ISEV Workshop on extracellular vesicle biomarkers held in Birmingham, UK during December 2017. Among the key messages was broad ...agreement about the importance of biospecimen science. Much greater attention needs to be paid towards the provenance of collected samples. The workshop also highlighted clear gaps in our knowledge about pre-analytical factors that alter extracellular vesicles (EVs). The future utility of certified standards for credentialing of instruments and software, to analyse EV and for tracking the influence of isolation steps on the structure and content of EVs were also discussed. Several example studies were presented, demonstrating the potential utility for EVs in disease diagnosis, prognosis, longitudinal serial testing and stratification of patients. The conclusion of the workshop was that more effort focused on pre-analytical issues and benchmarking of isolation methods is needed to strengthen collaborations and advance more effective biomarkers.
Introduction
There is clinical uncertainty regarding the optimal method of rehabilitation following flexor tendon repair. Many splint designs and rehabilitation regimens are reported in the ...literature; however, there is insufficient evidence to support the use of any one regimen. The aim of this study was to describe rehabilitation guidelines used in the United Kingdom (UK) following zone I/II flexor tendon repair.
Methods
Using a cross-sectional design, hand units in the UK were invited to complete a short survey and to upload their flexor tendon rehabilitation guidelines and patient information material. Approval was granted by the British Association of Hand Therapists. Data were extracted in duplicate, using a pre-piloted form, and analysed using descriptive statistics.
Results
Thirty-five hand units responded (21%), providing 52 treatment guidelines. Three splinting regimens were described, and all involved early active mobilisation: (i) long dorsal-blocking splint (DBS); (ii) short DBS; and (iii) relative motion flexion splint. Duration of full-time splint wear ranged from 4 to 6 weeks. There were variations in splint design and composition of home exercise programmes, particularly for the long DBS. Where reported, recommended return to driving ranged from 8 to 12 weeks, and return to light work activities ranged from 5 to 10 weeks.
Discussion
Treatment guidelines varied across UK hand therapy departments, suggesting that patients receive differing advice about how to protect, move and use their hand after zone I/II flexor tendon repair. The disparity in splint wear duration, home exercise frequency and prescribed functional restrictions raises potential financial and social implications for patients. Future research should explore rehabilitation burden in addition to clinical outcomes.
Introduction: In patients with detrusor hyperreflexia, intravesical instillation of ice-cold water results in the development of involuntary bladder contractions at volumes less than normal ...cystometric capacity. This is referred to as a positive ice-water test (+IWT) and can be reversed by vanilloid receptor agonists and potentiated by menthol. The present study was designed to investigate the existence of an analogous cooling reflex in the guinea-pig bladder that could be used as a small animal model in order to test the effects of drugs on the reflex.
Methods: Bladder pressure and external urethral sphincter electromyogram (EUS EMG) were recorded in α-chloralose/urethane anaesthetised guinea-pigs during rapid infusion of cold or warm saline into the bladder with or without prior intravesical exposure to menthol or resiniferatoxin (RTX).
Results: The mean control micturition threshold volume (TV) of 2.58 ml at 38 °C was reduced to 1.52 ml in response to saline infusion at 3 °C (
P
=
0.001). The cold-induced reduction in TV was reproducible during several subsequent repeat infusions at 38 °C and 3 °C and was accompanied by decreases in bladder voiding pressure. The duration of the micturition reflex was markedly increased following cold compared with warm saline infusion (mean 24.5 s at 3 °C, 10.2 s at 38 °C,
P
=
0.001) and was associated with oscillations in bladder pressure and concomitant bursting activity in the EUS EMG. During step-wise decreases in infusate temperature from 38 °C to 23 °C, 15 °C, 7 °C and 3 °C, the threshold infusate temperature to elicit a significant reduction in TV was 15 °C. The reduction in TV at 3 °C was potentiated by intravesical infusion of 0.6 mM menthol whilst intravesical infusion of 500 nM RTX reversed the reduction in TV at 3 °C.
Discussion: These data suggest that a bladder-cooling reflex is present in the anaesthetised guinea-pig and represents a useful small animal model of the clinical +IWT.
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