Snakebite envenoming: A systematic review and meta-analysis of global morbidity and mortality.

BACKGROUND: Snakebite envenoming represents a significant and often neglected public health challenge, particularly in rural communities across tropical and subtropical regions. An estimated 1.2-5.5 million people are envenomed by snakebites annually. More than 125,000 of these bites are fatal, and 3-4 times as many results in disability/disfigurement. Despite its prevalence, collecting accurate epidemiological data on snakebite is challenging. This systematic review and meta-analysis collates global epidemiology data on snakebite morbidity and mortality. METHODS: Medline, Embase, Cochrane and CINAHL Plus databases were searched for articles published between 2001-2022. Pooled incidence and mortality were obtained using random effects modelling, heterogeneity (I2) was tested, and sensitivity analyses performed. Newcastle-Ottawa Scale assessed study quality. RESULTS: Out of the four databases, 5,312 articles were found. After removing duplicates, 3,953 articles were screened by title and abstract and 65 articles containing information on snakebite epidemiology, encompassing 663,460 snakebites, were selected for analysis. The people most at risk for snakebite were men (59%), engaged in agricultural labour (27.5%), and residing in rural areas (66.7%). More than half (57%) of the reported bites resulted in envenoming. Incidents occurred frequently in the summer season (38.5%), during daytime (56.7%), and bites were most often to the lower limb (56.4%). Envenoming severity was frequently mild (46.7%), treated in hospital (68.3%), and was treated with anti-venom (64.7%). The pooled global incidence and mortality was 69.4 /100,000 population (95%CI: 36.8 to 101.9) and 0.33/100,000 population (95%CI, 0.14 to 0.52) per year, respectively. Stratified by continents, Asia had the highest incidence of 130.7/100,000 population (95%CI: 48.3 to 213.1) while Europe has the lowest with 0.7/100,000 population (95%CI: -0.2 to 1.5). The highest mortality was reported in Asia at 0.96/100,000 population (95% CI: 0.22 to 1.70), and Africa 0.44/100,000 population (95%CI: -0.03 to 0.84). Incidence was highest among inhabitants of lower-middle-income countries 132.7/100,000 population (95%CI: 55.4 to 209.9) while mortality was highest in low-income countries at 0.85/100,000 population (95% CI: -0.06 to 2.31). CONCLUSION: Incidence and mortality rates noted here highlight the global impact of snakebite and underscore the critical need to address the burden of snakebite envenoming. It also reveals that while reported snakebite incidence was higher in lower-middle-income countries, the burden of mortality was greatest among inhabitants of low-income countries, again emphasising the need for greater efforts to tackle this neglected tropical disease.

Enhancing Conductivity of Silver Nanowire Networks through Surface Engineering Using Bidentate Rigid Ligands.

Solution processable metallic nanomaterials present a convenient way to fabricate conductive structures, which are necessary in all electronic devices. However, they tend to require post-treatments to remove the bulky ligands around them to achieve high conductivity. In this work, we present a method to formulate a post-treatment free conductive silver nanowire ink by controlling the type of ligands around the silver nanowires. We found that bidentate ligands with a rigid molecular structure were effective in improving the conductivity of the silver nanowire networks as they could maximize the number of linkages between neighboring nanowires. In addition, DFT calculations also revealed that ligands with good LUMO to silver energy alignment were more effective. Because of these reasons, fumaric acid was found to be the most effective ligand and achieved a large reduction in sheet resistance of 70% or higher depending on the nanowire network density. The concepts elucidated from this study would also be applicable to other solution processable nanomaterials systems such as quantum dots for photovoltaics or LEDs which also require good charge transport being neighboring nanoparticles.

Phalloplasty Flap Salvage Using a Superficial Circumflex Iliac Artery Perforator Propeller Flap.

Background: Partial phalloplasty flap loss presents an evolving challenge, largely due to the complex demands required for both aesthetics and function. We describe our novel experience using the superficial circumflex iliac perforator (SCIP) propeller flap for neophallus salvage when skin grafting alone provides insufficient soft tissue bulk or coverage. Methods: We retrospectively reviewed patients who underwent SCIP propeller flap reconstruction after phalloplasty partial flap loss. After suprafascial dissection, superficial circumflex iliac vessel perforator(s) were isolated toward the femoral origin. The flap was rotated 180 degrees and inset into the ventral or distal neophallus depending on the region of flap loss. If glans reconstruction was required, the flap was tubularized before inset. Division and inset were performed at a second stage, followed by subsequent glansplasty, urethral creation, and/or penile implant placement. Results: SCIP propeller flap reconstruction was performed for four patients after one to six debridements at a mean of 6.5 (range 1.0-19.2) months following the initial phalloplasty. Three patients had lost the ventral phallus due to venous insufficiency, arterial insufficiency, and excessive postoperative swelling, respectively. The fourth patient experienced near-total loss of the glans following penile implant insertion. Division and inset was performed at an average of 7.5 (range 5.0-12.0) weeks after SCIP flap. There were no complications related to SCIP flap viability. Conclusion: The SCIP propeller flap allows salvage of partial flap loss following phalloplasty by providing thin, pliable soft tissue bulk and skin coverage with minimal donor site morbidity, without the need for microsurgery, allowing progression with subsequent reconstructive stages.

Predictors of recovery in a medium secure service: Influence of the Welsh Government's Mental Health (2010) Measure.

BACKGROUND: Research to date has failed to examine the effectiveness of MSUs in facilitating recovery, or the influence that mental health policy may have on this process. Examining predictors of short-term clinical outcomes during inpatient admission and the effects of policy changes may inform future policy, treatment planning and may improve service user outcomes. AIMS: To examine whether service user admission characteristics and length of stay predicted recovery status at discharge from medium secure care and whether a recovery-focused change in policy (introduction of the Mental Health (Wales) Measure (2010)) impacted either on recovery or the relationship between service user characteristics and recovery. METHODS: The study adopted a retrospective analysis of quantitative data obtained from healthcare records from a Welsh MSU between 2007 and 2017 (n = 198). The DUNDUM-4 scale assessed recovery whilst DUNDRUM-2 assessed security need at admission. Service user admission characteristics included HCR-20 subscale scores, previous security-level transitions, adverse childhood experiences, substance misuse histories. RESULTS: Shorter inpatient stays and higher scores on the dynamic HCR-20 clinical subscale were associated with poorer recovery outcomes. The relationship between admission characteristics and recovery endured despite changes in policy. Implementation of recovery focused legislation was associated with improved recovery. CONCLUSIONS: The findings suggest that treatment should focus on dynamic risk factors to improve service user outcomes and highlights the need for long-term medium-secure provision for some. Further research is needed to evaluate the success of MSUs and the validity of the DUNDRUM-4 across UK secure services.

Effects of High-Speed Training on Messenger RNA Expression in Two-Year-Old Thoroughbred Racehorses.

Accumulating high-speed exercise has been identified as a significant risk factor for catastrophic injuries in racing Thoroughbreds. Injuries, regardless of severity, are a main cause of withdrawal from the racing industry, raising animal welfare concerns and resulting in significant economic losses. While most of the current literature focuses on injuries incurred during racing rather than training, the present study aims to help fill this gap. As such, peripheral blood was collected weekly, prior to exercise or administration of medication, from eighteen, two-year-old Thoroughbreds throughout their first season of race training. Messenger RNA (mRNA) was isolated and used to analyze the expression of 34 genes via RT-qPCR. Statistical analysis of the noninjured horses (n = 6) showed that 13 genes were significantly correlated with increasing average weekly high-speed furlong performance. Additionally, there was a negative correlation for CXCL1, IGFBP3, and MPO with both cumulative high-speed furlongs and week of training for all horses. Comparison of both groups showed opposing correlations between the anti-inflammatory index (IL1RN, IL-10, and PTGS1) and average weekly high-speed furlong performance. Furthermore, evaluation of training effects on mRNA expression during the weeks surrounding injury, showed differences between groups in IL-13 and MMP9 at -3 and -2 weeks prior to injury. While some previously reported relationships between exercise adaptation and mRNA expression were not noted in this study, this may have been due to the small sample size. Several novel correlations, however, were identified and warrant further investigation as markers of exercise adaptation or potential risk for injury.

Assessing knowledge and awareness regarding snakebite and management of snakebite envenoming in healthcare workers and the general population: A systematic review and meta-analysis.

BACKGROUND: Snakebite envenoming is a serious and life-threatening medical condition that predominantly affects people living in rural communities across Africa, Asia, and Latin America. As our climate changes, there is a growing concern that negative human-snake interactions will increase. Our ability to prevent and manage snakebite requires effective antivenoms as well as knowledge regarding the prevention and management of snakebite among healthcare workers and affected communities across the globe. This systematic review aims to assess existing levels of knowledge regarding snakebite prevention and management in both healthcare workers and affected communities. METHODS: This review was conducted on studies reporting quantitative measurements to evaluate knowledge and practice regarding snakebite prevention and management published in major databases between 1 January 2000 and 31 December 2021. Random effects modelling was used to obtain the pooled proportion. Heterogeneity (I2) was tested, and sensitivity analyses performed. RESULTS: Out of 3,697 records, 16 studies from 12 countries assessing 7,640 participants were included. Four of the studies were ranked as good quality studies, 9 as fair, and 3 as poor. This study results demonstrated that 56% of the study population answered the knowledge question correctly (95% CI 48% to 63%, p < 0.001). High heterogeneity was observed (I2 = 97.29%), with marginal publication bias (Egger's regression test, p = 0.0814). Participants had relatively higher knowledge concerning use of antivenom as preferred treatment, followed by snakebite prevention, knowledge of signs and symptoms of snakebite, knowledge of first-aid, and knowledge of treatment. Participants had lower knowledge relating to types of snakes and the identification of snakes. CONCLUSION: Adequate knowledge about snakebites and its management among the general population and healthcare workers was 56%. Healthcare workers and communities across Asia showed higher relative knowledge compared to those in Africa and the Middle East. These data suggest that further education is needed in both the general population and among healthcare workers to ensure that appropriate preventative and patient management techniques are being utilised in snakebite endemic regions. Greater local awareness of the risks and appropriate management of snakebite is required to reduce the burden of snakebite mortality and morbidity.

Approach to Complex Upper Extremity Reconstruction.

The management of complex upper extremity trauma can be overwhelming in its urgency and complexity. Having a systematic approach that maintains a clear set of priorities focused on hand and upper extremity function, operative efficiency, and long-term planning for future operations allows the reconstructive extremity surgeon to effectively treat these complex injuries. This article addressed these overall clinical considerations and details the approach taken at the Buncke Clinic including replantation and revascularization as well as osseous and soft tissue reconstruction.

Great Toe Transplantation.

Despite being relatively uncommon in the general population, thumb amputations cause severe disability. More than 3,300 thumb amputations occurred in the United States. The thumb makes up around 40% of the function of the hand. Therefore, losing it would result in significant medical, hospital, and societal costs. Thumb reconstruction surgery's primary goal is to restore grip strength, including the range of motion, fine and tripod pinch, power grasp, strength, and sensibility, while secondary goals include restoring hand aesthetics. In cases of thumb replantation, like-for-like replacement is possible; however, when thumb replantation is not possible, great toe-to-hand transplantation is the best available reconstruction. When compared with other reconstructive options such as osteoplastic thumb reconstruction, pollicization, second toe transplantation, and the use of a thumb prosthesis, great toe transplantation provides superior function and aesthetics. For restoring pinch, sensitivity, strength, and aesthetics of the hand with well-tolerated donor site morbidity, toe to thumb transplantation is regarded as the gold standard.

Microsurgical Gender Affirmation Surgery.

Phalloplasty in the female to male transgender patient is a complex operation aimed at creating a functional and aesthetic phallus, external genitalia, and perineum. Functional goals include standing micturition and sexual function with erogenous and tactile sensation as well as the ability to participate in penetrative intercourse. Functional genital reconstruction relies on creating of a fully lengthened urethra from local tissues as well as the provision for additional length via tissue transplantation. This manuscript will review techniques for the creation of perineal urethral segment as well as primary flaps available for the creation of neophallus. Particular emphasis is given to our preferred method of reconstruction: single-stage urethral lengthening with radial forearm flap phalloplasty including a review of surgical techniques and complications.

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.

In vivo through-range passive stiffness of the lumbar spine: a meta-analysis of measurements and methods.

Passive spinal stiffness is an important property thought to play a significant role in controlling spinal position and movement. Measuring through-range passive stiffness in vivo is challenging with several methods offered in the literature. Currently, no synthesis of values or methods exists to which to compare literature to. This study aims to provide a contemporary review and quantitative synthesis of the through-range in vivo passive lumbar spinal stiffness values for each of the cardinal planes of movement. A structured systematic search, following PRISMA guidelines, of 28 electronic databases was conducted in 2022. Articles were restricted to peer-reviewed English language studies investigating in vivo through-range passive stiffness of the lumbar spine. Thirteen studies were included, ten relating to flexion/extension, four to lateral bending and five to axial rotation. Average stiffness values, as weighted means and confidence intervals, for each of the four sections of the moment-movement curves were synthesised for all planes of movement. Lateral bending was found to be the comparatively stiffest movement followed by flexion and then axial rotation. Future research should focus on the validity and reliability of measurement techniques. Axial rotation would also benefit from further study of its latter stages of range.

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.

Direct targeting of FOXP3 in Tregs with AZD8701, a novel antisense oligonucleotide to relieve immunosuppression in cancer.

BACKGROUND: The Regulatory T cell (Treg) lineage is defined by the transcription factor FOXP3, which controls immune-suppressive gene expression profiles. Tregs are often recruited in high frequencies to the tumor microenvironment where they can suppress antitumor immunity. We hypothesized that pharmacological inhibition of FOXP3 by systemically delivered, unformulated constrained ethyl-modified antisense oligonucleotides could modulate the activity of Tregs and augment antitumor immunity providing therapeutic benefit in cancer models and potentially in man. METHODS: We have identified murine Foxp3 antisense oligonucleotides (ASOs) and clinical candidate human FOXP3 ASO AZD8701. Pharmacology and biological effects of FOXP3 inhibitors on Treg function and antitumor immunity were tested in cultured Tregs and mouse syngeneic tumor models. Experiments were controlled by vehicle and non-targeting control ASO groups as well as by use of multiple independent FOXP3 ASOs. Statistical significance of biological effects was evaluated by one or two-way analysis of variance with multiple comparisons. RESULTS: AZD8701 demonstrated a dose-dependent knockdown of FOXP3 in primary Tregs, reduction of suppressive function and efficient target downregulation in humanized mice at clinically relevant doses. Surrogate murine FOXP3 ASO, which efficiently downregulated Foxp3 messenger RNA and protein levels in primary Tregs, reduced Treg suppressive function in immune suppression assays in vitro. FOXP3 ASO promoted more than 70% reduction in FOXP3 levels in Tregs in vitro and in vivo, strongly modulated Treg effector molecules (eg, ICOS, CTLA-4, CD25 and 4-1BB), and augmented CD8+ T cell activation and produced antitumor activity in syngeneic tumor models. The combination of FOXP3 ASOs with immune checkpoint blockade further enhanced antitumor efficacy. CONCLUSIONS: Antisense inhibitors of FOXP3 offer a promising novel cancer immunotherapy approach. AZD8701 is being developed clinically as a first-in-class FOXP3 inhibitor for the treatment of cancer currently in Ph1a/b clinical trial (NCT04504669).

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.

Infrapubic Insertion of Penile Implants in Transmen After Phalloplasty.

OBJECTIVE: To describe the infrapubic approach to penile prosthesis insertion in transmen after phalloplasty. MATERIALS AND METHODS: After verifying phalloplasty vascular pedicle anatomy and reliable micturition, patients may be considered for implant surgery. Specific modifications of the infrapubic approach to penile prosthesis insertion as well as individualization of commercially available implants are performed intraoperatively to help reduce the risk of postoperative complications. RESULTS: In our single surgeon series (MLC) using the infrapubic approach with these specific implants after phalloplasty, 17/107 (16%) patients from October 2017 to November 2020 required revision surgery after mean follow-up of 79.8 weeks. CONCLUSION: Our infrapubic prosthesis insertion after phalloplasty technique with modifications to commercially available implants may help reduce the risk of postoperative complications.

An abnormal clinical Allen's Test is not a contraindication for free radial forearm flap.

An abnormal clinical Allen's test is not a definitive exclusion criterion for free radial forearm flap use. A surgical Allen's test may be useful to determine whether flap harvest is feasible in patients with an abnormal clinical Allen's test.