A Digital Respiratory Ward in Leicester, Leicestershire, and Rutland, England, for Patients With COVID-19: Economic Evaluation of the Impact on Acute Capacity and Wider National Health Service Resource Use.

BACKGROUND: The COVID-19 pandemic stressed global health care systems' acute capacity and caused a diversion of resources from elective care to the treatment of acute respiratory disease. In preparing for a second wave of COVID-19 infections, England's National Health Service (NHS) in Leicester, Leicestershire, and Rutland sought to protect acute capacity in the winter of 2020-2021. Their plans included the introduction of a digital ward where patients were discharged home early and supported remotely by community-based respiratory specialists, who were informed about patient health status by a digital patient monitoring system. OBJECTIVE: The objective of the digital ward was to maintain acute capacity through safe, early discharge of patients with COVID-19 respiratory disease. The study objective was to establish what impact this digital ward had on overall NHS resource use. METHODS: There were no expected differences in patient outcomes. A cost minimization was performed to demonstrate the impact on the NHS resource use from discharging patients into a digital COVID-19 respiratory ward, compared to acute care length of stay (LOS). This evaluation included all 310 patients enrolled in the service from November 2020 (service commencement) to November 2021. Two primary methods, along with sensitivity analyses, were used to help overcome the uncertainty associated with the estimated comparators for the observational data on COVID-19 respiratory acute LOS, compared with the actual LOS of the 279 (90%) patients who were not discharged on oxygen nor were in critical care. Historic comparative LOS and an ordinary least squares model based on local monthly COVID-19 respiratory median LOS were used as comparators. Actual comparator data were sourced for the 31 (10%) patients who were discharged home and into the digital ward for oxygen weaning. Resource use associated with delivering care in the digital ward was sourced from the digital system and respiratory specialists. RESULTS: In the base case, the digital ward delivered estimated health care system savings of 846.5 bed-days and US $504,197 in net financial savings across the 2 key groups of patients-those on oxygen and those not on oxygen at acute discharge (both P<.001). The mean gross and net savings per patient were US $1850 and US $1626 in the base case, respectively, without including any savings associated with a potential reduction in readmissions. The 30-day readmission rate was 2.9%, which was below comparative data. The mean cost of the intervention was US $223.53 per patient, 12.1% of the estimated gross savings. It was not until the costs were increased and the effect reduced simultaneously by 78.4% in the sensitivity analysis that the intervention was no longer cost saving. CONCLUSIONS: The digital ward delivered increased capacity and substantial financial savings and did so with a high degree of confidence, at a very low absolute and relative cost.

Isolated tooth reveals hidden spinosaurid dinosaur diversity in the British Wealden Supergroup (Lower Cretaceous).

Isolated spinosaurid teeth are relatively well represented in the Lower Cretaceous Wealden Supergroup of southern England, UK. Until recently it was assumed that these teeth were referable to Baryonyx, the type species (B. walkeri) and specimen of which is from the Barremian Upper Weald Clay Formation of Surrey. British spinosaurid teeth are known from formations that span much of the c. 25 Ma depositional history of the Wealden Supergroup, and recent works suggest that British spinosaurids were more taxonomically diverse than previously thought. On the basis of both arguments, it is appropriate to doubt the hypothesis that isolated teeth from outside the Upper Weald Clay Formation are referable to Baryonyx. Here, we use phylogenetic, discriminant and cluster analyses to test whether an isolated spinosaurid tooth (HASMG G369a, consisting of a crown and part of the root) from a non-Weald Clay Formation unit can be referred to Baryonyx. HASMG G369a was recovered from an uncertain Lower Cretaceous locality in East Sussex but is probably from a Valanginian exposure of the Hastings Group and among the oldest spinosaurid material known from the UK. Spinosaurid affinities are both quantitatively and qualitatively supported, and HASMG G369a does not associate with Baryonyx in any analysis. This supports recent reinterpretations of the diversity of spinosaurid in the Early Cretaceous of Britain, which appears to have been populated by multiple spinosaurid lineages in a manner comparable to coeval Iberian deposits. This work also reviews the British and global records of early spinosaurids (known mainly from dental specimens), and revisits evidence for post-Cenomanian spinosaurid persistence.

Modified skulls but conservative brains? The palaeoneurology and endocranial anatomy of baryonychine dinosaurs (Theropoda: Spinosauridae).

The digital reconstruction of neurocranial endocasts has elucidated the gross brain structure and potential ecological attributes of many fossil taxa, including Irritator, a spinosaurine spinosaurid from the "mid" Cretaceous (Aptian) of Brazil. With unexceptional hearing capabilities, this taxon was inferred to integrate rapid and controlled pitch-down movements of the head that perhaps aided in the predation of small and agile prey such as fish. However, the neuroanatomy of baryonychine spinosaurids remains to be described, and potentially informs on the condition of early spinosaurids. Using micro-computed tomographic scanning (µCT), we reconstruct the braincase endocasts of Baryonyx walkeri and Ceratosuchops inferodios from the Wealden Supergroup (Lower Cretaceous) of England. We show that the gross endocranial morphology is similar to other non-maniraptoriform theropods, and corroborates previous observations of overall endocranial conservatism amongst more basal theropods. Several differences of unknown taxonomic utility are noted between the pair. Baryonychine neurosensory capabilities include low-frequency hearing and unexceptional olfaction, whilst the differing morphology of the floccular lobe tentatively suggests less developed gaze stabilisation mechanisms relative to spinosaurines. Given the morphological similarities observed with other basal tetanurans, baryonychines likely possessed comparable behavioural sophistication, suggesting that the transition from terrestrial hypercarnivorous ancestors to semi-aquatic "generalists" during the evolution of Spinosauridae did not require substantial modification of the brain and sensory systems.

The diagnosis of fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is a common widespread primary pain condition, with a worldwide prevalence of 2%-4%. Recent research has revealed important evidence for changes in central and peripheral nervous system functions and immunological activity. The diagnosis of FMS can be challenging with no known clinical laboratory investigations to confirm or refute its presence. Symptoms are commonly multiple, fluctuant and may not easily align with established medical diagnostic categories. It can be difficult for patients to articulate their array of symptoms, and for both patients and healthcare professionals to fully make sense of the complexities of the condition. As such, patients may be diagnosed inaccurately with alternative conditions, delaying diagnosis by years. The recent publication of the Royal College of Physicians' guidance aims to support clinicians in the diagnosis of FMS. Its purpose is to provide succinct, relevant information for patients and clinicians about FMS and its diagnosis.

Radiation Oncology AcaDemic Mentorship Program (ROADMAP) for Junior Faculty: One-Year Results of a Prospective Single Institution Initiative.

PURPOSE: Although mentorship has been associated with promotion, job satisfaction, and retention, data are limited on the mentorship experience of clinical- versus research-track physicians as well as feasibility and relative priority of formal program components. METHODS AND MATERIALS: Within a single-institution, multi-site, academic network, we implemented a Radiation Oncology AcaDemic Mentorship Program (ROADMAP) for junior faculty. Validated surveys assessing mentee satisfaction were distributed at baseline and 1 year. The statistical analysis included Wilcoxon rank sum and signed tests. Mentees assessed the likelihood to recommend each program component (10-point Likert-type scale), and means with standard error (SE) are reported. RESULTS: Among 42 eligible junior faculty, 36 (86%) opted into the program. The median time since residency was 2.5 years (interquartile range, 1.75-5.25) on the clinical track (n = 12) and 3 years (interquartile range, 2.75-5.00) on the research track (n = 24). At baseline, research-track physicians reported higher satisfaction with mentoring than physicians on the clinical track (2.92 vs 2.16; P = .02). Among 32 physicians completing 1 year, overall satisfaction with mentoring increased compared with baseline (2.72 vs 3.87; P < .001), which persisted on subset analysis for both clinical- (2.16 vs 4.03; P < .001) and research-track physicians (2.99 vs 3.77; P = .005). At 1 year, 28 mentees (88%) opted to continue the program. Program components were rated 8.25 (SE, 0.37) for mentor-mentee pairings, 7.22 (SE, 0.39) for goal setting, 6.84 (SE, 0.47) for administrative support, 6.69 (SE, 0.44) for peer mentoring, and 6.53 (SE, 0.45) for steering committee oversight. Ratings of peer mentoring were not associated with track (P = .59) or years in practice (P = .29). CONCLUSIONS: Clinical-track physicians may be less satisfied with mentorship than research-track faculty. However, all junior faculty, regardless of track, appeared to benefit from formalizing dyadic mentor-mentee relationships, goal setting, and peer mentoring. Further work is needed to determine the role of mentorship in addressing physician burnout.

A European giant: a large spinosaurid (Dinosauria: Theropoda) from the Vectis Formation (Wealden Group, Early Cretaceous), UK.

Postcranial elements (cervical, sacral and caudal vertebrae, as well as ilium, rib and limb bone fragments) belonging to a gigantic tetanuran theropod were recovered from the basal unit (the White Rock Sandstone equivalent) of the Vectis Formation near Compton Chine, on the southwest coast of the Isle of Wight. These remains appear to pertain to the same individual, with enormous dimensions similar to those of the Spinosaurus holotype and exceeding those of the largest European theropods previously reported. A combination of features-including the presence of spinodiapophyseal webbing on an anterior caudal vertebra-suggest that this is a member of Spinosauridae, though a lack of convincing autapomorphies precludes the identification of a new taxon. Phylogenetic analysis supports spinosaurid affinities but we were unable to determine a more precise position within the clade weak support for a position within Spinosaurinae or an early-diverging position within Spinosauridae were found in some data runs. Bioerosion in the form of curved tubes is evident on several pieces, potentially related to harvesting behaviour by coleopteran bioeroders. This is the first spinosaurid reported from the Vectis Formation and the youngest British material referred to the clade. This Vectis Formation spinosaurid is unusual in that the majority of dinosaurs from the Lower Cretaceous units of the Wealden Supergroup are from the fluviolacustrine deposits of the underlying Barremian Wessex Formation. In contrast, the lagoonal facies of the upper Barremian-lower Aptian Vectis Formation only rarely yield dinosaur material. Our conclusions are in keeping with previous studies that emphasise western Europe as a pivotal region within spinosaurid origination and diversification.

Using synthetic chromosome controls to evaluate the sequencing of difficult regions within the human genome.

BACKGROUND: Next-generation sequencing (NGS) can identify mutations in the human genome that cause disease and has been widely adopted in clinical diagnosis. However, the human genome contains many polymorphic, low-complexity, and repetitive regions that are difficult to sequence and analyze. Despite their difficulty, these regions include many clinically important sequences that can inform the treatment of human diseases and improve the diagnostic yield of NGS. RESULTS: To evaluate the accuracy by which these difficult regions are analyzed with NGS, we built an in silico decoy chromosome, along with corresponding synthetic DNA reference controls, that encode difficult and clinically important human genome regions, including repeats, microsatellites, HLA genes, and immune receptors. These controls provide a known ground-truth reference against which to measure the performance of diverse sequencing technologies, reagents, and bioinformatic tools. Using this approach, we provide a comprehensive evaluation of short- and long-read sequencing instruments, library preparation methods, and software tools and identify the errors and systematic bias that confound our resolution of these remaining difficult regions. CONCLUSIONS: This study provides an analytical validation of diagnosis using NGS in difficult regions of the human genome and highlights the challenges that remain to resolve these difficult regions.

Research Recommendations Following the Discovery of Pain Sensitizing IgG Autoantibodies in Fibromyalgia Syndrome.

BACKGROUND: Fibromyalgia syndrome (FMS) is the most common chronic widespread pain condition in rheumatology. Until recently, no clear pathophysiological mechanism for fibromyalgia had been established, resulting in management challenges. Recent research has indicated that serum immunoglobulin Gs (IgGs) may play a role in FMS. We undertook a research prioritisation exercise to identify the most pertinent research approaches that may lead to clinically implementable outputs. METHODS: Research priority setting was conducted in five phases: situation analysis; design; expert group consultation; interim recommendations; consultation and revision. A dialogue model was used, and an international multi-stakeholder expert group was invited. Clinical, patient, industry, funder, and scientific expertise was represented throughout. Recommendation-consensus was determined via a voluntary closed eSurvey. Reporting guideline for priority setting of health research were employed to support implementation and maximise impact. RESULTS: Arising from the expert group consultation (n = 29 participants), 39 interim recommendations were defined. A response rate of 81.5% was achieved in the consensus survey. Six recommendations were identified as high priority- and 15 as medium level priority. The recommendations range from aspects of fibromyalgia features that should be considered in future autoantibody research, to specific immunological investigations, suggestions for trial design in FMS, and therapeutic interventions that should be assessed in trials. CONCLUSIONS: By applying the principles of strategic priority setting we directed research towards that which is implementable, thereby expediating the benefit to the FMS patient population. These recommendations are intended for patients, international professionals and grant-giving bodies concerned with research into causes and management of patients with fibromyalgia syndrome.

New spinosaurids from the Wessex Formation (Early Cretaceous, UK) and the European origins of Spinosauridae.

Spinosaurids are among the most distinctive and yet poorly-known of large-bodied theropod dinosaurs, a situation exacerbated by their mostly fragmentary fossil record and competing views regarding their palaeobiology. Here, we report two new Early Cretaceous spinosaurid specimens from the Wessex Formation (Barremian) of the Isle of Wight. Large-scale phylogenetic analyses using parsimony and Bayesian techniques recover the pair in a new clade within Baryonychinae that also includes the hypodigm of the African spinosaurid Suchomimus. Both specimens represent distinct and novel taxa, herein named Ceratosuchops inferodios gen. et sp. nov. and Riparovenator milnerae gen. et sp. nov. A palaeogeographic reconstruction suggests a European origin for Spinosauridae, with at least two dispersal events into Africa. These new finds provide welcome information on poorly sampled areas of spinosaurid anatomy, suggest that sympatry was present and potentially common in baryonychines and spinosaurids as a whole, and contribute to updated palaeobiogeographic reconstructions for the clade.

Clinical Review of Proton Therapy in the Treatment of Unilateral Head and Neck Cancers.

Radiotherapy is a common treatment modality in the management of head and neck malignancies. In select clinical scenarios of well-lateralized tumors, radiotherapy can be delivered to the primary tumor or tumor bed and the ipsilateral nodal regions, while intentional irradiation of the contralateral neck is omitted. Proton beam therapy is an advanced radiotherapy modality that allows for the elimination of exit-dose through nontarget tissues such as the oral cavity. This dosimetric advantage is apt for unilateral treatments. By eliminating excess dose to midline and contralateral organs at risk and conforming dose around complex anatomy, proton beam therapy can reduce the risk of iatrogenic toxicities. Currently, there is no level I evidence comparing proton beam therapy to conventional photon radiation modalities for unilateral head and neck cancers. However, a growing body of retrospective and prospective evidence is now available describing the dosimetric and clinical advantages of proton beam therapy. Subsequently, the intent of this clinical review is to summarize the current evidence supporting the use of proton beam therapy in unilateral irradiation of head and neck cancers, including evaluation of disease site-specific evidence, unique challenging clinical scenarios, and ongoing clinical trials.

Systematic review and meta-analysis of therapeutic alliance, engagement, and outcome in psychological therapies for psychosis.

AIM: The moderate association between therapeutic alliance (TA) and psychological therapy outcome is well established. Historically, the field has not focused on people with a severe mental illness. This is the first review to conduct a meta-analysis of associations between TA and therapeutic engagement as well as outcome in psychological therapy for psychosis. ELIGIBILITY CRITERIA: Eligible studies conducted a quantitative investigation of the relationship between TA during a psychological therapy and outcome at a subsequent time-point. METHOD: A systematic review examined the relationship between TA and engagement as well as outcome measures within psychological therapy for psychosis. Correlational meta-analyses using an aggregate random effects model were conducted. RESULTS: Twenty-four studies were eligible for inclusion (n = 1,656) of which 13 were included in the meta-analyses. Client- and therapist-rated TA were associated with engagement in therapy (rclient (c)  = 0.36, p = .003; rtherapist (t)  = 0.40, p = .0053). TA was also associated with reduction in global (rc  = 0.29, p = .0005; rt  = 0.24, p = .0015) and psychotic symptoms (rc  = 0.17, p = .0115; rt  = 0.30, p = .0003). The systematic review identified no evidence or limited evidence for a relationship between TA during therapy and depression, substance use, physical health behaviours, global as well as social functioning, overall mental health recovery, and self-esteem at follow-up. Although number of studies was small, TA was related to a reduced risk of subsequent hospitalization in 40% of analyses (across two studies) and improved cognitive outcome in 50% of analyses (across three studies). CONCLUSIONS: The observed TA-therapy engagement and TA-outcome associations were broadly consistent with those identified across non-psychotic diagnostic groups. Well-powered studies are needed to investigate the relationship between TA and process as well as outcome in psychological therapy for psychosis specifically. PRACTITIONER POINTS: This is the first review to conduct a meta-analytic synthesis of the association between therapeutic alliance (TA) and both engagement and change in outcome in psychological therapies for psychosis. TA (as rated by therapist and client) was associated with the extent of therapeutic engagement as well as reduction in global mental health symptoms and psychotic symptoms. The significant associations between TA and engagement as well as change in outcome identified in the current review are broadly consistent with those observed across non-psychotic diagnostic groups. We consider factors that could impact upon the dynamic and potentially interdependent relationships between TA and therapeutic techniques, including attachment security and severity of paranoid ideation.

Early palliative radiation versus observation for high-risk asymptomatic or minimally symptomatic bone metastases: study protocol for a randomized controlled trial.

BACKGROUND: In patients with metastatic cancer, the bone is the third-most common site of involvement. Radiation to painful bone metastases results in high rates of pain control and is an integral part of bone metastases management. Up to one-third of inpatient consults are requested for painful bone metastases, and up to 60% of these patients had evidence of these lesions visible on prior imaging. Meanwhile recent advances have reduced potential side effects of radiation. Therefore, there is an opportunity to further improve outcomes for patients using prophylactic palliative radiation to manage asymptomatic bone metastases. METHODS/STUDY DESIGN: In this trial, 74 patients with metastatic solid tumors and high-risk asymptomatic or minimally symptomatic bone metastases will be enrolled and randomized to early palliative radiation or standard of care. This will be the first trial to assess the efficacy of prophylactic palliative radiation in preventing skeletal related events (SREs), the primary endpoint. This endpoint was selected to encompass patient-centered outcomes that impact quality of life including pathologic fracture, spinal cord compression, and intervention with surgery or radiation. Secondary endpoints include hospitalizations, Bone Pain Index, pain-free survival, pain-related quality of life, and side effects of radiation therapy. DISCUSSION: In this study, we propose a novel definition of high-risk bone metastases most likely to benefit from preventive radiation and use validated questionnaires to assess pain and impact on quality of life and health resource utilization. Observations from early patient enrollment have demonstrated robustness of the primary endpoint and need for minor modifications to Bone Pain Index and data collection for opioid use and hospitalizations. With increasing indications for radiation in the oligometastatic setting, this trial aims to improve patient-centered outcomes in the polymetastatic setting. TRIAL REGISTRATION: ISRCTN Number/Clinical trials.gov, ID: NCT03523351 . Registered on 14 May 2018.

Heterogeneity of Dengue Illness in Community-Based Prospective Study, Iquitos, Peru.

Measuring heterogeneity of dengue illness is necessary to define suitable endpoints in dengue vaccine and therapeutic trials and will help clarify behavioral responses to illness. To quantify heterogeneity in dengue illness, including milder cases, we developed the Dengue Illness Perceptions Response (IPR) survey, which captured detailed symptom data, including intensity, duration, and character, and change in routine activities caused by illness. During 2016-2019, we collected IPR data daily during the acute phase of illness for 79 persons with a positive reverse transcription PCR result for dengue virus RNA. Most participants had mild ambulatory disease. However, we measured substantial heterogeneity in illness experience, symptom duration, and maximum reported intensity of individual symptoms. Symptom intensity was a more valuable predicter of major activity change during dengue illness than symptom presence or absence alone. These data suggest that the IPR measures clinically useful heterogeneity in dengue illness experience and its relation to altered human behavior.

A universal and independent synthetic DNA ladder for the quantitative measurement of genomic features.

Standard units of measurement are required for the quantitative description of nature; however, few standard units have been established for genomics to date. Here, we have developed a synthetic DNA ladder that defines a quantitative standard unit that can measure DNA sequence abundance within a next-generation sequencing library. The ladder can be spiked into a DNA sample, and act as an internal scale that measures quantitative genetics features. Unlike previous spike-ins, the ladder is encoded within a single molecule, and can be equivalently and independently synthesized by different laboratories. We show how the ladder can measure diverse quantitative features, including human genetic variation and microbial abundance, and also estimate uncertainty due to technical variation and improve normalization between libraries. This ladder provides an independent quantitative unit that can be used with any organism, application or technology, thereby providing a common metric by which genomes can be measured.

Use of synthetic DNA spike-in controls (sequins) for human genome sequencing.

Next-generation sequencing (NGS) has been widely adopted to identify genetic variants and investigate their association with disease. However, the analysis of sequencing data remains challenging because of the complexity of human genetic variation and confounding errors introduced during library preparation, sequencing and analysis. We have developed a set of synthetic DNA spike-ins-termed 'sequins' (sequencing spike-ins)-that are directly added to DNA samples before library preparation. Sequins can be used to measure technical biases and to act as internal quantitative and qualitative controls throughout the sequencing workflow. This step-by-step protocol explains the use of sequins for both whole-genome and targeted sequencing of the human genome. This includes instructions regarding the dilution and addition of sequins to human DNA samples, followed by the bioinformatic steps required to separate sequin- and sample-derived sequencing reads and to evaluate the diagnostic performance of the assay. These practical guidelines are accompanied by a broader discussion of the conceptual and statistical principles that underpin the design of sequin standards. This protocol is suitable for users with standard laboratory and bioinformatic experience. The laboratory steps require ~1-4 d and the bioinformatic steps (which can be performed with the provided example data files) take an additional day.

Effectiveness of a Cancer Bereavement Therapeutic Group.

This study examined the effectiveness of a novel cancer bereavement group. Twenty-seven participants attended a sixsession cancer bereavement therapeutic group. Data were collected at baseline, intervention completion, and three-month follow-up. Grief intensity and symptoms of posttraumatic stress disorder (PTSD), depression, and anxiety were reduced postintervention, and self-compassion increased. At follow-up, improvement remained for grief, PTSD, and depression. A small quasi-experimental waiting-list comparison group showed no change on any measure between baseline and waiting-list end. This study provides preliminary evidence that a brief therapeutic group is an effective intervention for cancer bereavement.

A randomised controlled trial of guided internet-based cognitive behavioural therapy for perfectionism: Effects on psychopathology and transdiagnostic processes.

BACKGROUND AND OBJECTIVES: Perfectionism is a transdiagnostic process that has been associated with a range of psychopathology and also with other transdiagnostic processes. We have previously shown that guided internet-based cognitive behavioural therapy (ICBT) can reduce symptoms of dysfunctional perfectionism, however, no impact was observed on symptoms of depression and anxiety. Here we explore the impact of guided ICBT for perfectionism on symptoms of other associated psychopathology, specifically obsessive-compulsive disorder (OCD) and eating disorders, and also on other associated transdiagnostic processes (self-esteem, intolerance of uncertainty, and self-compassion). METHODS: Participants who presented with clinical levels of perfectionism were randomised to an experimental group that received the intervention (n = 62), or a wait list control group (n = 58). Questionnaires assessing symptoms of OCD, eating disorders, self-esteem, intolerance of uncertainty, and fear of self-compassion were completed pre-intervention, post-intervention (12 weeks), and at follow-up (24 weeks). Between group effect sizes are reported. RESULTS: The intervention led to significant decreases in symptoms of OCD (d = -0.9; CI: -1.4, -0.4) and eating disorders (d = -0.6; CI: -1.0, -0.1), and had an impact on other transdiagnostic processes resulting in increased self-esteem (d = 0.7; CI: 0.2, 1.2), decreases in intolerance of uncertainty (d = -0.9; CI: -1.4, -0.4), and fear of self-compassion (d = -0.8; CI: -1.3, -0.3). At follow-up changes were maintained in symptoms of OCD (d = -1.3; CI: -1.8, -0.8), disordered eating (d = -0.7; CI: -1.2, -0.2), intolerance of uncertainty (d = -0.8; CI: -1.2, -0.3), and fear of self-compassion (d = -1.0; CI: -1.5, -0.5). CONCLUSIONS: Guided ICBT for perfectionism improves associated psychopathology and transdiagnostic processes. ClinicalTrials.gov registration no. NCT02756871.

Chiral DNA sequences as commutable controls for clinical genomics.

Chirality is a property describing any object that is inequivalent to its mirror image. Due to its 5'-3' directionality, a DNA sequence is distinct from a mirrored sequence arranged in reverse nucleotide-order, and is therefore chiral. A given sequence and its opposing chiral partner sequence share many properties, such as nucleotide composition and sequence entropy. Here we demonstrate that chiral DNA sequence pairs also perform equivalently during molecular and bioinformatic techniques that underpin genetic analysis, including PCR amplification, hybridization, whole-genome, target-enriched and nanopore sequencing, sequence alignment and variant detection. Given these shared properties, synthetic DNA sequences mirroring clinically relevant or analytically challenging regions of the human genome are ideal controls for clinical genomics. The addition of synthetic chiral sequences (sequins) to patient tumor samples can prevent false-positive and false-negative mutation detection to improve diagnosis. Accordingly, we propose that sequins can fulfill the need for commutable internal controls in precision medicine.

Standards for the diagnosis and management of complex regional pain syndrome: Results of a European Pain Federation task force.

BACKGROUND: Complex regional pain syndrome is a painful and disabling post-traumatic primary pain disorder. Acute and chronic complex regional pain syndrome (CRPS) are major clinical challenges. In Europe, progress is hampered by significant heterogeneity in clinical practice. We sought to establish standards for the diagnosis and management of CRPS. METHODS: The European Pain Federation established a pan-European task force of experts in CRPS who followed a four-stage consensus challenge process to produce mandatory quality standards worded as grammatically imperative (must-do) statements. RESULTS: We developed 17 standards in 8 areas of care. There are 2 standards in diagnosis, 1 in multidisciplinary care, 1 in assessment, 3 for care pathways, 1 in information and education, 4 in pain management, 3 in physical rehabilitation and 2 on distress management. The standards are presented and summarized, and their generation and consequences were discussed. Also presented are domains of practice for which no agreement on a standard could be reached. Areas of research needed to improve the validity and uptake of these standards are discussed. CONCLUSION: The European Pain Federation task force present 17 standards of the diagnosis and management of CRPS for use in Europe. These are considered achievable for most countries and aspirational for a minority of countries depending on their healthcare resource and structures. SIGNIFICANCE: This position statement summarizes expert opinion on acceptable standards for CRPS care in Europe.

'Between a rock and a hard place': family members' experiences of supporting a relative with bipolar disorder.

PURPOSE: Clinical guidelines emphasise the central role of family members in supporting people with bipolar disorder. However, there has been little focus on the challenges family members face in supporting their relative. This qualitative study explored the challenges of providing support to a relative with bipolar disorder, and how family members attempted to meet these challenges. Factors that helped or hindered their efforts were also explored, including experiences of professional support. METHODS: Semi-structured interviews were conducted with 18 family members (partners, parents, adult children, and siblings). Transcripts were analysed using the Framework approach. RESULTS: Participants faced numerous challenges pertaining to the nature of the disorder and specific illness phases, their relative's responses to their attempts to help, and the limitations of support from healthcare professionals. Although participants were resourceful in managing these challenges, they strongly valued professional input. Six themes were identified: 'Not knowing: like being in a minefield', 'It's out of my control: sitting waiting for the next thing to happen', 'Treading on eggshells', 'Picking up on signs', 'Times of crisis: between a rock and a hard place', and 'I have to make my voice heard'. CONCLUSIONS: Family members supporting a relative with bipolar disorder face significant challenges but show considerable resourcefulness in managing them. The findings underline the importance of input from healthcare professionals to help family members effectively support their relative and manage the challenges they face. Professional support should be strengths-based, and tailored to family members' needs.