A Randomized Controlled Trial of β-Blockers Versus Endoscopic Band Ligation for Primary Prophylaxis: A Large Sample Size is Required to Show a Difference in Bleeding Rates

Primary prophylaxis with nonselective -blockers in high-risk subjects has been shown to be effective in reducing both esophageal variceal bleeding and mortality. Recently it has been suggested that band ligation may be a better option for primary prophylaxis. We compared nonselective -blockers with band ligation in patients with large varices (F2, F3) and elevated hepatic venous wedge pressure gradient (HVWPG, 12 mm Hg). All patients were prospectively followed for variceal bleeding, mortality, and treatment-related complications. Based on previous published studies, we estimated that 90 patients in each arm would be required to show a difference in bleeding rate. The study was prematurely terminated when we realized that our estimated sample size was inadequate to show a difference based on the observed bleeding rate. At the time of termination, 31 patients (Child A, 11; B, 14; C, 6), with a mean HVWPG of 19 ± 9.1 mm Hg, were randomized to either band ligation (group A; n = 16) or -blockers (group B; n = 15). Baseline demographics of both groups were similar and the mean follow-up period was 27.4 ± 12.9 months. During the follow-up, two patients in group A and one patient in group B had bleeding. Nine patients (29%; group A, six; group B, three; P = ns) died due to non-bleeding-related causes and five (16%) patients (group A, three; group B, two) underwent liver transplantation. Treatment-related complication were minimal in both groups. Despite the selection of high-risk patients, the observed bleeding rate was much lower than anticipated. Based on our observed bleeding rates, 424 patients would be required in each arm to show a difference between band ligation and -blocker therapy.     

Superiority of Higher-Volume Fresh Feces Compared to Lower-Volume Frozen Feces in Fecal Microbiota Transplantation for Recurrent Clostridioides Difficile Colitis

Digestive Diseases and Sciences - To compare the clinical outcomes of different protocols for fecal microbiota transplantation (FMT) in two community hospitals with similar patient demographics....     

Lipid-Lowering Biotechnological Drugs: from Monoclonal Antibodies to Antisense Therapies—a Clinical Perspective

Purpose

While low density lipoprotein cholesterol (LDL-C) remains a key contributor of atherosclerotic cardiovascular disease (ASCVD), additional risk factors identified through epidemiological and genetic studies have ushered in a fertile era of drug discovery in lipid-lowering therapy. Unlike contemporary small molecule medications, many of the novel agents are biologics utilizing monoclonal antibody (mAb) or RNA interference (RNAi) technologies. This report aims to review the evidence to date, focusing on completed and ongoing clinical trials and how these new agents will impact clinical practice.

Methods

We review data from pertinent studies on lipid-lowering biologics in clinical use or have translated to human studies and are undergoing clinical trials.

Results

Several targets affecting lipid metabolism have been identified to be causally associated with ASCVD including proprotein convertase subtilisin/kexin type 9 (PCSK9), angiopoietin-like protein 3 (ANGPTL3), apolipoprotein C3 (APOC3), and lipoprotein (a) (Lp[a]). Biotechnological modalities that have been developed for these targets include mAb, small interfering RNA (siRNA), and anti-sense oligonucleotide (ASO) agents. Agents such as alirocumab and evolocumab have shown efficacy in risk reduction of ASCVD in cardiovascular outcome trials and have been incorporated into evidence-based practice guidelines. Other agents included in this review are in various stages of clinical trials and have shown significant efficacy in the reduction of lipid parameters.

Conclusion

The development of new biologics targeting lipid risk factors will provide clinicians additional tools to reduce the risk for ASCVD. Important factors to consider will be cost-effectiveness and improving methods to personalize treatments to risk factors.

     

International Survey of Mechanical Thrombectomy Stroke Systems of Care During COVID-19 Pandemic

BackgroundThe COVID-19 pandemic has strained the healthcare systems across the world but its impact on acute stroke care is just being elucidated. We hypothesized a major global impact of COVID-19 not only on stroke volumes but also on various aspects of thrombectomy systems.AimsWe conducted a convenience electronic survey with a 21-item questionnaire aimed to identify the changes in stroke admission volumes and thrombectomy treatment practices seen during a specified time period of the COVID-19 pandemic.MethodsThe survey was designed using Qualtrics software and sent to stroke and neuro-interventional physicians around the world who are part of the Global Executive Committee (GEC) of Mission Thrombectomy 2020, a global coalition under the aegis of Society of Vascular and Interventional Neurology, between April 5th and May 15th, 2020.ResultsThere were 113 responses to the survey across 25 countries with a response rate of 31% among the GEC members. Globally there was a median 33% decrease in stroke admissions and a 25% decrease in mechanical thrombectomy (MT) procedures during the COVID-19 pandemic period until May 15th, 2020 compared to pre-pandemic months. The intubation policy for MT procedures during the pandemic was highly variable across participating centers: 44% preferred intubating all patients, including 25% of centers that changed their policy to preferred-intubation (PI) from preferred non-intubation (PNI). On the other hand, 56% centers preferred not intubating patients undergoing MT, which included 27% centers that changed their policy from PI to PNI. There was no significant difference in rate of COVID-19 infection between PI versus PNI centers (p=0.60) or if intubation policy was changed in either direction (p=1.00). Low-volume (<10 stroke/month) compared with high-volume stroke centers (>20 strokes/month) were less likely to have neurointerventional suite specific written personal protective equipment protocols (74% vs 88%) and if present, these centers were more likely to report them to be inadequate (58% vs 92%).ConclusionOur data provides a comprehensive snapshot of the impact on acute stroke care observed worldwide during the pandemic. Overall, respondents reported decreased stroke admissions as well as decreased cases of MT with no clear preponderance in intubation policy during MT.Data access statementThe corresponding author will consider requests for sharing survey data. The study was exempt from institutional review board approval as it did not involve patient level data.     

Malfeasance of KRAS mutations in carcinogenesis

Clinical and Experimental Medicine - Activating mutations in the KRAS gene (Kirsten rat sarcoma 2 viral oncogene homolog gene) are commonly seen across the various solid organ and hematolymphoid...     

Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: a North American open-label study

BackgroundThe efficacy of recombinant human C1 inhibitor (rhC1INH) for the treatment of patients with acute hereditary angioedema (HAE) attacks has been demonstrated in 2 randomized, double-blind, placebo-controlled studies.ObjectiveTo assess the safety and efficacy of rhC1INH for repeated treatment of acute attacks of HAE.MethodsIn this open-label extension study, patients with eligible HAE attacks were treated with an intravenous 50-U/kg dose of rhC1INH with an option for an additional dose of 50 U/kg based on clinical response. Time to beginning of relief was assessed by patients using a 100-mm visual analogue scale (VAS). Safety evaluation was based on the clinical laboratory results and adverse events.ResultsSixty-two patients were treated for 168 attacks (range, 1-8 attacks per patient). A total of 90% of the attacks were treated with a single 50-U/kg dose of rhC1INH. Median times to beginning of symptom relief for the first 5 attacks were 37 to 67 minutes. More than 90% of attacks responded within 4 hours after treatment with rhC1INH. There was no requirement for increased dosing with successive treatments. Thirty-nine patients (63%) reported at least 1 treatment-emergent adverse event, with most events rated mild to moderate. Seven severe treatment-emergent adverse events were reported, and all were considered to be unrelated to treatment with rhC1INH.ConclusionThe results of this open-label extension support continued efficacy of rhC1INH after repeated treatments for subsequent HAE attacks. There was no increase in adverse event reporting after repeated exposure to rhC1INH.Trial Registrationclinicaltrials.gov Identifier: NCT00225147     

Kapetansky-Juri Technique to Correct the Whistlers Lip in the Multiple Operated Cleft Patient

Purpose

One of the common sequels of a cleft lip repair may be “whistling lip deformity” but other deformities are also seen particularly in failed or multiple resurgery cases. This retrospective study was carried out to evaluate the usefulness of “Kapetansky-Juri” advancement flap technique to correct such deformities.

Methods

Ten patients of bilateral cleft lip with history of minimum five failed cleft lip surgeries and having residual lip deformity were operated using “Kapetansky-Juri” advancement flap technique and were followed up to minimum 36 months.

Results

All patients showed good tissue fullness and complete correction of the deformity. There was no contracture of surrounding skin or vermilion during follow-up period. In eight patients minimal scar formation was seen while two showed midline scar formation.

Conclusion

No tissue loss due to vascular insufficiency was observed. The technique gives good tissue distribution and minimal surface scar formation.     

Toll‐like receptor 6 mediated inflammatory and functional responses of zinc oxide nanoparticles primed macrophages

Macrophages are among the most sensitive immune cells because of their phagocytic activity and are prone to become dysfunctional or not able to perform properly if nanoparticle load increases. We have previously reported that zinc oxide nanoparticles (ZNPs) induce inflammatory responses in macrophages that contribute to their death. Recognition of ZNPs by pattern recognition receptors such as toll‐like receptors (TLRs) might be a factor in the initiation of these responses in macrophages. Therefore, in this study we explored the role played by TLR6 and mitogen‐activated protein kinase (MAPKs) pathways in the inflammatory responses of macrophages during ZNPs exposure. ZNPs‐activated macrophages showed enhanced expression of activation and maturation markers (CD1d, MHC‐II, CD86 and CD71). Among various TLRs screened, TLR6 emerged as the most potent activator for ZNPs‐induced inflammatory responses. Downstream signalling proteins myeloid differentiation 88, interleukin‐1 receptor associated kinase and tumour necrosis factor receptor‐associated factor were also enhanced. On inhibiting MAPKs pathways individually, the inflammatory responses such as interleukin‐1β, interleukin‐6, tumour necrosis factor‐α, cyclooxygenase‐2 and inducible nitric oxide synthase were suppressed. TLR6 silencing significantly inhibited the pro‐inflammatory cytokine levels, reactive nitrogen species generation and inducible nitric oxide synthase expression. Also, inhibition of MAPKs in the absence of TLR6 signalling validated the link between TLR6 and MAPKs in ZNPs‐induced inflammatory responses. TLR6 was found to be co‐localized with autophagosomes. Macrophages lacking TLR6 inhibited the autophagosome marker protein‐microtubule‐associated protein1 light chain 3‐isoform II formation and phagocytosis. These results demonstrate that inflammatory responses caused by ZNPs‐activated macrophages strongly depend on TLR6‐mediated MAPK signalling.