Insulin/IGF-1 Drives PERIOD Synthesis to Entrain Circadian Rhythms with Feeding Time.

In mammals, endogenous circadian clocks sense and respond to daily feeding and lighting cues, adjusting internal ∼24 h rhythms to resonate with, and anticipate, external cycles of day and night. The mechanism underlying circadian entrainment to feeding time is critical for understanding why mistimed feeding, as occurs during shift work, disrupts circadian physiology, a state that is associated with increased incidence of chronic diseases such as type 2 (T2) diabetes. We show that feeding-regulated hormones insulin and insulin-like growth factor 1 (IGF-1) reset circadian clocks in vivo and in vitro by induction of PERIOD proteins, and mistimed insulin signaling disrupts circadian organization of mouse behavior and clock gene expression. Insulin and IGF-1 receptor signaling is sufficient to determine essential circadian parameters, principally via increased PERIOD protein synthesis. This requires coincident mechanistic target of rapamycin (mTOR) activation, increased phosphoinositide signaling, and microRNA downregulation. Besides its well-known homeostatic functions, we propose insulin and IGF-1 are primary signals of feeding time to cellular clocks throughout the body.

Mechanisms and physiological function of daily haemoglobin oxidation rhythms in red blood cells.

Cellular circadian rhythms confer temporal organisation upon physiology that is fundamental to human health. Rhythms are present in red blood cells (RBCs), the most abundant cell type in the body, but their physiological function is poorly understood. Here, we present a novel biochemical assay for haemoglobin (Hb) oxidation status which relies on a redox-sensitive covalent haem-Hb linkage that forms during SDS-mediated cell lysis. Formation of this linkage is lowest when ferrous Hb is oxidised, in the form of ferric metHb. Daily haemoglobin oxidation rhythms are observed in mouse and human RBCs cultured in vitro, or taken from humans in vivo, and are unaffected by mutations that affect circadian rhythms in nucleated cells. These rhythms correlate with daily rhythms in core body temperature, with temperature lowest when metHb levels are highest. Raising metHb levels with dietary sodium nitrite can further decrease daytime core body temperature in mice via nitric oxide (NO) signalling. These results extend our molecular understanding of RBC circadian rhythms and suggest they contribute to the regulation of body temperature.

Chronic inflammatory arthritis drives systemic changes in circadian energy metabolism.

Chronic inflammation underpins many human diseases. Morbidity and mortality associated with chronic inflammation are often mediated through metabolic dysfunction. Inflammatory and metabolic processes vary through circadian time, suggesting an important temporal crosstalk between these systems. Using an established mouse model of rheumatoid arthritis, we show that chronic inflammatory arthritis results in rhythmic joint inflammation and drives major changes in muscle and liver energy metabolism and rhythmic gene expression. Transcriptional and phosphoproteomic analyses revealed alterations in lipid metabolism and mitochondrial function associated with increased EGFR-JAK-STAT3 signaling. Metabolomic analyses confirmed rhythmic metabolic rewiring with impaired ß-oxidation and lipid handling and revealed a pronounced shunt toward sphingolipid and ceramide accumulation. The arthritis-related production of ceramides was most pronounced during the day, which is the time of peak inflammation and increased reliance on fatty acid oxidation. Thus, our data demonstrate that localized joint inflammation drives a time-of-day­dependent build-up of bioactive lipid species driven by rhythmic inflammation and altered EGFR-STAT signaling.

Additive contributions of melanopsin and both cone types provide broadband sensitivity to mouse pupil control.

BACKGROUND: Intrinsically photosensitive retinal ganglion cells (ipRGCs) drive an array of non-image-forming (NIF) visual responses including circadian photoentrainment and the pupil light reflex. ipRGCs integrate extrinsic (rod/cone) and intrinsic (melanopsin) photoreceptive signals, but the contribution of cones to ipRGC-dependent responses remains incompletely understood. Given recent data revealing that cone-derived colour signals influence mouse circadian timing and pupil responses in humans, here we set out to investigate the role of colour information in pupil control in mice. RESULTS: We first recorded electrophysiological activity from the pretectal olivary nucleus (PON) of anaesthetised mice with a red-shifted cone population (Opn1mwR) and mice lacking functional cones (Cnga3-/-) or melanopsin (Opn1mwR; Opn4-/-). Using multispectral stimuli to selectively modulate the activity of individual opsin classes, we show that PON cells which receive ipRGC input also exhibit robust S- and/or L-cone opsin-driven activity. This population includes many cells where the two cone opsins drive opponent responses (most commonly excitatory/ON responses to S-opsin stimulation and inhibitory/OFF responses to L-opsin stimulation). These cone inputs reliably tracked even slow (0.025 Hz) changes in illuminance/colour under photopic conditions with melanopsin contributions becoming increasingly dominant for higher-contrast/lower temporal frequency stimuli. We also evaluated consensual pupil responses in awake animals and show that, surprisingly, this aspect of physiology is insensitive to chromatic signals originating with cones. Instead, by contrast with the situation in humans, signals from melanopsin and both cone opsins combine in a purely additive manner to drive pupil constriction in mice. CONCLUSION: Our data reveal a key difference in the sensory control of the mouse pupil relative to another major target of ipRGCs-the circadian clock. Whereas the latter uses colour information to help estimate time of day, the mouse pupil instead sums signals across cone opsin classes to provide broadband spectral sensitivity to changes in illumination. As such, while the widespread co-occurrence of chromatic responses and melanopsin input in the PON supports a close association between colour discrimination mechanisms and NIF visual processing, our data suggest that colour opponent PON cells in the mouse contribute to functions other than pupil control.

Growth Disturbances Following Paediatric Anterior Cruciate Ligament Reconstruction: A Systematic Review.

Growth disturbances after transphyseal paediatric anterior cruciate ligament (ACL) reconstruction have led to the development of physeal-sparing techniques. The aim of this study is to investigate growth disturbances following paediatric ACL reconstruction and identify associated risk factors. A systematic search on PubMed, Scopus and Web of Science databases was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify case series reporting paediatric ACL reconstructions. Of 518 articles, 78 met the inclusion criteria, and data related to growth disturbances and graft failures were extracted. A total of 2,693 paediatric ACL reconstructions resulted in 70 growth disturbances (2.6%): 17 were varus, 26 were valgus, 13 were shortening, 14 were lengthening and five patients had reduced tibial slope. Some patients showed deformities in more than one plane. Coronal plane deformities were seen more frequently with eccentric physeal arrest and lengthening with intraepiphyseal tunnelling. Shortening and reduced tibial slope were related to large central physeal arrest and anterior tibial physeal arrest, respectively. Sixty-two studies documented 166 graft failures in 2,120 reconstructions (7.8%). The extraphyseal technique was least likely to result in growth disturbances and graft failure. Paediatric ACL reconstruction is a safe and effective treatment of rupture. Growth disturbances are least likely following extraphyseal tunnelling, and those resulting from transphyseal techniques can be minimised by reducing drill size, drilling steep and avoiding the physeal periphery. The insertion of hardware, synthetic material, or a bone plug through the drilled physis should be avoided. There is a greater need for robust long-term data collection, such as national ligament registries, to standardise practice and evaluate the risk of growth disturbance and re-ruptures in this treatment.

Long-Term Follow-up (14 to 25 Years) Following Closed Reduction and Early Movement for Simple Dislocation of the Elbow.

BACKGROUND: We have previously reported on the midterm outcomes after a nonoperative protocol to treat simple dislocations of the elbow that included a short period of splinting followed by early movement. We have now performed extended follow-up of the original patient group from the prior study to determine whether the excellent results that previously had been reported were maintained in the long term and also to determine the rate of and need for any late surgical intervention. METHODS: We attempted to contact all of the patients from the original study group. We requested that they complete the Oxford Elbow Score (OES) survey, the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, and a validated patient satisfaction questionnaire. Patients also were requested to attend a face-to-face assessment to have a clinical examination that included neurovascular, range-of-motion, and ligamentous stability assessments. RESULTS: Seventy-one patients from the original patient group agreed to participate in the new study. The mean duration of follow-up was 19.3 years. At the time of the final follow-up, patients reported excellent functional outcome scores and a preserved functional range of movement in the injured elbow. The mean OES was 91.6 points, the mean DASH score was 5.22 points, and the mean satisfaction score was 90.9 points. None of the patients had undergone delayed or secondary surgery for instability during the interval period. CONCLUSIONS: This study demonstrated that the original excellent outcomes following treatment with a protocol of a short period of splinting and early movement remained excellent and were maintained into the very long term. LEVEL OF EVIDENCE: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Acute Carpal Tunnel Syndrome: Early Nerve Decompression and Surgical Stabilization for Bony Wrist Trauma.

We undertook this study to investigate the outcomes of surgical treatment for acute carpal tunnel syndrome following our protocol for concurrent nerve decompression and skeletal stabilization for bony wrist trauma to be undertaken within 48 hours. Methods: We identified all patients treated at our trauma center following this protocol between January 1, 2014 and December 31, 2019. All patients were clinically reviewed at least 12 months after surgery and assessed using the Brief Michigan Hand Outcomes Questionnaire, the Boston Carpal Tunnel Questionnaire, and sensory assessment with Semmes-Weinstein monofilament testing. Results: The study group was made up of 35 patients. Thirty-three patients were treated within 36 hours. Patients treated with our unit protocol for early surgery comprising nerve decompression and bony stabilization within 36 hours report excellent outcomes at medium term follow-up. Conclusions: We propose that nerve decompression and bony surgical stabilization should be undertaken as soon as practically possible once the diagnosis is made. This is emergent treatment to protect and preserve nerve function. In our experience, the vast majority of patients were treated within 24 hours; however, where a short period of observation was required, excellent results were generally achieved when treatment was completed within 36 hours.

Surgery with the Motec total wrist replacement: learning from earlier designs.

The design of and applications for wrist arthroplasty continue to evolve but lag behind the results for hip and knee arthroplasty with respect to demonstrable durability and effectiveness. As we develop our knowledge, experience and the indications for wrist replacement surgery, it is important that we learn from past design and surgical experience. We report the case of a female patient treated with a Motec cementless metal-on-metal wrist replacement (Swemac Orthopaedics AB, Linköping, Sweden) for post-traumatic arthritis of the radiocarpal joint. Based on our experience with this case and others, we make two specific technical recommendations to improve the success and longevity of this implant.

The Perceptions and Experience of Surgical Trainees Related to Patient Safety Improvement and Incident Reporting: Structured Interviews With 612 Surgical Trainees.

Background We undertook a prospective qualitative study to ascertain the perceptions and experience of trainee doctors in the first two years of formal core surgical training related to patient safety improvement and incident reporting. We sought to explore the beliefs, knowledge and opinions of core surgical trainees related to patient safety improvement, their understanding of existing patient safety initiatives and their experience and attitudes to incident reporting. Methods We identified 1133 doctors in formal core surgical training posts in the United Kingdom at this time, and we contacted these doctors to invite them to participate in our study. We received responses from 687 (60.6%) core surgical trainees, and 612 trainees (54%) agreed to participate. The study participants underwent an interview using structured questions asked by trained assessors with an opportunity to explore any particular themes identified by the trainee in more detail. Qualitative data related to the knowledge, experience and perceptions of safety improvement and incident reporting were collected. Results Overall, 163 surgical trainees (26.6%) reported that they felt that they could impact patient safety positively. A total of 222 trainees (36.3%) had been involved in or witnessed an adverse patient safety event, while 509 trainees (83.2%) reported that they had witnessed a 'near-miss' event. Only 81 trainees (13.2%) had submitted a patient safety report at some point in their career. In addition, 536 trainees (87.6%) reported that they considered a patient safety or incident report to be 'negative' or 'seriously negative' and that they would be discouraged from making these because of the negative connotations associated with them. Of the 81 core surgical trainees who had submitted a patient safety report, only nine trainees (11.1%) reported that they had received a meaningful reply and update following their report. Several themes were identified during the interviews in response to open questions. These included a perception that patient safety improvement is the responsibility of senior surgeons and managers and that surgical trainees did not feel empowered to influence patient safety improvement. Trainees expressed the view that incident reporting reflected negatively on clinicians and the standard of care provided, and there were reports of culture based on blame and the fear of litigation or complaints. Surgical trainees did not feel that incident reporting was an effective tool for patient safety improvement, and those trainees who had made patient safety reports felt that these did not result in change and that they often received no feedback. Conclusions Core surgical trainees report that they are not well engaged in patient safety improvement and that their perceptions and experience of incident reporting are not positive. This represents a missed opportunity. We suggest that in order to recruit the surgical workforce to the improvement work and learning associated with patient safety, opportunities for focused education, training and culture change are needed from the early years of surgical training. In addition, improvements to the processes and systems that allow trainees to engage with safety improvement are needed in order to make these more user-friendly and accessible.

Embracing virtual outpatient clinics in the era of COVID-19.

The response to the COVID-19 pandemic has raised the profile and level of interest in the use, acceptability, safety, and effectiveness of virtual outpatient consultations and telemedicine. These models of care are not new but a number of challenges have so far hindered widespread take-up and endorsement of these ways of working. With the response to the COVID-19 pandemic, remote and virtual working and consultation have become the default. This paper explores our experience of and learning from virtual and remote consultation and questions how this experience can be retained and developed for the future. Cite this article: Bone Jt Open 2021;2(5):301-304.

Repeat limited fasciectomy is a safe and effective treatment for recurrence of Dupuytren's disease.

AIMS: The results of surgery for Dupuytren's disease can be compromised by the potential for disease recurrence and loss of function. Selecting which patients will benefit from repeat surgery, when to operate, and what procedure to undertake requires judgement and an understanding of patient expectations and functional needs. We undertook this study to investigate patient outcomes and satisfaction following repeat limited fasciectomy for recurrent Dupuytren's disease. METHODS: We prospectively identified all patients presenting with recurrence of Dupuytren's disease who were selected for surgical treatment with repeat limited fasciectomy surgery between January 2013 and February 2015. Patients were assessed preoperatively, and again at a minimum of five years postoperatively. We identified 43 patients who were carefully selected for repeat fasciectomy involving 54 fingers. Patients with severe or aggressive disease with extensive skin involvement were not included; in our practice, these patients are instead counselled and preferentially treated with dermofasciectomy. The primary outcome measured was change in the Michigan Hand Outcomes Questionnaire (MHQ) score. Secondary outcomes were change in finger range of motion, flexion contracture, Semmes-Weinstein monofilament (SWM) values, and overall satisfaction. RESULTS: There was a significant improvement in MHQ scores, across all domains, with a mean overall score increase of 24 points (p < 0.001). The summed flexion contracture across the metacarpophalangeal joint (MCPJ) and the proximal interphalangeal joint (PIPJ) reduced from means of 72.0° (SD 15.9°) to 5.6° (SD 6.8°) (p < 0.001). A significant increase in maximal flexion was seen at the MCPJ (p < 0.001) but not the PIPJ (p = 0.550). The mean overall satisfaction score from the visual analogue scale was 8.9 (7.9 to 10.0). Complications were uncommon although five fingers showed reduced sensibility at final follow-up. CONCLUSION: Our study shows that repeat limited fasciectomy for selected patients presenting with recurrence of Dupuytren's disease can be an effective and safe treatment resulting in excellent patient-reported outcomes and levels of satisfaction. Cite this article: Bone Joint J 2021;103-B(5):946-950.

Distinct circadian mechanisms govern cardiac rhythms and susceptibility to arrhythmia.

Electrical activity in the heart exhibits 24-hour rhythmicity, and potentially fatal arrhythmias are more likely to occur at specific times of day. Here, we demonstrate that circadian clocks within the brain and heart set daily rhythms in sinoatrial (SA) and atrioventricular (AV) node activity, and impose a time-of-day dependent susceptibility to ventricular arrhythmia. Critically, the balance of circadian inputs from the autonomic nervous system and cardiomyocyte clock to the SA and AV nodes differ, and this renders the cardiac conduction system sensitive to decoupling during abrupt shifts in behavioural routine and sleep-wake timing. Our findings reveal a functional segregation of circadian control across the heart's conduction system and inherent susceptibility to arrhythmia.

Compensatory ion transport buffers daily protein rhythms to regulate osmotic balance and cellular physiology.

Between 6-20% of the cellular proteome is under circadian control and tunes mammalian cell function with daily environmental cycles. For cell viability, and to maintain volume within narrow limits, the daily variation in osmotic potential exerted by changes in the soluble proteome must be counterbalanced. The mechanisms and consequences of this osmotic compensation have not been investigated before. In cultured cells and in tissue we find that compensation involves electroneutral active transport of Na+, K+, and Cl- through differential activity of SLC12A family cotransporters. In cardiomyocytes ex vivo and in vivo, compensatory ion fluxes confer daily variation in electrical activity. Perturbation of soluble protein abundance has commensurate effects on ion composition and cellular function across the circadian cycle. Thus, circadian regulation of the proteome impacts ion homeostasis with substantial consequences for the physiology of electrically active cells such as cardiomyocytes.

Output from VIP cells of the mammalian central clock regulates daily physiological rhythms.

The suprachiasmatic nucleus (SCN) circadian clock is critical for optimising daily cycles in mammalian physiology and behaviour. The roles of the various SCN cell types in communicating timing information to downstream physiological systems remain incompletely understood, however. In particular, while vasoactive intestinal polypeptide (VIP) signalling is essential for SCN function and whole animal circadian rhythmicity, the specific contributions of VIP cell output to physiological control remains uncertain. Here we reveal a key role for SCN VIP cells in central clock output. Using multielectrode recording and optogenetic manipulations, we show that VIP neurons provide coordinated daily waves of GABAergic input to target cells across the paraventricular hypothalamus and ventral thalamus, supressing their activity during the mid to late day. Using chemogenetic manipulation, we further demonstrate specific roles for this circuitry in the daily control of heart rate and corticosterone secretion, collectively establishing SCN VIP cells as influential regulators of physiological timing.

The 'National Finals Revision Day' Teaching Strategy: A Cost-Effective Way to Pass Medical School 'Finals' and Upskill Junior Doctors.

Courses to help medical students pass 'Finals' already exist but are typically expensive or can only be attended by a limited number of students. We describe the success of 'The National Finals Revision Day' (NFRD) course, which we believe is sustainable and unique in terms of its combined scale and cost (£10 per person). The course was organised and taught by 12 junior doctors. In total, 300 students attended from 55% of UK medical schools. Attendees found the course both relevant (96.4%) and cost-effective (97%), whilst the 11 medical and surgical talks were of a high standard (90.1%). The organising committee felt confident to organise their own teaching course in the future with 100% having already run a course themselves since the NFRD course. The NFRD course was also used by 11/12 (91.7%) of the organising committee to achieve their Annual Review of Competency Progression (ARCP) and 12/12 (100%) of the organising committee to obtain jobs on training programmes in the UK. We provide guidance about how to organise similar large-scale events for those interested. Moving forward, the teaching course will be run at: (i) multiple times; (ii) multiple UK venues; (iii) run over two days to cover more medical and surgical topics; and (iv) include the option of attending via video link.