Readmission after discharge from a medium secure service between 1999 and 2017: A retrospective cohort study.

BACKGROUND: Previous research into outcomes after treatment in medium secure psychiatric hospitals has mostly relied on pre-millennium data. AIMS: To examine patient and inpatient service-related factors associated with readmission within 2 years following discharge to the community or open conditions from conditions of medium security. METHODS: A retrospective cohort study of 137 patients discharged either to the community or to open conditions from one 64-bed South Wales Regional Medium Secure Hospital Unit between July 1999 and November 2017 was completed using data from healthcare records to document demographics, diagnosis and nature of index offences together with researcher-completed ratings of inpatient progress using the Dangerousness Understanding Recovery and Urgency Manual (DUNDRUM) Programme Completion and DUNDRUM Recovery scales. Binary logistic regression analyses were used to identify independent associations between inpatient progress according to these measures and readmission. RESULTS: Forty-three patients (31%) were readmitted within 2 years of discharge and 23 (17%) in breach of legal conditions on discharge. Most readmitted patients (n = 29, 67%) returned directly to medium secure care. There were significant binary level associations between readmission and severity of the index offences (lower), number of adverse childhood experiences (higher), history of drug misuse (more likely) and number of previous psychiatric admissions (higher). Binary logistic regression confirmed that these relationships were not independent. No inpatient service-related variables, according to DUNDRUM scale scores, showed an independent association with readmission within 2 years post-discharge. CONCLUSIONS: The proportion of medium security hospital patients who were readmitted within 2 years of discharge aligns with estimates found in earlier national research using the same follow-up period. Since levels of inpatient progress bore little if any relationship to longer term outcomes, our findings highlight the need for investigating factors in the discharge environment that are linked to readmission. It is possible that readmission may indicate effective monitoring and responsive care to the changing needs of patients, but a better understanding of this is essential.

Antisense oligonucleotides ameliorate kidney dysfunction in podocyte-specific APOL1 risk variant mice.

Coding variants (named G1 and G2) in Apolipoprotein L1 (APOL1) can explain most excess risk of kidney disease observed in African American individuals. It has been proposed that risk variant APOL1 dose, such as increased risk variant APOL1 level serves as a trigger (second hit) for disease development. The goal of this study was to determine whether lowering risk variant APOL1 levels protects from disease development in a podocyte-specific transgenic mouse disease model. We administered antisense oligonucleotides (ASO) targeting APOL1 to podocyte-specific G2APOL1 mice and observed efficient reduction of APOL1 levels. APOL1 ASO1, which more efficiently lowered APOL1 transcript levels, protected mice from albuminuria, glomerulosclerosis, tubulointerstitial fibrosis, and renal failure. Administration of APOL1 ASO1 was effective even for established disease in the NEFTA-rtTA/TRE-G2APOL1 (NEFTA/G2APOL1) mice. We observed a strong correlation between APOL1 transcript level and disease severity. We concluded that APOL1 ASO1 may be an effective therapeutic approach for APOL1-associated glomerular disease.

Modification of the single-tube radial forearm phalloplasty technique to allow for urinary meatal reconstruction: A report of two cases.

The free radial forearm flap is the gold standard technique for transgender phalloplasty due to superior complication rates compared to other methods. However, reconstruction of the urinary tract, including urethral lengthening and creation of a pars pendula urethra within the flap, carries a high rate of complications. The risk of complications and a lack of desire for standing urination are reasons patients elect for single-tube phalloplasty. However, to date, single-tube phalloplasties lack creation of a urinary meatus, which affects the aesthetics of the reconstruction. The purpose of this report is to describe a technique for creating an aesthetic urinary meatus in single-tube phalloplasty. We herein describe the technique in the use of two healthy transgender males (ages 31 and 39). Both patients did not desire micturition through the neophallus, but still desired the appearance of a meatus at the tip of the neophallus. Single-tube radial forearm phalloplasty was performed for both patients. The radial forearm flaps for each patient were 14 × 15 cm. Meatoplasty was performed at the time of flap elevation utilizing an intact 1 × 4 cm intact strip of ulnar sided skin during flap tubularization. This strip of skin was then invaginated to create a neomeatal pouch. The postoperative course was uncomplicated for both patients following at 5-day hospital stay for flap monitoring. Follow up time was 7 and 8 months. The neomeatal pouch persisted in both patients and the patients were satisfied with the appearance of the tips of the neophalluses.

The Macroeconomic Imbalance Procedure at the Heart of EU Economic Governance Reform.

While the euro officially came into being in 1999, it was the introduction of euro notes and coins 20 years ago in January 2002 that made the common currency a tangible reality for European citizens. The circle of member states has since grown from 11 to 19, and a growing section of the population no longer has any personal experience with a "national" currency, yet the debate on the legal and institutional framework underpinning the common currency has never gone away.

Transgender Scrotoplasty and Perineal Reconstruction With Labia Majora Flaps: Technique and Outcomes From 147 Consecutive Cases.

PURPOSE: Labia majora, the embryologic homologs of the scrotum, are ideal donor tissue for transgender scrotoplasty. The technique is detailed, and surgical outcomes are assessed for scrotoplasty using labia majora rotational advancement flaps. METHODS: We retrospectively reviewed the outcomes of phalloplasty patients who underwent either primary or secondary labia majora flap scrotoplasty and perineal reconstruction from October 1, 2017, to December 1, 2019. Bilateral elevation and rotational flap advancement from the posterior to anterior position formed a pouch-like scrotum. Perineal reconstruction involved multilayered closure with apposition of the inner thigh skin. RESULTS: The mean follow-up was 12.5 months (0.5-26 months). One hundred forty-seven scrotoplasties were performed. Of the 147 total scrotoplasty patients, 133 had labia majora flap scrotoplasty and perineal reconstruction with single-stage phalloplasty. Distal flap necrosis occurred in 6 patients (4.1%); 5 were ipsilateral to the groin dissection required for phalloplasty. Large (>1 cm diameter) perineoscrotal junction dehiscence occurred in 7 patients (4.7%). All wounds were managed conservatively except for 3 patients who developed urethrocutaneous fistulas at the perineoscrotal junction. All 3 patients required fistula repair. Two (1.4%) scrotal hematomas and 3 (2.0%) perineal hematomas were seen; all required operative intervention. CONCLUSIONS: Labia majora flap scrotoplasty via the bilateral rotational advancement technique and perineal reconstruction can be safely performed during phalloplasty. Minor wound complications are common and frequently heal with conservative management. Wounds that do not heal may be associated with urethral complications. Hematomas are rare but usually require operative intervention.

Bilaminate Synthetic Dermal Matrix versus Free Fascial Flaps: A Cost-Effectiveness Analysis for Full-Thickness Hand Reconstruction.

BACKGROUND: Full-thickness injuries to the hand require durable soft tissue coverage to preserve tendon gliding and hand motion. We aim to investigate the cost effectiveness of hand resurfacing comparing free fascial flap reconstruction versus bilaminate synthetic dermal matrices. METHODS: Cost effectiveness was modeled using decision tree analysis with the rollback method. Total active range of motion was modeled as the common outcome variable based on systematic literature review. Costing was performed from a payer perspective using national Medicare reimbursements. The willingness to pay threshold was determined by average worker's compensation for hand disability. Probabilistic sensitivity analysis was conducted for range of motion outcomes and the costs using 10,000 Monte Carlo simulations. RESULTS: The average cost of free fascial flap reconstruction was $14,201.24 compared with $13,674.20 for Integra, yielding an incremental cost difference of $527.04. Incremental range of motion improvement was 18.0 degrees with free fascial flaps, yielding an incremental cost effectiveness ratio of $29.30/degree of motion. Assuming willingness to pay thresholds of $557.00/degree of motion, free-fascial flaps were highly cost effective. On probabilistic sensitivity analysis, free fascial flaps were dominant in 25.5% of simulations and cost effective in 32.1% of simulations. Thus, microsurgical reconstruction was the economically sound technique in 57.5% of scenarios. CONCLUSION: Free fascial flap reconstruction of complex hand wounds was marginally more expensive than synthetic dermal matrix and yielded incrementally better outcomes. Both dermal matrix and microsurgical techniques were cost effective in the base case and in sensitivity analysis. In choosing between dermal matrix and microsurgical reconstruction of complex hand wounds, neither technique has a clear economic advantage.

Use of the subscapular system by maintaining unilateral decubitus placement without repositioning in microvascular free tissue transplantation.

BACKGROUND: In microvascular free-tissue harvest and transfer, the need for repositioning from lateral decubitus position and the inability to use a two-team approach are major drawbacks of the subscapular system. We present our experience with the subscapular system for upper and lower extremity reconstruction using a two-team approach without need for repositioning. METHODS: We conducted a retrospective chart review for all patients undergoing free flap transplant based on the subscapular system to the upper or lower extremity at our microsurgical facility from January 1, 2007 to December 31, 2011. Only cases not requiring intraoperative repositioning were included. Sixty-four patients underwent the two-team approach (37 upper extremity and 27 lower extremity transplants). Flap types included latissimus dorsi musculocutaneous, partial superior latissimus, dorsal thoracic fascia, serratus, scapular bone, and thoracodorsal artery perforator, either alone or as chimeric flaps. All patients were placed in the lateral decubitus position for the duration of the surgery. RESULTS: The ipsilateral subscapular system was used in 16% of cases for lower extremity defects, where the anterior tibial vessels served as recipient vessels. The contralateral subscapular system was used in all remaining cases for upper extremity or the vast majority for lower extremity (84%) defects, where either the superficial femoral, genicular, popliteal, sural, or posterior tibial vessels served as recipient vessels. With the exception of one partial flap loss secondary to infection, all flaps survived. CONCLUSIONS: Proper lateral decubitus positioning allows for a two-team approach without compromising safety or outcomes.

Why Current EU Proposals for Corona-Related Financial Aid Cannot Replace Coronabonds.

With public debt-to-GDP levels now set to surpass post-war records and Italy's ratio approaching levels reached in Greece on the eve of the country's debt restructuring in early 2012, fears of a return of the sovereign debt crisis have emerged.

Joint European Society of Paediatric Radiology (ESPR) and International Society for Forensic Radiology and Imaging (ISFRI) guidelines: paediatric postmortem computed tomography imaging protocol.

Postmortem CT for investigating childhood deaths is increasingly utilised as a noninvasive adjunct or alternative to standard autopsy; however there are no standardised published imaging protocols. This article describes a standardised imaging protocol that has been developed based on current practices of international postmortem imaging practitioners and experts. This recommendation is expected to be useful for postmortem imaging centres wishing to update their existing practices and for those starting paediatric postmortem CT as a new service.

Influence of Multistep Surface Passivation on the Performance of PbS Colloidal Quantum Dot Solar Cells.

The performance of devices containing colloidal quantum dot (CQD) films is strongly dependent on the surface chemistry of the CQDs they contain. Multistep surface treatments, which combine two or more strategies, are important for creating films with high carrier mobility that are well passivated against trap states and oxidation. Here, we examine the effect of a number of these surface treatments on PbS CQD films, including cation exchange to form PbS/CdS core/shell CQDs, and solid-state ligand-exchange treatments with Cl, Br, I, and 1,2-ethanedithiol (EDT) ligands. Using laboratory-based and synchrotron-radiation-excited X-ray photoelectron spectroscopy (XPS), we examine the compositions of the surface layer before and after treatment, and correlate this with the performance data and stability in air. We find that halide ion treatments may etch the CQD surfaces, with detrimental effects on the air stability and solar cell device performance caused by a reduction in the proportion of passivated surface sites. We show that films made up of PbS/CdS CQDs are particularly prone to this, suggesting Cd is more easily etched from the surface than Pb. However, by choosing a less aggressive ligand treatment, a good coverage of passivators on the surface can be achieved. We show that halide anions bind preferentially to surface Pb (rather than Cd). By isolating the part of XPS signal originating from the topmost surface layer of the CQD, we show that air stability is correlated with the total number of passivating agents (halide + EDT + Cd) at the surface.

The nuclear-retained noncoding RNA MALAT1 regulates alternative splicing by modulating SR splicing factor phosphorylation.

Alternative splicing (AS) of pre-mRNA is utilized by higher eukaryotes to achieve increased transcriptome and proteomic complexity. The serine/arginine (SR) splicing factors regulate tissue- or cell-type-specific AS in a concentration- and phosphorylation-dependent manner. However, the mechanisms that modulate the cellular levels of active SR proteins remain to be elucidated. In the present study, we provide evidence for a role for the long nuclear-retained regulatory RNA (nrRNA), MALAT1 in AS regulation. MALAT1 interacts with SR proteins and influences the distribution of these and other splicing factors in nuclear speckle domains. Depletion of MALAT1 or overexpression of an SR protein changes the AS of a similar set of endogenous pre-mRNAs. Furthermore, MALAT1 regulates cellular levels of phosphorylated forms of SR proteins. Taken together, our results suggest that MALAT1 regulates AS by modulating the levels of active SR proteins. Our results further highlight the role for an nrRNA in the regulation of gene expression.

Society for Endocrinology UK guidance on the initial evaluation of an infant or an adolescent with a suspected disorder of sex development (Revised 2015).

It is paramount that any child or adolescent with a suspected disorder of sex development (DSD) is assessed by an experienced clinician with adequate knowledge about the range of conditions associated with DSD. If there is any doubt, the case should be discussed with the regional DSD team. In most cases, particularly in the case of the newborn, the paediatric endocrinologist within the regional team acts commonly as the first point of contact. This clinician should be part of a multidisciplinary team experienced in management of DSD and should ensure that the affected person and parents have access to specialist psychological support and that their information needs are comprehensively addressed. The underlying pathophysiology of DSD and the strengths and weaknesses of the tests that can be performed should be discussed with the parents and affected young person and tests undertaken in a timely fashion. Finally, in the field of rare conditions, it is imperative that the clinician shares the experience with others through national and international clinical and research collaboration.

ESPR postmortem imaging task force: where we begin.

A new task force on postmortem imaging was established at the annual meeting of the European Society of Paediatric Radiology (ESPR) in Graz, Austria, in 2015. The postmortem task force is separate from the child abuse task force as it covers all aspects of fetal, neonatal and non-forensic postmortem imaging. The main focus of the task force is the guidance and standardization of non-radiographic postmortem imaging, particularly postmortem CT and postmortem MRI. This manuscript outlines the starting point of the task force, with a mission statement, outline of current experience, and short- and long-term goals.

Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration.

Expanded hexanucleotide repeats in the chromosome 9 open reading frame 72 (C9orf72) gene are the most common genetic cause of ALS and frontotemporal degeneration (FTD). Here, we identify nuclear RNA foci containing the hexanucleotide expansion (GGGGCC) in patient cells, including white blood cells, fibroblasts, glia, and multiple neuronal cell types (spinal motor, cortical, hippocampal, and cerebellar neurons). RNA foci are not present in sporadic ALS, familial ALS/FTD caused by other mutations (SOD1, TDP-43, or tau), Parkinson disease, or nonneurological controls. Antisense oligonucleotides (ASOs) are identified that reduce GGGGCC-containing nuclear foci without altering overall C9orf72 RNA levels. By contrast, siRNAs fail to reduce nuclear RNA foci despite marked reduction in overall C9orf72 RNAs. Sustained ASO-mediated lowering of C9orf72 RNAs throughout the CNS of mice is demonstrated to be well tolerated, producing no behavioral or pathological features characteristic of ALS/FTD and only limited RNA expression alterations. Genome-wide RNA profiling identifies an RNA signature in fibroblasts from patients with C9orf72 expansion. ASOs targeting sense strand repeat-containing RNAs do not correct this signature, a failure that may be explained, at least in part, by discovery of abundant RNA foci with C9orf72 repeats transcribed in the antisense (GGCCCC) direction, which are not affected by sense strand-targeting ASOs. Taken together, these findings support a therapeutic approach by ASO administration to reduce hexanucleotide repeat-containing RNAs and raise the potential importance of targeting expanded RNAs transcribed in both directions.

In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides.

Huntington disease (HD) is a dominant, genetic neurodegenerative disease characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there is currently no disease-modifying therapy. HD is caused by the expansion of a CAG tract in the huntingtin (HTT) gene. The mutant HTT protein (muHTT) acquires toxic functions, and there is significant evidence that muHTT lowering would be therapeutically efficacious. However, the wild-type HTT protein (wtHTT) serves vital functions, making allele-specific muHTT lowering strategies potentially safer than nonselective strategies. CAG tract expansion is associated with single nucleotide polymorphisms (SNPs) that can be targeted by gene silencing reagents such as antisense oligonucleotides (ASOs) to accomplish allele-specific muHTT lowering. Here we evaluate ASOs targeted to HD-associated SNPs in acute in vivo studies including screening, distribution, duration of action and dosing, using a humanized mouse model of HD, Hu97/18, that is heterozygous for the targeted SNPs. We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses throughout the central nervous system for 16 weeks or more after a single intracerebroventricular (ICV) injection. With further validation, these ASOs could provide a therapeutic option for individuals afflicted with HD.

Rational design of antisense oligonucleotides targeting single nucleotide polymorphisms for potent and allele selective suppression of mutant Huntingtin in the CNS.

Autosomal dominant diseases such as Huntington's disease (HD) are caused by a gain of function mutant protein and/or RNA. An ideal treatment for these diseases is to selectively suppress expression of the mutant allele while preserving expression of the wild-type variant. RNase H active antisense oligonucleotides (ASOs) or small interfering RNAs can achieve allele selective suppression of gene expression by targeting single nucleotide polymorphisms (SNPs) associated with the repeat expansion. ASOs have been previously shown to discriminate single nucleotide changes in targeted RNAs with ∼5-fold selectivity. Based on RNase H enzymology, we enhanced single nucleotide discrimination by positional incorporation of chemical modifications within the oligonucleotide to limit RNase H cleavage of the non-targeted transcript. The resulting oligonucleotides demonstrate >100-fold discrimination for a single nucleotide change at an SNP site in the disease causing huntingtin mRNA, in patient cells and in a completely humanized mouse model of HD. The modified ASOs were also well tolerated after injection into the central nervous system of wild-type animals, suggesting that their tolerability profile is suitable for advancement as potential allele-selective HD therapeutics. Our findings lay the foundation for efficient allele-selective downregulation of gene expression using ASOs-an outcome with broad application to HD and other dominant genetic disorders.

Do current therapeutic anti-Aß antibodies for Alzheimer's disease engage the target?

Reducing amyloid-ß peptide (Aß) burden at the pre-symptomatic stages of Alzheimer's disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aß is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aß in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aß with high affinity. All of the antibodies were able to bind Aß in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aß species, the Aß detected using solanezumab was barely above detection limits while crenezumab did not detect any Aß. None of the antibodies were able to detect any Aß species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aß related proteins. Bapineuzumab demonstrated target engagement with brain Aß, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD.

High gain, wide field of view concentrator for optical communications.

The field of view and gain of optical concentrators used within free space optical communications systems are constrained by conservation of etendue. In this Letter, consideration of the processes in a fluorescent concentrator leads to a simple design strategy for these concentrators for this application. Significantly, because fluorescent concentrators do not conserve etendue, this can lead to concentrators with wider fields of view and higher gains. A model of a fluorescent concentrator containing a quantum dot material suggests that it could have a gain 50 times higher than an etendue conserving concentrator with the same field of view.

Prospective randomized controlled trial comparing 1- versus 7-day manipulation following collagenase injection for dupuytren contracture.

PURPOSE: To compare the efficacy, tolerance, and safety of manual manipulation at day 7 to day 1 following collagenase Clostridium histolyticum (CCH) injection for Dupuytren contracture. METHODS: Eligible patients were randomized to manipulation at day 1 versus day 7 following CCH injection. Preinjection, premanipulation, postmanipulation, and 30-day follow-up metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joint contractures were measured. Pain scores were recorded at each time point. Data were stratified per cohort based on primary joint treated (MCP vs PIP). Means were compared using paired and unpaired t-tests. RESULTS: Forty-three patients with 46 digits were eligible and were randomized to 1-day (22 digits) and 7-day (24 digits) manipulation. For MCP joints, there were no significant differences in flexion contractures between 1- and 7-day cohorts for initial (47° vs 46°), postmanipulation (0° vs 2°), or 30-day follow-up (1° vs 2°) measurements. Premanipulation, the residual contracture was significantly lower in the 7-day group (23° vs 40°). For PIP joints, there were no significant differences between 1- and 7-day cohorts for initial (63° vs 62°), premanipulation (56° vs 52°), postmanipulation (13° vs 15°), or 30-day (14° vs 16°) measurements. There were no significant differences in pain or skin tears between the 2 groups. No flexor tendon ruptures were observed. CONCLUSIONS: The effectiveness of CCH in achieving correction of Dupuytren contractures was preserved when manipulation was performed on day 7, with no differences in correction, pain, or skin tears. These data suggest that manipulation can be scheduled at the convenience of the patient and surgeon within the first 7 days after injection. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic I.