Efficacy, safety, and pharmacokinetics of capsid assembly modulator linvencorvir plus standard of care in chronic hepatitis B patients.

BACKGROUND/AIMS: Four-week treatment of linvencorvir (RO7049389) was generally safe and well tolerated, and showed anti-viral activity in chronic hepatitis B (CHB) patients. This study evaluated the efficacy, safety, and pharmacokinetics of 48-week treatment with linvencorvir plus standard of care (SoC) in CHB patients. METHODS: This was a multicentre, non-randomized, non-controlled, open-label phase 2 study enrolling three cohorts: nucleos(t)ide analogue (NUC)-suppressed patients received linvencorvir plus NUC (Cohort A, n=32); treatment-naïve patients received linvencorvir plus NUC without (Cohort B, n=10) or with (Cohort C, n=30) pegylated interferon-α (Peg-IFN-α). Treatment duration was 48 weeks, followed by NUC alone for 24 weeks. RESULTS: 68 patients completed the study. No patient achieved functional cure (sustained HBsAg loss and unquantifiable HBV DNA). By Week 48, 89% of treatment-naïve patients (10/10 Cohort B; 24/28 Cohort C) reached unquantifiable HBV DNA. Unquantifiable HBV RNA was achieved in 92% of patients with quantifiable baseline HBV RNA (14/15 Cohort A, 8/8 Cohort B, 22/25 Cohort C) at Week 48 along with partially sustained HBV RNA responses in treatment-naïve patients during follow-up period. Pronounced reductions in HBeAg and HBcrAg were observed in treatment-naïve patients, while HBsAg decline was only observed in Cohort C. Most adverse events were grade 1-2, and no linvencorvir-related serious adverse events were reported. CONCLUSION: 48-week linvencorvir plus SoC was generally safe and well tolerated, and resulted in potent HBV DNA and RNA suppression. However, 48-week linvencorvir plus NUC with or without Peg-IFN did not result in the achievement of functional cure in any patient.

First-in-human randomized study of RNAi therapeutic RG6346 for chronic hepatitis B virus infection.

BACKGROUND & AIMS: RG6346 is an N-acetyl-D-galactosamine (GalNAc)-conjugated, double-stranded RNA interference agent targeting the HBV genome S-region. We investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RG6346 in healthy volunteers and patients with chronic HBV infection (CHB). METHODS: This first-in-human, adaptive, randomized, double-blinded, phase I study recruited three groups of participants: Group A, 30 healthy volunteers received single-dose RG6346 at 0.1, 1.5, 3.0, 6.0, or 12.0 mg/kg, or placebo; Group B, nucleos(t)ide analogue-naïve participants with CHB received single-dose RG6346 at 3.0 mg/kg (n = 6) or placebo (n = 3); Group C, participants with nucleos(t)ide-suppressed CHB received four doses (every 28 days) of RG6346 at 1.5, 3.0, or 6.0 mg/kg (n = 4 in each cohort) or placebo (n = 6). RESULTS: RG6346 treatment for up to 4 months was safe and well tolerated. The most common adverse event was a mild injection site reaction. Several nucleos(t)ide-naïve participants exhibited self-resolving transaminase elevations with preserved liver function. By the end of RG6346 treatment in Group C (Day 112), the mean reduction from baseline in hepatitis B surface antigen (HBsAg) was 1.39, 1.80, and 1.64 log10 IU/ml in the 1.5, 3.0, and 6.0 mg/kg cohorts, respectively. Of the 12 participants in Group C, 11 (91.7%) achieved a ≥1 log10 IU/ml reduction in HBsAg (3 of 11 [27.3%] had the response sustained at conditional follow-up Day 448). No dose-response relationship was apparent between RG6346 and serum HBsAg levels. The RG6346-induced HBsAg response was independent of hepatitis B e antigen status. Moderate-to-marked sustained reductions of hepatitis B core-related antigen, HBV RNA, HBV DNA (in nucleos[t]ide analogue-naïve participants), and hepatitis B e antigen levels were observed. CONCLUSIONS: These favorable safety and pharmacodynamic data support the clinical development of RG6346 as the backbone of a finite antiviral treatment regimen, with the goal of sustained HBsAg loss (functional cure) in patients with CHB. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT03772249. IMPACT AND IMPLICATIONS: Currently available therapies for chronic HBV infection are associated with low rates of functional cure and new, more efficacious treatments are needed. This first-in-human study of RG6346, an RNA interference therapy, showed a favorable safety profile as well as marked and durable reductions in hepatitis B surface antigen levels. These results support the continued development of RG6346 as the backbone of a finite treatment regimen targeting high functional cure rates and are important for HBV researchers and physicians.

Effectiveness of Brachial Plexus Blocks in Obesity: Secondary Analysis of Randomized Controlled Trial.

BACKGROUND: Brachial plexus block for hand and upper extremity procedures in the obese presents a unique set of technical challenges. The authors examined how obesity affects procedural success, quality of anesthesia, and patient satisfaction. METHODS: Secondary analysis of a randomized control trial comparing the retroclavicular versus supraclavicular brachial plexus block for distal upper extremity surgery was conducted. Patients were randomized to supraclavicular or retroclavicular brachial plexus block groups in the original trial. In this study, the authors dichotomized patients by obesity to compare differences in outcomes. RESULTS: Sixteen of 117 patients (13.7%) were obese. The groups were statistically well balanced in terms of baseline and operative variables. Obese patients had increased imaging time 2.7 minutes (95% confidence interval [CI], 1.44-3.92) versus 1.9 minutes (95% CI, 1.64-2.16), P value = .05; needling time 6.6 minutes (95% CI, 5.17-7.95) versus 5.8 minutes (95% CI, 5.04-5.74), P = .02; and procedure time 9.3 minutes (95% CI, 7.04-11.46) versus 7.3 minutes (95% CI, 6.79-7.79), P = .01. Block success and complications were not statistically significant. The visual analog scores during the block, at 2 hours, and 24 hours after were not statistically different. Patient satisfaction score among obese patients was 9.1 (95% CI, 8.6-9.6) versus 9.2 (95% CI, 9.1-9.4), P = .63. CONCLUSION: Findings from this trial suggest that despite an increased procedural difficulty, the use of both supraclavicular and retroclavicular brachial plexus blocks is associated with comparable quality of anesthesia, similar complication profile, equal opioid requirements, and similar patient satisfaction in the obese.

Combination treatments including the small-interfering RNA JNJ-3989 induce rapid and sometimes prolonged viral responses in patients with CHB.

BACKGROUND & AIMS: RNA interference therapy has been shown to reduce hepatitis B surface antigen (HBsAg) levels in preclinical models, which could confer functional cure in patients with chronic hepatitis B. This phase IIa trial (ClinicalTrials.gov Identifier: NCT03365947) assessed the safety and efficacy of the small-interfering RNA JNJ-73763989 (JNJ-3989) plus a nucleos(t)ide analogue (NA), with/without the capsid assembly modulator JNJ-56136379 (JNJ-6379) in patients with chronic hepatitis B. METHODS: Treatment-naïve and NA-suppressed patients received 3 subcutaneous JNJ-3989 doses every week (QW; 100, 200, or 300 mg), 2 weeks (Q2W; 100 mg) or 4 weeks (Q4W; 25, 50, 100, 200, 300, or 400 mg), or JNJ-3989 Q4W (200 mg) plus oral JNJ-6379 250 mg daily for 12 weeks. Patients received NAs throughout. RESULTS: Eighty-four patients were recruited. All treatments were well tolerated, with all 5 serious adverse events considered unrelated to study drugs. JNJ-3989 100 to 400 mg Q4W resulted in HBsAg reductions ≥1 log10 IU/ml from baseline in 39/40 (97.5%) patients at the nadir. All patients receiving the triple combination (n = 12) had HBsAg reductions ≥1 log10 IU/ml from baseline at the nadir. HBsAg reductions were similar for HBeAg-positive (n = 21) and HBeAg-negative (n = 47) patients in all JNJ-3989 Q4W treatment arms, including the triple combination (n = 68). Smaller HBsAg reductions were seen with 25 mg (n = 8) and 50 mg (n = 8) than with 100 to 400 mg (n = 40). Shorter dosing intervals (QW [n = 12] and Q2W [n = 4]) did not improve response vs. Q4W dosing. HBsAg reductions ≥1 log10 IU/ml from baseline persisted in 38% of patients 336 days after the last JNJ-3989 dose. CONCLUSIONS: JNJ-3989 plus an NA, with/without JNJ-6379, was well tolerated and resulted in HBsAg reductions up to 336 days after the last JNJ-3989 Q4W dose. CLINICAL TRIAL NUMBER: NCT03365947. LAY SUMMARY: Hepatitis B virus affects people's livers and produces particles called hepatitis B surface antigen (HBsAg) that damage a person's liver and can help the virus infect a person for a long time, known as chronic hepatitis B (CHB). In this study, a new treatment called JNJ-3989 was assessed (in combination with normal treatment known as nucleos(t)ide analogues), for its safety and effectiveness in reducing the number of HBsAg particles in people with CHB. The results of this study showed that treatment with JNJ-3989 could be safe for people with CHB, lowered their HBsAg levels, and kept HBsAg levels lowered for 336 days in 38% of patients after receiving their last dose of JNJ-3989.

Plasma and breast milk pharmacokinetics of tenofovir alafenamide in mothers with chronic hepatitis B infection.

BACKGROUND: Antenatal antiviral therapy (AVT) is effective in preventing mother-to-child transmission (MTCT) in chronic hepatitis B (CHB); tenofovir disoproxil fumarate (TDF) is the preferred agent. Tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) similar to TDF, with improved bone and renal safety. There are no data on TAF breast milk pharmacokinetics and exposure to breastfeeding infants in CHB. AIM: To assess the pharmacokinetics of TAF/TFV in breastfeeding women with CHB on TAF monotherapy. METHODS: Pregnant women with CHB requiring AVT commenced TAF 25 mg daily at third trimester or postpartum. Sample collection occurred while breastfeeding and taking TAF for minimum 4 weeks. Maternal blood, breast milk and infant urine samples were collected. Drug concentrations were measured by LCMS/MS analyses using validated methods. Non-compartmental analyses were performed to quantify the pharmacokinetic parameters. RESULTS: Eight women provided samples. In breast milk and plasma, median TAF half-life was 0.81 and 0.94 h, respectively, and Cmax 1.69 and 120.5 ng/ml, respectively. Median maternal breast milk to plasma (M/P) ratio of TAF was 0.029; for and TFV it was 2.809. The relative infant dose of TAF was 0.005% of maternal dose, well below safety threshold of 5-10%. TFV was detectable in three out of seven infant urine samples with median steady-state concentration of 5 ng/ml being 300-2500 times less than reported adult steady-state urine concentrations in those taking TAF and TDF, respectively. CONCLUSIONS: In this first pharmacokinetic study of TAF monotherapy in breastfeeding women with CHB, concentrations of TAF and TFV were low in breast milk with negligible infant exposure, supporting the use of TAF to prevent MTCT.

Therapeutic vaccine BRII-179 restores HBV-specific immune responses in patients with chronic HBV in a phase Ib/IIa study.

BACKGROUND & AIMS: Functional cure of chronic HBV infection (CHB) without life-long treatment requires the restoration of defective HBV-specific humoral and cellular immunity. Therapeutic vaccines based on the major structural and non-structural proteins have been tested in patients with CHB but have shown scarce immunogenicity. BRII-179, also known as VBI-2601, is a novel formulation comprised of all 3 HBV surface envelope proteins (Pre-S1, Pre-S2, and S). Safety, antiviral activity, and immunogenicity of BRII-179 admixed with co-adjuvant interferon (IFN)-α were assessed in patients with CHB. METHOD: This randomized, open-label, controlled phase Ib/IIa study included 2 dose levels, 20 µg BRII-179 (Part 1, n = 25) and 40 µg BRII-179 (Part 2, n = 24). Patients, virally suppressed under nucleos(t)ide analogue (NA) therapy were randomized 1:2:2 into 3 cohorts in Part 1 and 1:1 into 2 cohorts in Part 2 to receive 4 monthly intramuscular injections of BRII-179 admixed with/without 3 MIU IFN-α. Antibody and cellular responses to HBsAg, as well as evolution of circulating HBsAg were monitored. RESULTS: Both 20 µg and 40 µg BRII-179 with/without IFN-α were well tolerated with no severe adverse events. BRII-179 induced anti-HBs responses in >30% patients in all treatment cohorts, however, moderate anti-Pre-S1 or anti-Pre-S2 antibody responses were only observed in patients receiving BRII-179 with IFN-α. BRII-179 also restored S-, Pre-S1-, Pre-S2-specific IFN-γ-producing T-cells in the majority of treated patients. Overall, no notable reduction of HBsAg was observed after BRII-179 treatment. CONCLUSION: In patients with CHB under NA therapy, BRII-179 with/without IFN-α exhibited a good safety profile and induced HBV-specific B- and T-cell immune responses. These data support further clinical evaluation of BRII-179 in combination with other therapies. CLINICAL TRIAL NUMBER: ACTRN12619001210167. LAY SUMMARY: BRII-179 is a therapeutic vaccine designed to improve the immune response in patients with chronic hepatitis B. In this study, BRII-179 alone or with a low dose of interferon-α was safe, well tolerated, and induced enhanced HBV-specific antibody and T-cell responses in patients with chronic hepatitis B. However, BRII-179 treatment alone had minimal effect on patient's virological status. The potential of BRII-179 to achieve a functional cure in conjunction with other agents is being evaluated in the clinic.

Avascular necrosis of the lunate secondary to perilunate fracture dislocation: Case report and review of the literature.

This is a 39-year-old male, fell from a bike, left wrist with trans-styloid perilunate fracture dislocation that underwent open reduction internal fixation, 20 months after surgery the patient developed avascular necrosis of the lunate, final wrist fusion was performed secondary to the arthritic changes on the wrist. Anatomic dissection was performed and vascularity of the lunate was identified, its origin is from the volar palmar arch, when dislocated palmarly and more than 90 degrees the vessel is still intact. More than 512 patients with perilunate dislocation and perilunate fracture dislocation are included we identified in the literature transient avascular necrosis of the lunate in nine and seventeen of pure avascular necrosis of the lunate. Concluding that avascular necrosis of the lunate after perilunate dislocation or perilunate fracture dislocation is an infrequent finding especially when the volar ligaments are intact.

Clinical Study of Single-Stranded Oligonucleotide RO7062931 in Healthy Volunteers and Patients With Chronic Hepatitis B.

BACKGROUND AND AIMS: RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded locked nucleic acid oligonucleotide complementary to HBV RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This two-part phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO7062931 in healthy volunteers and patients with chronic hepatitis B (CHB) who were virologically suppressed. APPROACH AND RESULTS: Part 1 was a single ascending dose study in healthy volunteers randomized to receive a single RO7062931 dose (0.1-4.0 mg/kg), or placebo. Part 2 was a multiple ascending dose study in patients with CHB randomized to receive RO7062931 at 0.5, 1.5, or 3.0 mg/kg or placebo every month for a total of 2 doses (Part 2a) or RO7062931 at 3.0 mg/kg every 2 weeks, 3.0 mg/kg every week (QW), or 4.0 mg/kg QW or placebo for a total of 3-5 doses (Part 2b). Sixty healthy volunteers and 59 patients received RO7062931 or placebo. The majority of adverse events (AEs) reported were mild in intensity. Common AEs included self-limiting injection site reactions and influenza-like illness. Supradose-proportional increases in RO7062931 plasma exposure and urinary excretion occurred at doses ≥3.0 mg/kg. In patients with CHB, RO7062931 resulted in dose-dependent and time-dependent reduction in HBsAg versus placebo. The greatest HBsAg declines from baseline were achieved with the 3.0 mg/kg QW dose regimen (mean nadir ~0.5 log10  IU/mL) independent of HBeAg status. CONCLUSIONS: RO7062931 is safe and well tolerated at doses up to 4.0 mg/kg QW. Supradose-proportional exposure at doses of 3.0-4.0 mg/kg was indicative of partial saturation of the ASGPR-mediated liver uptake system. Dose-dependent declines in HBsAg demonstrated target engagement with RO7062931.

Bilateral bipartite lunate misdiagnosed as carpal fracture: a case report and brief review of literature.

Bilateral bipartite lunate is a very rare congenital anomaly of the lunate. A 36-year-old military European male was referred to our service diagnosed with a lunate fracture. Symptoms began 3 months before our encounter, after falling on his outstretched left hand. The patient was misdiagnosed with a lunate fracture, therefore treated with a cast and then transitioned to a removable splint over 2 months in total; When the patient presented to our facility, on physical examination, he referred pain over the dorso-ulnar side of the wrist, especially the ulnar snuff. Tenderness to palpation over the fovea and positive triangular fibrocartilage complex axial compression test was encountered. Bilateral wrist X-rays were taken, and a diagnosis of bilateral bipartite lunate was made by our team. The patient was treated for ulnar-sided wrist pain with steroid injection and physical rehabilitation. A literature review on bipartite lunate was conducted, and cases share three basic common features: unilateral involvement, incidentally diagnosed after a traumatic event, and absence of positive clinical findings related to the bipartition.

Current Status of Vascularized Composite Allotransplantation.

The field of vascularized composite allotransplantation (VCA) has moved from a highly experimental procedure to, at least for some patients, one of the best treatment alternatives for catastrophic tissue loss or dysfunction. Although the worldwide experience is still limited, progress has been made in translation to the clinic, and hand transplantation was recently designated standard of care and is now covered in full by the British Health System. This progress is tempered by the long-term challenges of systemic immunosuppression, and the rapidly evolving indications for VCA such as urogenital transplantation. This update will cover the state of and recent changes in the field, and an update of the Louisville VCA program as our initial recipient, the first person to receive a hand transplant in the United States celebrates the 20th anniversary of his transplant. The achievements and complications encountered over the last two decades will be reviewed. In addition, potential directions for research and collaboration as well as practical issues of how third party payers and funding are affecting growth of the field are presented.

The role of B cell immunity in VCA graft rejection and acceptance.

Vascularized composite allotransplantation (VCA) has emerged as the most recent field of transplantation to offer an alternative treatment for those patients that have failed or are not suitable candidates for conventional therapy. Most of the current clinical experience in this field is with recipients of skin containing grafts such as the face, upper extremity and abdominal wall transplants. Like solid organ recipients, VCA recipients require lifelong systematic immunosuppression to maintain their grafts. To date, the most successful immunosuppressant regimens are calcineurin inhibitor based and have been targeted to the control of T cells. While these regimens have resulted in excellent short term graft survival in solid organ transplantation, achieving significant improvements in long term survival has been more challenging. The reasons are multi-factorial, but a role for B cells and humoral immunity has been proposed. Antibody mediated rejection leading to chronic rejection has been cited as the leading cause of renal graft loss. While the number of VCA transplants performed is still small, evidence to date suggests that antibody mediated rejection may occur less frequently than seen in solid organ transplants. Here we will discuss the role of B cell immunity in solid organ transplantation as it pertains and contrasts to the field of VCA and present some examples of possible sequela of B cell immunity in a series of hand transplant recipients.

Location and Extent of A1, A2 Release and Its Impact on Tendon Subluxation and Bowstringing-A Cadaveric Study.

Surgical treatment of trigger finger involves release of A1 pulley. Some authors have theorized that the loss of A1 pulley can lead to ulnar subluxation of flexor tendons, which can be prevented by release of A1 pulley radially, even in a nonrheumatoid hand. However, there is no evidence in literature to either support or oppose this hypothesis. Occasionally, difficulty is encountered to precisely identify where A1 ends and A2 begins. While incomplete release of A1 can cause relapse of triggering, release of substantial A2 can cause bowstringing. Knowledge of the safe limit of concomitant A2 release is beneficial. The study was conducted in 12 cadaver upper extremity specimens. A1 pulleys of 48 fingers were divided at the radial (24 fingers) or ulnar (24 fingers) attachment. A 20lb traction force was applied on the flexor tendons. Any subluxation or bowstringing was noted. The experiment was repeated following serial release of the A2-initially 25%, followed by 50% and 100%. No bowstringing or subluxation was noted when A1 pulley was opened, either by radial or ulnar incision. The same was true for A1 + 25% A2 release. When A1 + 50% A2 pulley were released, bowstringing was observed in 3/48 fingers. When A1 + 100% of the A2 pulley were released, bowstringing occurred in all cases. The location of incision for release of the A1 pulley has no effect on bowstringing or tendon subluxation. Release of additional 25% of the A2 pulley can be performed safely, which corresponds to the level of palmar digital crease.

Prognosis of Traumatic Ulnar Nerve Injuries: A Systematic Review.

Ulnar nerve injury (UNI) is not uncommon and often results in incomplete motor recovery after the initial nerve repair and requires secondary functional reconstruction. To clarify the prognosis and predicting factor of UNI, and if it is reasonable to wait after the initial repair, a systematic literature review from PubMed computerized literature database and Google scholar was performed. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist and guidelines were followed to develop the search protocol for this literature review. Two reviewers independently assessed titles, abstracts, and full-text articles, and a third reviewer resolved any disagreements. Seventeen articles with 260 cases were found with sufficient data and enough follow-up. After multiple logistic regression, age, injury level, gap of lesion, and delayed time to surgery were significant prognostic factors in UNI. If considering only high-level injuries (injury at or above proximal forearm), age became the only predicting factor. In cases with likely poor prognosis, their motor recovery tends to be unsatisfactory, and observation for months after the initial repair might not be reasonable. Other surgical interventions such as early nerve transfer may be an option to improve the outcome.

HBsAg loss in a New Zealand community study with 28-year follow-up: rates, predictors and long-term outcomes.

BACKGROUND AND AIMS: HBsAg seroclearance is the most desired endpoint in chronic hepatitis B (CHB) but occurs uncommonly. Recent studies have shown baseline HBsAg levels to be predictive of HBsAg loss up to 10 years. We report the 28-year rates of HBsAg loss and outcomes in the Kawerau study cohort from New Zealand, and assess the predictive value of baseline HBsAg levels to predict long-term HBsAg loss. METHODS: The 1984 Kawerau community study identified 572 CHB patients, followed up for 28 years (41 % HBeAg-positive, median age 17 years, range 1-71 years). In 2012, surviving individuals attended a local clinic for an interview, blood tests and transient elastography. RESULTS: 384/218 (74 %) surviving individuals attended the clinic in 2012. Spontaneous HBsAg loss occurred in 145 (33 %) after 12,702 person-years of follow-up (1.14 per 100 person-years). Liver stiffness measurements were significantly lower if HBsAg loss occurred <50 years (mean 6.1 kPa) versus >50 years (mean 11.6 kPa), p = 0.0002. No HCC occurred following HBsAg loss (median follow-up 72 months). Predictors of HBsAg loss were older age and lower baseline HBsAg level (HR for HBsAg loss at 28 years 2.7 (95 % CI 1.7-4.2), 6.7 (95 % CI 3.9-11.4) and 9.4 (95 % CI 5.2-16.9), respectively, for HBsAg 1000-9999, 100-999 and <100 IU/mL compared to HBsAg >10,000 IU/mL at baseline, (p < 0.0001). Baseline HBsAg was a superior predictor of HBsAg loss compared to HBV DNA at all time-points: AUROC at 15 years: 0.87 (95 % CI 0.82-0.93) versus 0.73 (95 % CI 0.66-0.80) (p < 0.0001) and AUROC at 28 years: 0.74 (95 % CI 0.69-0.79) versus 0.67 (95 % CI 0.62-0.72) (p = 0.0007). The optimal cut-off HBsAg level to predict HBsAg seroclearance at 28 years is HBsAg <10,000 IU/mL (sensitivity 72 %, specificity 64 %, NPV 88 %). CONCLUSIONS: Rates of HBsAg loss in our community cohort were high, and occurred earlier than previously reported. Earlier HBsAg loss was associated with less severe liver fibrosis. Baseline HBsAg level was a good predictor of long-term HBsAg loss up to 28 years and superior to HBV DNA.

Immunobiology in VCA.

Transplantation of vascularized composite tissue is a relatively new field that is an amalgamation of experience in solid organ transplantation and reconstructive plastic and orthopedic surgery. What is novel about the immunobiology of VCA is the addition of tissues with unique immunologic characteristics such as skin and vascularized bone, and the nature of VCA grafts, with direct exposure to the environment, and external forces of trauma. VCAs are distinguished from solid organ transplants by the requirement of rigorous physical therapy for optimal outcomes and the fact that these procedures are not lifesaving in most cases. In this review, we will discuss the immunobiology of these systems and how the interplay can result in pathology unique to VCA as well as provide potential targets for therapy.

Endoscopic Therapy for Treatment of Staple Line Leaks Post-Laparoscopic Sleeve Gastrectomy (LSG): Experience from a Large Bariatric Surgery Centre in New Zealand.

BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is one of the most commonly performed bariatric procedures for treatment of morbid obesity. Despite its popularity, it is not without risks, the most serious of which is the staple line leak. Staple line leaks are difficult to manage and require significant resources in the form of surgical, radiological and endoscopic interventions; long hospital and intensive care stay and significant morbidity. International experience is slowly emerging, but there are still no clear guidelines regarding optimal management of leaks. This study aims to describe the experience of endoscopic management of these leaks by the authors and the development of a customised stent for this condition. METHODS: Middlemore Hospital is the largest bariatric surgery centre in New Zealand. Since June 2007, a total of 21 patients have received endotherapy for post-LSG leak management. Treatment included the deployment of primary self-expanding metal stents (SEMS) across the leak site, combined with complementary endoscopic modalities. Persistent leaks were treated with follow-up stenting. This study aimed to evaluate the effectiveness of post-LSG staple line leak management at Middlemore Hospital. RESULTS: A total of 20/21 (95 %) patients now have resolved leaks following a mean of 75 days of treatment (median 47, range 9-187). The mean number of endoscopic procedures required was five. Inpatient stay and average duration till leak resolution has been notably reduced since the addition of customised stents. Clinically significant stent migration occurred in 19 % of primary stents. CONCLUSION: The use of SEMS in conjunction with complementary endotherapy has shown to be both safe and effective in treating sleeve leaks; however, migration is the limiting factor for optimal management. Recent improvements in stent design, such as the one proposed in this paper, show promise in addressing this problem. Earlier use of SEMS seems to reduce the time till closure as well as the total hospital stay, as is apparent from our data.

Comparison between Collagenase Injection and Partial Fasciectomy in the Treatment of Dupuytren's Contracture.

BACKGROUND: A comparative study between two treatment methods (collagenase injection and open partial fasciectomy) for Dupuytren's contracture. This study will determine differences in clinical outcome, complication rate and patient satisfaction. METHODS: 37 patients with 62 metacarpophalangeal joints (MCP) and 44 proximal interphalangeal joints (PIP) treated. There were 21 MCP joints (34%) and 8 PIP joints (18%) treated with injection. The remaining 66% of MCP joints and 82% of PIP joints were treated by open partial fasciectomy. RESULTS: Overall, both treatment methods were successful in correcting the passive extension deficit in the MCP and PIP joints. Minor complications were reported in 45% of patients in the injection group versus 42% in the surgery group. Patient satisfaction was nearly equal for both groups. CONCLUSIONS: Both treatment options have proven their effectiveness in treating Dupuytren's contracture. Open surgery is able to address additional joint contracture problems commonly associated with Dupuytren's disease. Collagenase injection has the advantage of early return of hand function and avoidance of surgical complications.

Anatomical study of anterior supramalleolar artery and its potential application to design a bi-foliate fasciocutaneous flap.

PURPOSE: A further understanding of the anterior supramalleolar artery (ASMA) and its potential applications in reconstructive surgery. MATERIALS AND METHODS: A total of 24 fresh lower limbs from fresh cadavers were injected with red latex for dissection. The type of origin, course, diameter of the pedicle, and the distance between the origin of the ASMA from the anterior tibial artery to the extensor retinaculum (O-R) were recorded. Bi-foliate fasciocutaneous flaps were harvested using the branches of the ASMA. RESULTS: We found four types of origin of the ASMA, and we have accordingly classified them into four types. 10 of them were type A, 7 were type B, 6 were type C and 1 was type D. The mean O-R (origin of ASMA to retinaculum) distance was 2.0 ± 0.8 cm. The diameter of the medial branch (D1), the diameter of the lateral branch (D2), and the diameter of artery stem (D3) (only in type A) were 1.0 ± 0.2 mm, 0.8 ± 0.3 mm, 1.1 ± 0.2 mm, respectively. The mean pedicle length of the lateral flap (L1) and medial flap (L2) were 5.1 ± 1.0 cm and 3.7 ± 0.6 cm, respectively. CONCLUSIONS: The ASMA exists constantly with four different types of origin. Its sizable diameter and lengthy pedicle make it suitable for bi-foliate fasciocutaneous flap transfer.

Step by step: microsurgical training method combining two nonliving animal models.

The learning of microsurgical techniques and the maintenance of microsurgical skills have been traditionally based on the use of living animals, mainly laboratory rats. This method although extremely valuable can be economically demanding both for the surgeon and the sponsoring institution; it also requires special training facilities that may not always be available or accessible. Furthermore ethical concerns can limit the use of living animals for training purposes. Alternative training methods, such as inert tubes and gloves have not gained popularity among surgeons since they do not offer an experience similar to that of a clinical situation. Non-living animal models include the use of chicken thighs and wings; they offer a practice experience that resembles a clinical situation to a considerable extent. This type of training is relatively cheap and easily available. The microscope and instruments required can be acquired over the internet, and the chicken pieces can be bought at the local supermarket. This approach allows a motivated trainee to rehearse different types of surgical techniques several times at a reasonable expense, helping to develop or maintain his surgical expertise if more complex facilities are not available. On the current manuscript we describe how to setup a small practice station, how to dissect the specimens, and how to practice both with the chicken thighs and with the chicken wings in a progressive fashion. This approach takes advantage on the versatility of the chicken thigh model and the small size of the chicken wing Brachial artery.

Serological and clinical outcomes of horizontally transmitted chronic hepatitis B infection in New Zealand Maori: results from a 28-year follow-up study.

BACKGROUND: Chronic hepatitis B infection is endemic in New Zealand and has high prevalence in New Zealand Maori. Previous longitudinal studies in populations with predominantly vertically acquired chronic hepatitis B have shown low spontaneous hepatitis B surface-antigen (HBsAg) seroclearance rates: 0.5-1.4% annually (mean age of clearance 48 years). We report the 28-year follow-up data on clinical and serological outcomes in indigenous New Zealand Maori with early horizontally acquired HBV. METHODS: In 1984, community seroprevalence study identified 572 HBsAg-positive individuals, followed for 28 years. Liver-related mortality and hepatocellular carcinoma (HCC) incidence were compared between these 572 HBV carriers and 1140 HBsAg-negative matched case-controls. Surviving HBsAg-positive individuals have been followed up in 2012 with clinical assessment, blood tests and liver transient elastography. Rates of hepatitis B e-antigen (HBeAg) and HBsAg seroconversion were determined. RESULTS: After total 13 187.4 person-years follow-up, 15 HBsAg-positive patients have developed HCC compared with none of the HBsAg-negative controls (p<0.001). 12 HBsAg-positive patients died from liver-related causes compared with none in the controls (p<0.001). Spontaneous HBeAg-seroconversion occurred in 91% of HBeAg-positive patients. Spontaneous HBsAg loss occurred in 33% overall (annual clearance rate 1.34%), with higher rates at older ages (1.05% in patients<20 years at entry vs 4.3% per annum >40 years at entry, p<0.0001). Median ages of HBeAg loss and HBsAg loss were 23 years (range 6-66 years) and 40 years (range 4-80 years), respectively. CONCLUSIONS: Horizontally transmitted HBV in Maori is similarly associated with increased risk of liver-related mortality and HCC compared with Chinese, although absolute incidence rates are lower. The rates of HBeAg and HBsAg loss are high, and occur at an earlier age than previously reported.