Current perspectives on peripheral nerve repair and management of the nerve gap.

From the first surgical repair of a nerve in the 6th century, progress in the field of peripheral nerve surgery has marched on; at first slowly but today at great pace. Whether performing primary neurorrhaphy or managing multiple large nerve defects, the modern nerve surgeon has an extensive range of tools, techniques and choices available to them. Continuous innovation in surgical equipment and technique has enabled the maturation of autografting as a gold standard for reconstruction and welcomed the era of nerve transfer techniques all while bioengineers have continued to add to our armamentarium with implantable devices, such as conduits and acellular allografts. We provide the reader a concise and up-to-date summary of the techniques available to them, and the evidence base for their use when managing nerve transection including current use and applicability of nerve transfer procedures.

A comparison of career plans of gastroenterology fellows compared to fellows in other internal medicine subspecialties.

Background: The career trajectory of medical professionals, particularly in specialized fields like gastroenterology, can significantly impact healthcare and research. This study aimed to analyze career choices among gastroenterology fellows in the US and investigate the factors influencing these choices. Methods: We utilized data from the American Medical Association on internal medicine subspecialty fellows. The study examined career plans of gastroenterology fellows and compared them with those of other subspecialties. A chi-square test was performed to assess differences in career choices and practice settings. Results: Among gastroenterology fellows, 46% opted for private practice, 28% pursued further training, and 26% chose academia. Notably, gastroenterology fellows were more inclined toward private practice than their counterparts in other subspecialties (46.3% vs 38.4%) and were less likely to pursue academic careers (25.6% vs 30.7%). Conclusion: This study highlights a concerning trend among recent gastroenterology fellowship graduates favoring private practice over academic careers or additional training. To sustain and strengthen academic medicine in gastroenterology, interventions such as scholarships, mentorship programs, and loan repayment initiatives tailored to academic pursuits could play a crucial role.

Release of miR-29 Target Laminin C2 Improves Skin Repair.

miRNAs are small noncoding RNAs that regulate mRNA targets in a cell-specific manner. miR-29 is expressed in murine and human skin, where it may regulate functions in skin repair. Cutaneous wound healing model in miR-29a/b1 gene knockout mice was used to identify miR-29 targets in the wound matrix, where angiogenesis and maturation of provisional granulation tissue was enhanced in response to genetic deletion of miR-29. Consistently, antisense-mediated inhibition of miR-29 promoted angiogenesis in vitro by autocrine and paracrine mechanisms. These processes are likely mediated by miR-29 target mRNAs released upon removal of miR-29 to improve cell-matrix adhesion. One of these, laminin (Lam)-c2 (also known as laminin γ2), was strongly up-regulated during skin repair in the wound matrix of knockout mice. Unexpectedly, Lamc2 was deposited in the basal membrane of endothelial cells in blood vessels forming in the granulation tissue of knockout mice. New blood vessels showed punctate interactions between Lamc2 and integrin α6 (Itga6) along the length of the proto-vessels, suggesting that greater levels of Lamc2 may contribute to the adhesion of endothelial cells, thus assisting angiogenesis within the wound. These findings may be of translational relevance, as LAMC2 was deposited at the leading edge in human wounds, where it formed a basal membrane for endothelial cells and assisted neovascularization. These results suggest a link between LAMC2, improved angiogenesis, and re-epithelialization.

A pilot prospective cohort study using experimental quantification of early peripheral nerve regeneration with high-frequency three-dimensional tomographic ultrasound (HFtUS).

Quantification of peripheral nerve regeneration after injury relies upon subjective outcome measures or electrophysiology assessments requiring fully regenerated neurons. Nerve surgeons and researchers lack objective, quantifiable information on the site of surgical repair and regenerative front. To address this need, we developed a quantifiable, visual, clinically available measure of early peripheral nerve regeneration using high-frequency, three-dimensional, tomographic ultrasound (HFtUS). We conducted a prospective, longitudinal study of adult patients with ulnar and/or median nerve injury of the arm undergoing direct epineurial repair within 5 days of injury. Assessment of morphology, volumetric and 3D grey-scale quantification of cross-sectional views were made at baseline up to 15 months post-surgery. Sensory and motor clinical outcome measures and patient reported outcome measures (PROMs) were recorded. Five participants were recruited to the study. Our data demonstrated grey-scale values (an indication of axonal density) increased in distal stumps within 2-4 months after repair, returning to normal as regeneration completed (4-6 months) with concomitant reduction in intraneural volume as surgical oedema resolved. Two patients with abnormal regeneration were characterized by increased intraneural volume and minimal grey-scale change. HFtUS may quantify early peripheral nerve regeneration offering a window of opportunity for surgical intervention where early abnormal regeneration is detected.

Treatment of Symptomatic Lymphedema in the Hand with Omental Flow-through Flap.

Vascularized lymph node transfer (VLNT) is a surgical option to improve physiologic lymphatic drainage. This technique transfers healthy vascularized lymphatic tissue from various available donor sites to the existing lymphatics of the affected area. Here, we present a successful case halting the size progression and reversing lymphedema symptoms in a patient treated with vascularized omental lymph node transfer. A 56-year-old man presented with stage III malignant sarcoma of his left medial upper arm. Two-years after excision, flap reconstruction, and radiation brachytherapy, worsening diffuse left arm edema developed, causing pain, decreased range of motion, and paresthesia. A vascularized omental lymph node transfer was performed. The omental flap required a flow-through design, requiring anastomosis of both gastroepiploic arteries to obtain Dopplerable signals. The patient experienced progressive relief of lymphedema symptoms after this transfer. Treatment outcomes with the use of VLNT have been largely encouraging; however, objective measures of improvement and timing of neolymphangiogenesis in recipient lymph node sites still need to be defined. Understanding omental VLNT flow dynamics and expected time point changes during the postoperative course will define expected outcomes and allow for treatment of a greater number of patients affected by lymphedema.

Glomerulonephritis.

Glomerulonephritis (GN) encompasses several disorders that cause glomerular inflammation and injury through an interplay of immune-mediated mechanisms, host characteristics, and environmental triggers, such as infections. GN can manifest solely in the kidney or in the setting of a systemic illness, and presentation can range from chronic and relatively asymptomatic hematuria to fulminant renal failure. Classic acute GN is characterized by hematuria, edema, and hypertension, the latter 2 of which are the consequence of sodium and water retention in the setting of renal impairment. Although presenting signs and symptoms and a compatible clinical history can suggest GN, serologic and urinary testing can further refine the differential diagnosis, and renal biopsy can be used for definitive diagnosis. Treatment of GN can include supportive care, renin-angiotensin-aldosterone system blockade, immunomodulatory therapy, and renal transplant. Prognosis is largely dependent on the underlying cause of GN and can vary from a self-limited course to chronic kidney disease. This review focuses on lupus nephritis, IgA nephropathy, IgA vasculitis, and postinfectious GN.

Breast-Q sensory outcomes of non-neurotized, autologous, unilateral breast reconstruction with a minimum of 3-year follow-up.

INTRODUCTION: Sensory reinnervation of autologous breast tissue after free flap reconstruction is highly variable. There is no long-term follow-up data exploring spontaneous reinnervation and how this affects patients' quality of life nor the nerve-related symptoms they experience. To address this issue, we invited patients with a minimum of 3 years after non-neurotized, free flap breast reconstruction to complete patient-reported outcome measures exploring sensation, quality of life and breast-related symptoms. METHODS: We performed a retrospective cohort study of patients undergoing unilateral Muscle-Sparing Transverse Rectus Abdominus Muscle (MS-TRAM) or deep inferior epigastric artery perforator (DIEP) flap breast reconstruction between 01-01-2015 and 31-12-2019 in the Department of Plastic and Reconstructive Surgery at Manchester University NHS Foundation Trust. We invited participants to complete the recently developed Breast-Q© Breast Sensation Module. RESULTS: All patients had undergone unilateral immediate (n = 85) or delayed (n = 82) breast reconstruction after mastectomy using either a free DIEP (n = 150) or TRAM (n = 17) flap reconstruction a minimum of 3 years prior. The median age at operation was 48. Sensation after reconstruction was significantly reduced in the reconstructed breast compared with the contralateral breast (P < 0.0001) with a reduction in reported quality of life (immediate (68.0 [54.0, 89.0]) and delayed (68.0 [62.0, 83.8])). The sensation was significantly better in immediate vs delayed procedures (P = 0.024). Sensory scores after reconstruction increased with age (P = 0.036). DISCUSSION: Breast sensation after non-neurotized reconstruction with autologous tissue is significantly reduced at long-term follow-up with a reduction in quality of life. A minimum outcome set for quantification of breast sensation is required and future research into the cost-benefit of neurotized, autologous breast reconstruction is needed.

Long-Term Follow-Up of Open Gustilo-Anderson IIIB Fractures Treated With an Adjuvant Local Antibiotic Hydroxyapatite Bio-Composite.

Background Open fractures associated with significant tissue loss are complex and present challenges in management; they are associated with poor outcomes such as infection, non-union or amputation. This study aimed to evaluate outcomes of using an adjuvant local antibiotic hydroxyapatite bio-composite in the management of open Gustilo-Anderson IIIB fractures with up to eight years of follow-up. Methods This was a retrospective study. A total of 81 patients with Gustilo-Anderson IIIB fractures treated with "fix and flap" limb reconstruction with adjuvant local antibiotic therapy using a bio-composite carrier were reviewed. Results  The mean follow-up time for all the patients, at the time of data collection, was 55.8 months. Union was achieved in 96% with a limb salvage rate of 96.3% and a deep infection rate of 3.7%. Conclusion The use of local antibiotic therapy, together with a combined orthoplastic "fix and flap" approach for Gustilo-Anderson IIIB open fractures, was found to be associated with a very low rate of metalwork infection and high union and limb salvage rates. Future studies should include some functional and quality of life outcome measures to see the efficacy of this method.

A Very Uncommon Case of Transudative Chylothorax: A Case Report and Literature Review.

The presence of chyle in the pleural cavity is referred to as chylothorax. Exudative chylothorax is usually related to damage or obstruction of the lymphatic vasculature with subsequent leakage into the pleural space. In contrast, transudative chylothorax is related to increased hydrostatic pressure caused by elevated intra-abdominal pressure, which leads to the translocation of chylous fluid into the pleural space. Cirrhosis is the most common cause of transudative chylothorax, commonly presenting with ascites and portal hypertension. To the best of our knowledge, isolated transudative chylothorax as a consequence of cirrhosis is exceptionally rare and has been scarcely reported in the literature. We herein report a female patient in her fifties who presented to our hospital with isolated unilateral transudative hepatic chylothorax, with no clinical evidence of cirrhosis or any stigmata of portal hypertension at the time of presentation.

Toward novel treatment against filariasis: Insight into genome-wide co-evolutionary analysis of filarial nematodes and Wolbachia.

Infectious diseases caused by filarial nematodes are major health problems for humans and animals globally. Current treatment using anti-helminthic drugs requires a long treatment period and is only effective against the microfilarial stage. Most species of filarial nematodes harbor a specific strain of Wolbachia bacteria, which are essential for the survival, development, and reproduction of the nematodes. This parasite-bacteria obligate symbiosis offers a new angle for the cure of filariasis. In this study, we utilized publicly available genome data and putative protein sequences from seven filarial nematode species and their symbiotic Wolbachia to screen for protein-protein interactions that could be a novel target against multiple filarial nematode species. Genome-wide in silico screening was performed to predict molecular interactions based on co-evolutionary signals. We identified over 8,000 pairs of gene families that show evidence of co-evolution based on high correlation score and low false discovery rate (FDR) between gene families and obtained a candidate list that may be keys in filarial nematode-Wolbachia interactions. Functional analysis was conducted on these top-scoring pairs, revealing biological processes related to various signaling processes, adult lifespan, developmental control, lipid and nucleotide metabolism, and RNA modification. Furthermore, network analysis of the top-scoring genes with multiple co-evolving pairs suggests candidate genes in both Wolbachia and the nematode that may play crucial roles at the center of multi-gene networks. A number of the top-scoring genes matched well to known drug targets, suggesting a promising drug-repurposing strategy that could be applicable against multiple filarial nematode species.

Identification of gametocyte-associated pir genes in the rodent malaria parasite, Plasmodium chabaudi chabaudi AS.

OBJECTIVE: To analyse the transcriptional profiles of the pir multigene family of Plasmodium chabaudi chabaudi in male and female gametocytes isolated from the blood of infected mice. RESULTS: Infected red blood cells containing female and male P. chabaudi gametocytes transcribe a distinct set of genes encoded by the multigene family pir. The overall patterns are similar to what has been observed in the close relative P. berghei, but here we show that gametocyte-associated pir genes are distinct from those involved in chronic blood-stage infection and highlight a male-associated pir gene which should be the focus of future studies.

The incidence and management of peripheral nerve injury in England (2005-2020).

Peripheral nerve injury (PNI) is a significant health problem that confers lifelong impact on those injured. Current interventions are purely surgical; however, outcomes remain poor. There is a lack of high-quality epidemiological data that is needed to identify populations involved, current healthcare demands, and ensure resources are distributed to the greatest effect, to reduce the injury burden. METHODS: Anonymized hospital episode statistical (HES) data on admitted patient care was obtained from NHS Digital for all National Health Service (NHS) patients sustaining PNI of all body regions between 2005 and 2020. Total numbers of finished consultant episodes (FCEs) or FCEs/100,000 population were used to demonstrate changes in demographic variables, anatomical locations of injury, mechanisms of injury, speciality, and main operation. RESULTS: There was a mean national incidence of 11.2 (95% CI 10.9, 11.6) events per 100,000 population per year. Males were at least twice as likely (p < 0.0001) to sustain a PNI. Upper limb nerves at or distal to the wrist were most commonly injured. Knife injuries increased (p < 0.0001), whereas glass injuries decreased (p < 0.0001). Plastic surgeons increasingly managed PNI (p = 0.002) as opposed to orthopaedic surgeons (p = 0.006) or neurosurgeons (p = 0.001). There was an increase in neurosynthesis (p = 0.022) and graft procedures (p < 0.0001) during the study period. DISCUSSION: PNI is a significant national healthcare problem predominantly affecting distal, upper limb nerves of men of working age. Injury prevention strategies, improved targeted funding and rehabilitation pathways are needed to reduce the injury burden and improve patient care.

Urology case report: Multifactorial bladder dysfunction in the setting of down syndrome.

A 16-year-old male patient with Down syndrome diagnosed with AKI and urinary tract infection was treated with meropenem for ESBL-positive E. coli in urine culture. Persistently elevated creatinine and persistent post-void residual (PVR) of >300 mL led to further testing, which revealed urethral stricture and a lower sacral Tarlov cyst. Due to no complete improvement with urethral dilatation, he underwent laminectomy and Tarlov cyst fenestration. Creatinine normalized, with increased urine output and robust flow. Due to a PVR of >100 mL, he received behavioral therapy, including sitting and timed voiding, and the PVR was reduced to <5 mL.

A manually curated annotation characterises genomic features of P. falciparum lncRNAs.

BACKGROUND: Important regulation occurs at the level of transcription in Plasmodium falciparum and growing evidence suggests that these apicomplexan parasites have complex regulatory networks. Recent studies implicate long noncoding RNAs (lncRNAs) as transcriptional regulators in P. falciparum. However, due to limited research and the lack of necessary experimental tools, our understanding of their role in the malaria-causing parasite remains largely unelucidated. In this work, we address one of these limitations, the lack of an updated and improved lncRNA annotation in P. falciparum. RESULTS: We generated long-read RNA sequencing data and integrated information extracted and curated from multiple sources to manually annotate lncRNAs. We identified 1119 novel lncRNAs and validated and refined 1250 existing annotations. Utilising the collated datasets, we generated evidence-based ranking scores for each annotation and characterised the distinct genomic contexts and features of P. falciparum lncRNAs. Certain features indicated subsets with potential biological significance such as 25 lncRNAs containing multiple introns, 335 lncRNAs lacking mutations in piggyBac mutagenic studies and lncRNAs associated with specific biologic processes including two new types of lncRNAs found proximal to var genes. CONCLUSIONS: The insights and the annotation presented in this study will serve as valuable tools for researchers seeking to understand the role of lncRNAs in parasite biology through both bioinformatics and experimental approaches.

Advancing Our Understanding of the Chronically Denervated Schwann Cell: A Potential Therapeutic Target?

Outcomes for patients following major peripheral nerve injury are extremely poor. Despite advanced microsurgical techniques, the recovery of function is limited by an inherently slow rate of axonal regeneration. In particular, a time-dependent deterioration in the ability of the distal stump to support axonal growth is a major determinant to the failure of reinnervation. Schwann cells (SC) are crucial in the orchestration of nerve regeneration; their plasticity permits the adoption of a repair phenotype following nerve injury. The repair SC modulates the initial immune response, directs myelin clearance, provides neurotrophic support and remodels the distal nerve. These functions are critical for regeneration; yet the repair phenotype is unstable in the setting of chronic denervation. This phenotypic instability accounts for the deteriorating regenerative support offered by the distal nerve stump. Over the past 10 years, our understanding of the cellular machinery behind this repair phenotype, in particular the role of c-Jun, has increased exponentially, creating opportunities for therapeutic intervention. This review will cover the activation of the repair phenotype in SC, the effects of chronic denervation on SC and current strategies to 'hack' these cellular pathways toward supporting more prolonged periods of neural regeneration.

Highly Variable Expression of Merozoite Surface Protein MSPDBL2 in Diverse Plasmodium falciparum Clinical Isolates and Transcriptome Scans for Correlating Genes.

The merozoite surface protein MSPDBL2 of Plasmodium falciparum is under strong balancing selection and is a target of naturally acquired antibodies. Remarkably, MSPDBL2 is expressed in only a minority of mature schizonts of any cultured parasite line, and mspdbl2 gene transcription increases in response to overexpression of the gametocyte development inducer GDV1, so it is important to understand its natural expression. Here, MSPDBL2 in mature schizonts was analyzed in the first ex vivo culture cycle of 96 clinical isolates from 4 populations with various levels of infection endemicity in different West African countries, by immunofluorescence microscopy with antibodies against a conserved region of the protein. In most isolates, less than 1% of mature schizonts were positive for MSPDBL2, but the frequency distribution was highly skewed, as nine isolates had more than 3% schizonts positive and one had 73% positive. To investigate whether the expression of other gene loci correlated with MSPDBL2 expression, whole-transcriptome sequencing was performed on schizont-enriched material from 17 of the isolates with a wide range of proportions of schizonts positive. Transcripts of particular genes were highly significantly positively correlated with MSPDBL2 positivity in schizonts as well as with mspdbl2 gene transcript levels, showing overrepresentation of genes implicated previously as involved in gametocytogenesis but not including the gametocytogenesis master regulator ap2-g. Single-cell transcriptome analysis of a laboratory-adapted clone showed that most individual parasites expressing mspdbl2 did not express ap2-g, consistent with MSPDBL2 marking a developmental subpopulation that is distinct but likely to co-occur alongside sexual commitment. IMPORTANCE These findings contribute to understanding malaria parasite antigenic and developmental variation, focusing on the merozoite surface protein encoded by the single locus under strongest balancing selection. Analyzing the initial ex vivo generation of parasites grown from a wide sample of clinical infections, we show a unique and highly skewed pattern of natural expression frequencies of MSPDBL2, distinct from that of any other antigen. Bulk transcriptome analysis of a range of clinical isolates showed significant overrepresentation of sexual development genes among those positively correlated with MSPDBL2 protein and mspdbl2 gene expression, indicating the MSPDBL2-positive subpopulation to be often coincident with parasites developing sexually in preparation for transmission. Single-cell transcriptome data confirm the absence of a direct correlation with the ap2-g master regulator of sexual development, indicating that the MSPDBL2-positive subpopulation has a separate function in asexual survival and replication under conditions that promote terminal sexual differentiation.

Characterising genome architectures using genome decomposition analysis.

Genome architecture describes how genes and other features are arranged in genomes. These arrangements reflect the evolutionary pressures on genomes and underlie biological processes such as chromosomal segregation and the regulation of gene expression. We present a new tool called Genome Decomposition Analysis (GDA) that characterises genome architectures and acts as an accessible approach for discovering hidden features of a genome assembly. With the imminent deluge of high-quality genome assemblies from projects such as the Darwin Tree of Life and the Earth BioGenome Project, GDA has been designed to facilitate their exploration and the discovery of novel genome biology. We highlight the effectiveness of our approach in characterising the genome architectures of single-celled eukaryotic parasites from the phylum Apicomplexa and show that it scales well to large genomes.

Transretroperitoneal Pedicled Omental Flap for Coverage of Traumatic Sacral Defect: A Case Report.

The greater omentum is a reliable choice for salvage soft-tissue reconstruction. Benefits include consistent anatomy, long pedicle length, and a high concentration of lymphatic tissue that is resistant to infection. We report the case of a 46-year-old man with a complex traumatic sacral wound resulting in severe limitation of reconstructive options. A pedicled greater omentum flap was transposed through the retroperitoneum via the lumbosacral triangle, resulting in durable soft-tissue coverage.