Eight-year efficacy and safety of tenofovir alafenamide for treatment of chronic hepatitis B virus infection: Final results from two randomised phase 3 trials.

BACKGROUND: In two phase 3 studies, tenofovir alafenamide (TAF) showed non-inferior efficacy versus tenofovir disoproxil fumarate (TDF), with more favourable renal and bone safety in patients with chronic hepatitis B (CHB). AIMS: Here, we report the studies' final 8-year results. METHODS: CHB patients (hepatitis B e antigen [HBeAg]-negative and HBeAg-positive) were randomised (2:1) to double-blind TAF 25 mg/day or TDF 300 mg/day for up to 3 years, followed by open-label (OL) TAF through year 8. Virological, biochemical, serological and fibrosis responses, and safety, including bone and renal parameters, were evaluated. Resistance to TAF was assessed annually by deep sequencing of polymerase/reverse transcriptase and by phenotyping. RESULTS: Among 1298 patients randomised to double-blind TAF (n = 866) or double-blind TDF (n = 432), 775 in the TAF group and 382 in the TDF group received OL TAF, including 180 and 202 who switched from TDF to TAF at year 2 (TDF2y → TAF6y) or year 3 (TDF3y → TAF5y), respectively. At year 8, among patients in the TAF8y, TDF2y → TAF6y and TDF3y → TAF5y groups, 69%, 66% and 73% (missing-equals-failure analysis) and 95%, 94% and 97% (missing-equals-excluded) of patients, respectively, achieved HBV DNA <29 IU/mL. Estimated glomerular filtration rate (Cockcroft-Gault method; eGFRCG) and hip/spine bone mineral density (BMD) remained stable in patients receiving double-blind/OL TAF, with only small declines at year 8. Decreases in eGFRCG and hip/spine BMD observed during double-blind TDF improved after switching to OL TAF. No patients developed resistance to TAF. CONCLUSION: Long-term TAF treatment exhibited favourable safety and tolerability with high rates of viral suppression and no development of resistance. CLINICALTRIALS: gov numbers NCT01940341 and NCT01940471.

Re-188 lipiodol in hepatocellular carcinoma with portal vein thrombosis: a pilot study using novel chelating agent N-DEDC and its comparison with (A)HDD.

OBJECTIVE: Hepatocellular carcinoma (HCC) with portal vein thrombosis (PVT) have limited therapeutic options, Re-188 lipiodol transarterial therapy being one of them. We aimed to assess the safety and efficacy of Re-188 lipiodol exclusively in HCC with PVT as well as to compare two chelating agents for the synthesis of Re-188 lipiodol: novel bis-(diethyldithiocarbamato) nitrido (N-DEDC) with existing acetylated 4-hexadecyl 1-2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol [(A)HDD]. METHODS: Patients with radiological diagnosis of HCC with PVT having Eastern Cooperative Oncology Group (ECOG) performance status ≤2 and Child Pugh score (PS) A or B were recruited. Patients received an empirical dose of transarterial Re-188 lipiodol, labelled with (A)HDD or N-DEDC. Radiological response on MRI (modified response evaluation criteria in solid tumors), biochemical response with serum alpha fetoprotein and clinical response with ECOG PS was assessed at three months and survival was estimated at the end of the study. RESULTS: Fifteen therapies were performed in 14 patients with a median age of 62 years (range: 41-70 years). Eight therapies were with Re-188 (A)HDD lipiodol and seven with Re-188 N-DEDC lipiodol. Overall mean injected dose was 2.6 ±â€…0.37 GBq. Radiological objective response rate was 31% and disease control rate was 85%. Mean overall survival was 14.21 months and mean progression free survival was 10.23 months. Percentage survival assessed at 3, 6 and 9 months was 93%, 64% and 57%, respectively. Safety parameters, response and survival outcome were comparable for (A)HDD and N-DEDC groups. CONCLUSION: Transarterial Re-188 lipiodol in HCC with PVT is safe and effective in disease control as well as improving survival outcome. Additionally, cost-effective and high-yielding novel agent N-DEDC appears to be a comparable alternative to (A)HDD for the same.

Educating Future Generations of Surgeons across Borders: Novel Global Linked Hybrid Live Cadaveric Peripheral Nerve Surgical Training Course.

Background: This study aimed to evaluate a novel, multi-site, technology-facilitated education and training course in peripheral nerve surgery. The program was developed to address the training gaps in this specialized field by integrating a structured curriculum, high-fidelity cadaveric dissection, and surgical simulation with real-time expert guidance. Methods: A collaboration between the Global Nerve Foundation and Esser Masterclass facilitated the program, which was conducted across three international sites. The curriculum was developed by a panel of experienced peripheral nerve surgeons and included both text-based and multimedia resources. Participants' knowledge and skills were assessed using pre- and postcourse questionnaires. Results: A total of 73 participants from 26 countries enrolled and consented for data usage for research purposes. The professional background was diverse, including hand surgeons, plastic surgeons, orthopedic surgeons, and neurosurgeons. Participants reported significant improvements in knowledge and skills across all covered topics (p < 0.001). The course received a 100% recommendation rate, and 88% confirmed that it met their educational objectives. Conclusions: This study underscores the potential of technology-enabled, collaborative expert-led training programs in overcoming geographical and logistical barriers, setting a new standard for globally accessible, high-quality surgical training. It highlights the practical and logistical challenges of multi-site training, such as time zone differences and participant fatigue. It also provides practical insights for future medical educational endeavors, particularly those that aim to be comprehensive, international, and technologically facilitated.

Long-term Treatment With Tenofovir Alafenamide for Chronic Hepatitis B Results in High Rates of Viral Suppression and Favorable Renal and Bone Safety.

OBJECTIVES: Results from two Phase 3 studies, through 2 years, in chronic hepatitis B infection (CHB) showed tenofovir alafenamide (TAF) had similar efficacy to tenofovir disoproxil fumarate (TDF) with superior renal and bone safety. Here, we report updated results through 5 years. METHODS: Patients with HBeAg-negative or -positive CHB with or without compensated cirrhosis were randomized (2:1) to TAF 25 mg or TDF 300 mg once daily in double-blind (DB) fashion for up to 3 years, followed by open-label (OL) TAF up to 8 years. Efficacy (antiviral, biochemical, serologic), resistance (deep sequencing of polymerase/reverse transcriptase and phenotyping), and safety, including renal and bone parameters, were evaluated by pooled analyses. RESULTS: Of 1298 randomized and treated patients, 866 receiving TAF (DB and OL) and 432 receiving TDF with rollover to OL TAF at year 2 (n = 180; TDF→TAF3y) or year 3 (n = 202; TDF→TAF2y) were included. Fifty (4%) TDF patients who discontinued during DB were excluded. At year 5, 85%, 83%, and 90% achieved HBV DNA < 29 IU/mL (missing = failure) in the TAF, TDF→TAF3y, and TDF→TAF2y groups, respectively; no patient developed TAF or TDF resistance. Median eGFR (by Cockcroft-Gault) declined < 2.5 mL/min, and mean declines of < 1% in hip and spine bone mineral density were seen at year 5 in the TAF group; patients in the TDF→TAF groups had improvements in these parameters at year 5 after switching to OL TAF. CONCLUSIONS: Long-term TAF treatment resulted in high rates of viral suppression, no resistance, and favorable renal and bone safety.

Lacertus Syndrome: an Outcome Analysis After Lacertus Release.

Purpose: The lacertus fibrosus or bicipital aponeurosis is a sheet of ligamentous tissue just distal to the elbow joint and can be a compression point for the median nerve. Essentially, lacertus syndrome is a subset of pronator syndrome and an uncommon diagnosis by itself. Surgical release of the lacertus consists of a small 2-cm incision that can be performed under local anesthesia. This study aimed to evaluate the outcome of lacertus release in resolving median nerve symptoms. Methods: This retrospective study was performed at Prince Court Medical Centre, Kuala Lumpur, Malaysia, from January 2020 until June 2021. Ninety-three patients who presented with numbness of fingers, hand, or upper limb; forearm pain; and muscle weakness. They were diagnosed with lacertus syndrome on the basis of local tenderness at the lacertus fibrosus with either weakness of flexor pollicis longus and flexor digitorum profundus of the index finger or paresthesia over the thenar eminence. The patients underwent 3 months of hand therapy, and those with no symptom improvement were offered lacertus release performed by a single surgeon. The surgical technique consists of a surgical incision starting from a point 2 cm distally and 2 cm radially to the medial epicondyle. The incision projects 2 cm distally in an oblique fashion toward the radial styloid. A wide-awake local anesthesia no tourniquet (WALANT) technqiue was utilized and 20 mL of local anesthesic was injected subcutaneously around this region at least 20 minutes before the surgery. Careful dissection was made subcutaneously, and the lacertus fibrosus was identified as a thickened, shiny white structure and released. The Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score, grip strength, and pinch strength were tested before and after surgery. At 6 months after surgery, the QuickDASH score was again assessed with a WALANT satisfactory questionnaire. Results: A total of 93 patients were included in the study. The mean age of the patients was 38.7 years, and most were women (77.4%). The mean operating time was 70 minutes. The mean preoperative QuickDASH score was 53, which significantly reduced immediately after surgery to 7.8 (P < .001) and remained low at 6 months after surgery (10.6). The mean grip strength showed a significant increase from a preoperative mean of 16 kg to a postoperative mean of 24 kg (P < .001). Pinch strength also significantly increased from a preoperative mean of 9 kg to 13 kg after surgery (P < .001). Conclusions: Lacertus syndrome remains an underdiagnosed disease that can be treated efficiently with a directed minimal surgical incision under wide-awake local anesthesia. Lacertus release appears to significantly reduce pain and numbness with markedly improved hand grip and pinch strength. The corresponding QuickDASH scores also improved significantly after surgery. This study is vital to our understanding of proximal median nerve entrapment and to accurately diagnose it. Type of study/level of evidence: Therapeutic III.

A Prospective Study Comparing the Infection Rate Between Buried vs Exposed Kirschner Wires in Hand and Wrist Fixations.

INTRODUCTION: Kirschner wires (K-wires) are used in fracture fixations but are often associated with pin tract infections. This prospective study compared the infection rate between buried and exposed K-wires in closed injuries of the wrist and hands in individuals with no comorbidities. METHODS: Fifteen patients were recruited with a total of 41 K-wires (21 buried K-wires; 20 exposed K-wires). Clinical and radiographic evidence of infection was assessed at three months based on the Modified Oppenheim classification. RESULTS: Two out of 21 wires in the buried group developed grade 4 infection, while 20 wires in the exposed group did not have any significant infection. No significant difference in infection rate based on K-wire size or number in both groups. CONCLUSION: There is no significant difference in infection rate between buried and exposed K-wires in healthy individuals with closed injuries of the wrist and hand.

Increased Longevity of a Novel Gas Exchanger System for Low-Flow Veno-Venous Extracorporeal CO2 Removal in Acute Hypercapnic Respiratory Failure.

INTRODUCTION: Low-flow veno-venous extracorporeal CO2 removal (ECCO2R) is an adjunctive therapy to support lung protective ventilation or maintain spontaneous breathing in hypercapnic respiratory failure. Low-flow ECCO2R is less invasive compared to higher flow systems, while potentially compromising efficiency and membrane lifetime. To counteract this shortcoming, a high-longevity system has recently been developed. Our hypotheses were that the novel membrane system provides runtimes up to 120 h, and CO2 removal remains constant throughout membrane system lifetime. METHODS: Seventy patients with pH ≤ 7.25 and/or PaCO2 ≥9 kPa exceeding lung protective ventilation limits, or experiencing respiratory exhaustion during spontaneous breathing, were treated with the high-longevity ProLUNG system or in a control group using the original gas exchanger. Treatment parameters, gas exchanger runtime, and sweep-gas VCO2 were recorded across 9,806 treatment-hours and retrospectively analyzed. RESULTS: 25/33 and 23/37 patients were mechanically ventilated as opposed to awake spontaneously breathing in both groups. The high-longevity system increased gas exchanger runtime from 29 ± 16 to 48 ± 36 h in ventilated and from 22 ± 14 to 31 ± 31 h in awake patients (p < 0.0001), with longer runtime in the former (p < 0.01). VCO2 remained constant at 86 ± 34 mL/min (p = 0.11). Overall, PaCO2 decreased from 9.1 ± 2.0 to 7.9 ± 1.9 kPa within 1 h (p < 0.001). Tidal volume could be maintained at 5.4 ± 1.8 versus 5.7 ± 2.2 mL/kg at 120 h (p = 0.60), and peak airway pressure could be reduced from 31.1 ± 5.1 to 27.5 ± 6.8 mbar (p < 0.01). CONCLUSION: Using a high-longevity gas exchanger system, membrane lifetime in low-flow ECCO2R could be extended in comparison to previous systems but remained below 120 h, especially in spontaneously breathing patients. Extracorporeal VCO2 remained constant throughout gas exchanger system runtime and was consistent with removal of approximately 50% of expected CO2 production, enabling lung protective ventilation despite hypercapnic respiratory failure.

Safety of Lidocaine During Wide-Awake Local Anesthesia No Tourniquet for Distal Radius Plating.

Purpose: This study evaluated the clinical and biochemical safety profile of infiltration of lidocaine with adrenaline in wide-awake local anesthesia no tourniquet for distal radius plating. Methods: Twenty-four participants were randomly assigned to the therapeutic group (n = 19) (1% lidocaine in 1:100,000 adrenaline) and control group (n = 5) (2% lidocaine alone). Clinical parameters, including skin necrosis, duration of recovery of sensation, and lidocaine toxicity, were monitored. The serum lidocaine level was measured at different time intervals using a high-performance liquid chromatography reagent. Results: No lidocaine toxicity was recorded in any participant. The therapeutic group had a longer time for recovery of sensation. There was a significant difference in the serum lidocaine levels between both the groups at all time intervals up to 6 hours, with all participants exhibiting serum lidocaine levels below the mild toxicity level of 6.0 µg/mL. Conclusions: Lidocaine used within a safe recommended dose in wide-awake local anesthesia no tourniquet for distal radius plating is clinically and biochemically safe. Clinical relevance: Determining the clinical and biochemical safety profile of lidocaine with adrenaline in wide-awake local anesthesia no tourniquet can promote wider use of this technique.

Technique of Wide-Awake Local Anesthesia No Tourniquet Injection for a Transradial Forearm Amputation in an Ischemic Hand.

A 48-year-old man with drug addiction presented with gangrene of the right hand following an inadvertent intra-arterial administration of crushed dihydrocodeine tartrate (DF 118) tablets (GlaxoSmithKline S.A.) dissolved in water; the solution was injected into his right antecubital fossa. After 3 weeks of pain, paresthesia, and cyanosis, his right hand became gangrenous. We performed a right forearm amputation by use of the wide-awake local anesthesia no tourniquet technique. After surgery, his wound healed well, and he was successfully fitted with a hand prosthesis.

Prospective Evaluation of Pain and Anxiety Levels Between Wide-Awake Local Anesthesia No Tourniquet and General Anesthesia With Tourniquet in Excision of Wrist Ganglions.

Purpose: Excision of wrist ganglions is a common procedure in hand surgery. Our objective was to determine whether the type of anesthesia (general anesthesia [GA] vs wide-awake local anesthesia no tourniquet [WALANT] technique) would affect patient satisfaction regarding intraoperative pain control, postoperative pain management, and anxiety. Methods: This was a prospective study with patients divided into either the WALANT or GA cohort. The waiting time for surgery, Amsterdam Preoperative Anxiety and Information Scale, blood pressure, and heart rate were measured. Postsurgical questionnaires with the visual analog scale were completed. The surgeon's feedback on the ease of ganglion stalk visibility and usage of diathermy as a measure of a bloodless field was recorded. Patients reported the amount of analgesia consumed and overall satisfaction with the operation via the Surgical Satisfaction-8 questionnaire. Results: A total of 42 patients underwent wrist ganglion excision in 2 orthopedic centers over a period of 2 years, with 21 undergoing GA and 22 undergoing WALANT. The GA group was more anxious about anesthetic use with a higher demand for information about GA (P = .04). The duration of surgery was significantly shorter in the WALANT group and with a lower diathermy usage (P < .001). There was no difference in terms of surgical difficulty and stalk visualization. The visual analog scale pain score was significantly lower in the WALANT group than in the GA group immediately after surgery (P = .04) and on discharge (P = .004). While at home for 2 weeks, the WALANT group (mean = 2.91 tablets) consumed significantly fewer analgesic tablets than the GA group (mean = 6.25 tablets). However, both groups were satisfied with their experience. Conclusions: Wide-awake local anesthesia no tourniquet technique in the excision of ganglions provides another option of anesthesia with painless experiences, and no pain rebound after surgery. Patients were less anxious about WALANT than GA. Excision can be performed without diathermy usage with similar visualization of the stalk. Type of study/level of evidence: Therapeutic II.

Case report: Kaposi hemangioendothelioma of the right upper limb with the Kasabach-Merritt phenomenon: A potentially lethal diagnostic challenge.

Kaposi hemangioendothelioma (KHE) is a rare vascular neoplasm that presents usually within the first year of life. Because of its rarity and complexity, there is often a delay in diagnosis. KHE could be associated with a life-threatening consumptive coagulopathy named the Kasabach-Merritt phenomenon (KMP). Here, we present the case of a 2-month-old girl who presented with progressive redness and swelling of her right upper limb over 6 weeks. Multiple health practitioners misdiagnosed her condition as an insect bite, cellulitis, and necrotizing fasciitis and gave treatment accordingly, which proved futile. A full blood count revealed bicytopenia of anemia and thrombocytopenia, a normal coagulation cascade, low fibrinogen, and raised D-Dimer levels. The imaging was suggestive of a high-flow vascular tumor likely to be a KHE. Subsequently, she was started on single-agent oral sirolimus with a dose increment to achieve satisfactory therapeutic levels and was treated for 1 year. She successfully completed the treatment regimen and had only transient hypertriglyceridemia, which resolved upon the completion of treatment. Currently, she is in remission 3 years after treatment. Keeping her case as an example, we would like to highlight the potentially lethal misdiagnosis of KHE with KMP, the importance of an early diagnosis of this condition, and the successful treatment outcome with single-agent sirolimus.

A Survey of Zone II Flexor Tendon Repair Techniques and Rehabilitation Protocols Preferred by Malaysian Orthopaedic Practitioners.

Introduction: Flexor tendon repair is challenging mainly due to the need to balance between a strong repair technique, ease of tendon gliding and early mobilisation to prevent adhesions while preventing tendon rupture. While different countries have different preferences in repair techniques, core sutures and suture types, there is still no study in Malaysia regarding our preference and whether we are following the current evidence. Materials and methods: We performed a survey with a standard questionnaire distributed during our annual national orthopaedic meeting in 2019. The standard questionnaire consisted of 24-objective multiple-choice questions concerning the treatment of flexor tendon injury were distributed with consent. A total of 290 questionnaires that were filled out correctly were included in this study. Results: The majority of respondents preferred the Modified Kessler technique (n=96, 33.1%) followed by the Adelaide technique (n=81, 27.9%) and Double Modified Kessler (n=45, 15.5%). However, for the number of core strands in the repair, the majority utilised the 4-strand (n=203, 70%), followed by 2-strand (n=34, 11.7%) and 6-strand (n=21, 7.2%). The majority utilised Prolene sutures (n=259, 89.3%) with a suture size of 4/0 (n=157, 54.1%). For rehabilitation, 56.9% (n=165) preferred early passive motion, 27.6% (n=80) early active motion and 14.8% (n=43) would strictly immobilise. Conclusion: There is still no consensus as to the best technique; however, the aim of tendon repairs is still the same around the world. It would be helpful to know our preferences to improve our current practice and outcomes following these common flexor tendon injuries in hand.

Human endogenous retrovirus-R envelope is a host restriction factor against severe acute respiratory syndrome-coronavirus-2

Coronavirus induced disease-19 (COVID-19), caused by the SARS-CoV-2 remains a major global health challenge. Human endogenous retroviruses (HERVs) represent retroviral elements that got integrated into the ancestral human genome. HERVs are important in development and diseases, including cancer, inflammation and viral infections. Here, we analyzed the expression of several HERVs in SARS-CoV-2 infected cells and observed increased activity of HERV-E, HERV-V, HERV-FRD, HERV-MER34, HERV-W and HERV-KHML2. In contrast, HERV-R-envelope was downregulated in cell-based models and COVID-19 patient PBMCs. HERV-R overexpression inhibited SARS-CoV-2 replication, suggesting its antiviral action. Further studies demonstrated the role of extracellular signal-regulated kinase (ERK) in regulating HERV-R antiviral activity. Cross-talk between the ERK and p38 MAPK controls HERV-R envelope synthesis, which in turn modulates the replication of SARS-CoV-2. These findings establish the importance of HERV-R envelope as a host restriction factor against SARS-CoV-2 and illustrate the advantage of integration and evolutionary maintenance of retroviral-elements in the human genome.

The Outcome of Neurotization of Brachial Plexus Injury in a Tertiary Centre: A Nine-Year Review.

INTRODUCTION: In neurotization or nerve transfer, a healthy but less valuable nerve is transferred to re-innervate a more important motor territory that has lost its innervation through irreparable damage to its nerve. METHODOLOGY: In this study, the outcomes of surgery were analyzed in relation to the muscle strength, range of motion of the upper limb, and functional outcome. The results were analyzed in 19 patients who were operated on between 2008 and 2016 with adequate follow-up.  Result: Of the 19 patients (15 complete brachial plexus injuries and four incomplete brachial plexus injuries), 13 patients (68%) recovered partial function after the neurotization surgery. Shoulder abduction and elbow flexion were achieved in 11 patients (58%). Six of the 10 patients (32%) in complete pre-ganglionic brachial plexus injury had recovered partial function. Whereas five of the six patients (83%) in complete post-ganglionic had recovered partial function. In incomplete upper trunk brachial plexus injury, three of the four patients (75%) recovered some function after the neurotization surgery. CONCLUSION: Nerve transfer is an effective treatment option to restore the function of the affected upper limb. Neurotization without intervening nerve graft shows better recovery. Earlier surgical intervention at a younger age can yield better outcomes.

Advancement of Electrospun Nerve Conduit for Peripheral Nerve Regeneration: A Systematic Review (2016-2021).

Peripheral nerve injury (PNI) is a worldwide problem which hugely affects the quality of patients' life. Nerve conduits are now the alternative for treatment of PNI to mimic the gold standard, autologous nerve graft. In that case, with the advantages of electrospun micro- or nano-fibers nerve conduit, the peripheral nerve growth can be escalated, in a better way. In this systematic review, we focused on 39 preclinical studies of electrospun nerve conduit, which include the in vitro and in vivo evaluation from animal peripheral nerve defect models, to provide an update on the progress of the development of electrospun nerve conduit over the last 5 years (2016-2021). The physical characteristics, biocompatibility, functional and morphological outcomes of nerve conduits from different studies would be compared, to give a better strategy for treatment of PNI.

Mistaking a Tumour for an Infection - Acrometastasis of the Finger from Endocervical Adenosquamous Carcinoma: A Case Report.

Acrometastasis is rare with a very low incidence of all bone metastasis. It can present with swelling, pain and warmth with erythema that may mimic an infection especially in the distal phalanx. Due to its rarity and subtle clinical presentation, it can be misdiagnosed as an infection causing the treatment to be delayed. We report a 42-year-old female with an acrometastasis to the distal phalanx of the left middle finger which we mistook as an infection thus delaying her treatment. It was a terminal presentation of her endocervical adenosquamous carcinoma. We would like to highlight that acrometastasis has an indistinct presentation and in cases where the lesion does not respond to treatment, acrometastasis should be included as one of the differential diagnoses. Thus, physicians need to have a high level of suspicion in patients with a primary malignant tumour.