Comparison of the Colonic J-Pouch Versus Side-To-End Anastomosis Following Low Anterior Resection: A Systematic Review and Meta-Analysis.

BACKGROUND: The aim of this systematic review and meta-analysis is to evaluate clinical, functional, and anorectal physiology outcomes of the side-to-end vs colonic J-pouch (CJP) anastomosis following anterior resection for rectal cancer. METHODS: A PRISMA-compliant systematic review and meta-analysis was conducted using multiple electronic databases and clinical trial registers and all studies comparing side-to-end vs CJP anastomosis were included. Peri-operative complications, mortality rate, functional bowel, and anorectal outcomes were evaluated. RESULTS: Eight randomized controlled trials (RCTs) and two observational studies with 1125 patients (side-to-end: n = 557; CJP: n = 568) were included. Of the entire functional bowel outcome parameters analyzed, only the sensation of incomplete bowel evacuation was significant in the CJP group at 6 months [OR: 2.07; 95% CI 1.06 - 4.02, P = .03]. Peri- and post-operative clinical parameters were comparable in both groups (total operative time, intra-operative blood loss, anastomotic leak rate, return to theater, anastomotic stricture formation and mortality). Equally, most of the analyzed anorectal physiology parameters (anorectal volume, anal squeeze pressure, maximum anal volume) were not significantly different between the two groups. However, anal resting pressure (mmHg) 2 years post-operatively was noted to be significantly higher in the side-to-end group than that of the CJP configuration [MD: -8.76; 95% CI - 15.91 - 1.61, P = .02]. DISCUSSION: Clinical and functional outcomes following CJP surgery and side-to-end coloanal anastomosis are comparable. Neither technique appears to proffer solution to low anterior resection syndrome in the short term but future well-designed; high-quality RCTs with long term follow-up are required.

Liberal or restrictive antimicrobial prophylaxis for surgical site infection: systematic review and meta-analysis of randomised trials.

BACKGROUND: Antimicrobial prophylaxis is widely used to prevent surgical site infection. Amid growing concern about antimicrobial resistance, we determined the effectiveness of antimicrobial prophylaxis. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and WHO-ICTRP between January 1, 1990 and January 1, 2020 for trials randomising adults undergoing surgery to liberal (more doses) or restrictive (fewer or no doses) perioperative antimicrobial prophylaxis. Pairs of researchers reviewed articles and extracted data, and a senior author resolved discrepancies. The primary outcome measure was surgical site infection or bacteriuria for urological procedures. We calculated average risk difference (RD) with 95% confidence intervals and prediction intervals (PI) using random effects models, and present risk ratios (RR). We assessed evidence certainty using GRADE methodology, and risk of bias using the Cochrane Risk of Bias tool (PROSPERO: CRD42018116946). RESULTS: From 6593 records, we identified 294 trials including 86 146 patients. Surgical site infection occurred in 2237/44 113 (5.1%) patients receiving liberal prophylaxis vs 2889/42 033 (6.9%) receiving restrictive prophylaxis (RD -0.01 [-0.02 to -0.01]; relative risk 0.72 [0.67-0.77]; I2=52%, PI -0.05-0.02). There was a small benefit of prophylaxis in 161 trials comparing no prophylaxis with ≥1 dose (RD -0.02 [-0.03 to -0.02]; RR 0.58 [0.52-0.65]; I2=62%, PI -0.06-0.02). Treatment effect varied from a strong effect in urology to no benefit in 7/19 specialities. Tests for publication bias suggest 62 unreported trials and evidence certainty was very low. Treatment harms were reported in 43/294 trials. CONCLUSIONS: A systematic review and meta-analysis of randomised trials revealed that more liberal antimicrobial prophylaxis is associated with a small reduction in the risk of surgical site infection, although antimicrobial harms are poorly reported. Further evidence about the risks of antimicrobial prophylaxis to inform current widespread use is urgently needed.

Attractivity criterion on a delayed tick population dynamics equation with a reproductive function $ f(u) = ru

The aim of this article is to analyze the delay influence on the attraction for a scalar tick population dynamics equation accompanying two disparate delays. Taking advantage of the fluctuation lemma and some dynamic inequalities, we derive a criterion to assure the persistence and positiveness on the considered model. Furthermore, a time-lag-dependent condition is proposed to insure the global attractivity for the addressed model. Besides, we give some simulation diagrams to substantiate the validity of the theoretical outcomes.

Aegle marmelos Leaf Extract Phytochemical Analysis, Cytotoxicity, In Vitro Antioxidant and Antidiabetic Activities.

For many years, Aegle marmelos (A. marmelos) has been used medicinally and as a dietary supplement. Despite this, there are minimal research data on A. marmelos phytochemical properties and pharmacological effects. This study aimed to explore the phytoconstituents, cytotoxicity, glucose uptake, and antioxidant and antidiabetic potential of an alcoholic extract of A. marmelos leaf. The cytotoxicity of A. marmelos in HepG2 cells was tested in vitro, and the results revealed that it has strong cytocompatibility and cytoprotective properties. The extract's antioxidant activities were investigated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) methods. Antioxidant potential was shown to be quite impressive. The enzymes α-amylase and α-glycosidase were found to be substantially inhibited by A. marmelos, with IC50 values of 46.21 and 42.07 mg/mL, respectively. In HepG2 cells, A. marmelos significantly reduced ROS levels that were elevated due to high glucose and enhanced glucose consumption (p < 0.05). These activities might be due to the enrichment of bioactive phytoconstituents analyzed chromatographically using GC/MS and HPLC. The findings of this study show that A. marmelos could be an effective restorative therapy for diabetes and related diseases.

Distributed Consensus Tracking Control of Chaotic Multi-Agent Supply Chain Network: A New Fault-Tolerant, Finite-Time, and Chatter-Free Approach.

Over the last years, distributed consensus tracking control has received a lot of attention due to its benefits, such as low operational costs, high resilience, flexible scalability, and so on. However, control methods that do not consider faults in actuators and control agents are impractical in most systems. There is no research in the literature investigating the consensus tracking of supply chain networks subject to disturbances and faults in control input. Motivated by this, the current research studies the fault-tolerant, finite-time, and smooth consensus tracking problems for chaotic multi-agent supply chain networks subject to disturbances, uncertainties, and faults in actuators. The chaotic attractors of a supply chain network are shown, and its corresponding multi-agent system is presented. A new control technique is then proposed, which is suitable for distributed consensus tracking of nonlinear uncertain systems. In the proposed scheme, the effects of faults in control actuators and robustness against unknown time-varying disturbances are taken into account. The proposed technique also uses a finite-time super-twisting algorithm that avoids chattering in the system's response and control input. Lastly, the multi-agent system is considered in the presence of disturbances and actuator faults, and the proposed scheme's excellent performance is displayed through numerical simulations.

Incision and drainage of cutaneous abscess with or without cavity packing: a systematic review, meta-analysis, and trial sequential analysis of randomised controlled trials.

AIMS: To evaluate comparative outcomes of incision and drainage of cutaneous abscess with and without packing of the abscess cavity. METHODS: A systematic search of multiple electronic data sources was conducted, and all randomised controlled trials (RCTs) comparing incision and drainage of cutaneous abscess with and without packing were included. Abscess recurrence at maximum follow-up period, need for second intervention, and development of fistula in-ano were the evaluated outcome parameters for the meta-analysis A Trial Sequential Analysis was conducted to determine the robustness of the findings. RESULTS: Eight RCTs reporting a total number of 485 patients who underwent incision and drainage of cutaneous abscess with (n = 243) or without (n = 242) packing of the abscess cavity were included. There was no significant difference in the risk of recurrence (risk ratio (RR) 1.31, P = 0.56), fistula-in-ano (RR 0.63, P = 0.28), and need for second intervention (RR 0.70, P = 0.05) between two groups. The results remained unchanged on sub-group analyses for ano-rectal abscess, paediatric patients, adult patients, and the use of antibiotics. The Trial Sequential Analysis demonstrated that the meta-analysis was not conclusive, and the results for recurrence were subject to type 2 error. CONCLUSION: Incision and drainage of cutaneous abscess with or without packing have comparable outcomes. However, considering the cost and post-operative pain associated with packing, performing the procedure without packing of the abscess cavity may be more favourable. The findings of the better quality ongoing RCTs may provide stronger evidence in favour of packing or non-packing.

Extraction, GC-MS Evaluation and Anti-epileptic Potential of Seeds Ethanolic Extract of Putranjiva roxburghii Wall.

BACKGROUND: Putranjiva roxburghii Wall is traditionally known to cure many pathological conditions including epilepsy. OBJECTIVE: The present study is aimed at determining bioactive compounds in ethanolic extract of Putranjiva roxburghii test extract (PRTE) seeds by GCMS analysis and to assess its antiepileptic potential using various experimental models of epilepsy. METHODS: The ethanolic extract of seeds of Putranjiva roxburghii was subjected to GC-MS analysis to detect the bioactive phytoconstituents. Acute oral toxicity of the extract was performed using OCED guideline 420. Pentylenetetrazol (PTZ) kindling model of epilepsy and Maximal electroshock epilepsy (MES) model of epilepsy were used to determine anti-epileptic potential. RESULTS: The GC-MS analysis of the extract revealed the presence of 20 phytoconstituents. The major phytoconstituents included n-Propyl heptyl ether (25.25%), 5-Ethyl hydantoin (8%), octadec- 9-enoic acid (16.25%) and 1, 2-Benzene dicarboxylic acid (11.86%). The PRTE (50 mg/kg and 100 mg/kg) afforded a significant and dose-dependent protection against PTZ-induced kindling epilepsy and MES induced epilepsy (p<0.001 and p<0.01). CONCLUSION: Based on the above findings, it is evident that Putranjiva roxburghii seeds contain biologically active compounds. It can also be concluded that the extract possesses anti-epileptic potential.

Facile functionalization of Teriflunomide-loaded nanoliposomes with Chondroitin sulphate for the treatment of Rheumatoid arthritis.

This research aims to coat Teriflunomide (TEF) loaded conventional nanoliposomes (CON-TEF-LIPO) with Chondroitin sulphate (CS) to produce CS-TEF-LIPO for the effective treatment of Rheumatoid arthritis (RA). Both CON-TEF-LIPO and CS-TEF-LIPO were produced, characterized and evaluated for their active targeting potential towards CD44 receptors. Cell cytotoxicity, cell viability and intracellular uptake study on differentiated U937 and MG-63 cells demonstrated the active targeting of CS-TEF-LIPO towards CD44 receptors. Furthermore, in vivo pharmacodynamic, biochemical, radiological and histopathological studies performed in adjuvant induced arthritic (AIA) rat model showed a significant (P < 0.05) reduction in inflammation in arthritic rat paw in CS-TEF-LIPO group compared to TEF and CON-TEF-LIPO groups. Moreover, liver toxicity study revealed that CS-TEF-LIPO showed no signs of toxicity and biodistribution study revealed the accumulation of CS-TEF-LIPO in synovial region of arthritic rat. Taken together, results suggest that CS-TEF-LIPO could provide a new insight for an effective treatment of RA.

Insights into Transdermal Drug Delivery: Approaches for Redressal of a Burgeoning Issue of Osteoporosis.

Osteoporosis is a progressive bone disease that remains unnoticed until a fracture occurs. It is more predominant in the older age population, particularly in females due to reduced estrogen levels and ultimately limited calcium absorption. The cost burden of treating osteoporotic fractures is too high, therefore, primary focus should be treatment at an early stage. Most of the marketed drugs are available as oral delivery dosage forms. The complications, as well as patient non-compliance, limit the use of oral therapy for prolonged drug delivery. Transdermal delivery systems seem to be a promising approach for the delivery of anti-osteoporotic active moieties. One of the confronting barriers is the passage of drugs through the SC layers followed by penetration to deeper dermal layers. The review focuses on how anti-osteoporotic drugs can be molded through different approaches so that they can be exploited for the skin to systemic delivery. Insights into the various challenges in transdermal delivery and how the novel delivery system can be used to overcome these have also been detailed.

Design and development of a commercially viable in situ nanoemulgel for the treatment of postmenopausal osteoporosis.

Aim: To investigate the potential of a thermosensitive intranasal formulation of raloxifene hydrochloride (RH) for systemic delivery with the possibility of enhanced bioavailability and anti-osteoporotic efficacy. Methods: In this work, a commercially scalable nanoemulsion in thermosensitive gel, aligned with better clinical acceptability, has been developed and evaluated. Results: A significant 7.4-fold improvement in bioavailability of RH was recorded when compared with marketed tablets. Likewise, in vivo pharmacodynamics studies suggested 162% enhanced bone density and significantly improved biochemical markers compared with per-oral marketed tablet. Conclusion: The formulation, being safe and patient compliant, successfully tuned anti-osteoporotic effects with improved therapeutic performance. Further, the work provided an exceptional lead to carry out the study in clinical settings.

No association between proton pump inhibitor use and risk of dementia: Evidence from a meta-analysis.

BACKGROUND AND AIM: A growing body of literature suggests the association between dementia risk and proton pump inhibitor (PPI) use. Therefore, we aimed to investigate the association between PPI use and dementia risk. METHODS: An extensive literature search was performed in PubMed, Embase, and Cochrane till March 31, 2019. All the studies (cohort and case-control) assessing the association between PPI use and dementia risk were eligible for inclusion. Articles were selected based on the screening of title and abstract, data were extracted, and risk of bias was assessed using Newcastle-Ottawa scale. The primary outcome was pooled risk of dementia among PPI user as compared with non-PPI user. Secondary outcomes include dementia risk based on subgroups. Statistical analysis was performed using review manager software. RESULTS: Twelve studies (eight cohort and four case-control) were found to be eligible for inclusion. Majority of the studies were of high quality. Dementia was diagnosed based on International Classification of Diseases 9/10 codes in majority of the included studies. PPI use was not associated with the dementia risk, with a pooled relative risk (RR) of 1.05 (95% confidence interval [CI]: 0.96-1.15), P = 0.31. Subgroup analysis based on study design (cohort: P = 0.14; case-control: P = 0.14), sex (RR 1.25 [95% CI: 0.97-1.60], P = 0.08), histamine 2 receptor antagonist blockers (P = 0.93), and Alzheimer's disease (RR 1.00 [95% CI: 0.91-1.09], P = 0.93) revealed no significant association between PPI use and dementia risk. CONCLUSION: We found no significant association between PPI use and the risk of dementia or Alzheimer's disease.

Targeted Distraction: Spinal Growth in Children With Early-Onset Scoliosis Treated With a Tail-gating Technique for Magnetically Controlled Growing Rods.

STUDY DESIGN: Prospective cohort study OBJECTIVE.: To understand the efficacy of a tail-gating technique (TGT) to mirror the normal spinal growth of children with early-onset scoliosis (EOS) treated with magnetically controlled growing rods (MCGR). SUMMARY OF BACKGROUND DATA: MCGR allow outpatient distraction and guided spinal growth without the need for repeat surgery. Two techniques (maximal and targeted) are currently employed to determine the distraction amount, however the efficacy of each is unknown. This study specifically assesses the ability of targeted distraction to achieve physiological growth. METHODS: We performed a retrospective review of European children treated with MCGR using a TGT and analyzed the post-operative clinical and radiographic outcomes, including the sitting height, standing height, coronal Cobb angle, T1-T12 and T1-S1 height. Furthermore, we compared the post-operative sitting/standing height ratio every 6 months to those reported for normal age- and sex-matched European children. RESULTS: Thirty-five children were included with a mean follow-up of 3.4 years (1.8-5.8 years). All clinical and radiographic parameters significantly (P < 0.05) improved immediately post-operatively and were maintained until final follow-up. The TGT mirrored the normative sitting/standing height ratios for expected spinal growth (Pearson correlation 0.95 for males and 0.90 for females). The mean difference between the reference values for the sitting/standing height ratio and our results was 0.0124 (P < 0.001) for males and 0.0068 (P = 0.010) for females. CONCLUSION: MCGR can reliably improve the coronal deformity in children with EOS while maintaining spinal growth. A TGT to determine the distraction amount at follow-up accurately mirrors the normal growth pattern of age-, sex-, and ethnicity-matched children. However, patients treated with this technique have a statistically significant, but clinically insignificant, shorter than physiologically normal spinal height. LEVEL OF EVIDENCE: 3.

Paper #31: The Oxford 5 year observational study on 35 patients with Magnetically Controlled Growing Rods (MCGR).

MCGR controls scoliosis progression and allows growth. Functional activity also improves generally. Primary infection rates are low. The overall unplanned return to theatre rates are still high but the psychosocial benefits are obvious.

Paper #25: Quantifying the 'Law of Diminishing Returns' in Magnetically Controlled Growing Rods.

The 'law of diminishing returns' can also be observed following serial distraction in MCGR. In comparison to previously published data for CGRS, there is a gradual linear decline as opposed to a rapid initial decline in lengthening. In the older, heavier child a reduced distraction ratio in the concave rod of the MCGR device is noted over time.

A review of prednisolone prescribing for children with acute asthma in the UK.

INTRODUCTION: Worldwide asthma guidelines recommend short courses of oral prednisolone in children with acute exacerbations generating high prescription numbers. There is a paucity of evidence to inform the optimal dose and course duration. This has led to a variation in the recommendations for prednisolone prescribing. Our objective was to assess prednisolone prescribing practise for children with acute asthma in a representative sample of UK prescribers. METHODS: We developed an online questionnaire asking prescribers the prednisolone dosage, course duration and formulation used, whether they discussed oral prednisolone side effects with the family and at what child's age they changed from prescribing soluble to non-soluble formulations. This was sent to 1006 UK prescribers including Paediatric Respiratory Consultants, doctors in training, asthma nurses and General Practitioners. RESULTS: 200 complete responses were received (response rate 20%). The majority of surveyed prescribers follow the British National Formulary for Children recommendations on dosage rather than those included in the British Thoracic Society and the Scottish Intercollegiate Guidelines Network. Despite this, we highlighted a 4-fold variation in prednisolone dosages for acute asthma. The majority of prescribers chose 3 days as the course duration. High use of soluble formulations was highlighted. CONCLUSIONS: There is wide variation in the dose of prednisolone prescribed for children with acute asthma in the UK. This reflects a relative lack of evidence that needs addressing.

Inflammatory abdominal aortic aneurysm: a persistent painful hip.

The presentation of an abdominal aortic aneurysm (AAA) with isolated hip pain is a rare phenomenon. We present an atypical case of a 58-year-old previously fit man who presented with a 6-month history of progressively worsening left hip pain associated with unintentional weight loss, tender bilateral testicular swellings and a large non-tender palpable mass on abdominal examination. Urgent abdominal CT scan findings revealed a 15 cm infrarenal abdominal aortic aneurysm extending to the aortic bifurcation associated with an extensive left hydronephrosis. In theatre, the diagnosis of inflammatory AAA (IAAA) was confirmed following the presence of pyuria and a successful repair with an open approach using a bifurcated dacron graft was performed.

High-level production of human interleukin-10 fusions in tobacco cell suspension cultures.

The production of pharmaceutical proteins in plants has made much progress in recent years with the development of transient expression systems, transplastomic technology and humanizing glycosylation patterns in plants. However, the first therapeutic proteins approved for administration to humans and animals were made in plant cell suspensions for reasons of containment, rapid scale-up and lack of toxic contaminants. In this study, we have investigated the production of human interleukin-10 (IL-10) in tobacco BY-2 cell suspension and evaluated the effect of an elastin-like polypeptide tag (ELP) and a green fluorescent protein (GFP) tag on IL-10 accumulation. We report the highest accumulation levels of hIL-10 obtained with any stable plant expression system using the ELP fusion strategy. Although IL-10-ELP has cytokine activity, its activity is reduced compared to unfused IL-10, likely caused by interference of ELP with folding of IL-10. Green fluorescent protein has no effect on IL-10 accumulation, but examining the trafficking of IL-10-GFP over the cell culture cycle revealed fluorescence in the vacuole during the stationary phase of the culture growth cycle. Analysis of isolated vacuoles indicated that GFP alone is found in vacuoles, while the full-size fusion remains in the whole-cell extract. This indicates that GFP is cleaved off prior to its trafficking to the vacuole. On the other hand, IL-10-GFP-ELP remains mostly in the ER and accumulates to high levels. Protein bodies were observed at the end of the culture cycle and are thought to arise as a consequence of high levels of accumulation in the ER.

Green biofactories: recombinant protein production in plants.

Until recently, low accumulation levels have been the major bottleneck for plant-made recombinant protein production. However, several breakthroughs have been described in the past few years allowing for very high accumulation levels, mainly through chloroplast transformation and transient expression, coupled with subcellular targeting and protein fusions. Another important factor influencing our ability to use plants for the production of recombinant proteins is the availability of quick and simple purification strategies. Recent developments using oleosin, zein, ELP and hydrophobin fusion tags have shown promise as efficient and cost-effective methods for non-chromatographic separation. Furthermore, plant glycosylation is a major barrier to the parenteral administration of plant-made biopharmaceuticals because of potential immunogenicity concerns. A major effort has been invested in humanizing plant glycosylation, and several groups have been able to reduce or eliminate immunogenic glycans while introducing mammalian-specific glycans. Finally, biosafety issues and public perception are essential for the acceptance of plants as bioreactors for the production of proteins. Over recent years, it has become clear that food and feed plants carry an inherent risk of contaminating our food supply, and thus much effort has focused on the use of non-food plants. Presently, Nicotiana benthamiana has emerged as the preferred host for transient expression, while tobacco is most frequently used for chloroplast transformation. In this review, we focus on the main issues hindering the economical production of recombinant proteins in plants, describing the current efforts for addressing these limitations, and we include an extensive list of recent patents generated with the intention of solving these limitations.

Green Biofactories: Recombinant Protein Production in Plants.

Until recently, low accumulation levels have been the major bottleneck for plant-made recombinant protein production. However, several breakthroughs have been described in the past few years allowing for very high maccumulation levels, mainly through chloroplast transformation and transient expression, coupled with subcellular targeting and protein fusions. Another important factor influencing our ability to use plants for the production of recombinant proteins is the availability of quick and simple purification strategies. Recent developments using oleosin, zein, ELP and hydrophobin fusion tags have shown promise as efficient and cost-effective methods for nonchromatographic separation. Furthermore, plant glycosylation is a major barrier to the parenteral administration of plantmade biopharmaceuticals because of potential immunogenicity concerns. A major effort has been invested in humanizing plant glycosylation, and several groups have been able to reduce or eliminate immunogenic glycans while introducing mammalian-specific glycans. Finally, biosafety issues and public perception are essential for the acceptance of plants as bioreactors for the production of proteins. Over recent years, it has become clear that food and feed plants carry an inherent risk of contaminating our food supply, and thus much effort has focused on the use of non-food plants. Presently, Nicotiana benthamiana has emerged as the preferred host for transient expression, while tobacco is most frequently used for chloroplast transformation. In this review, we focus on the main issues hindering the economical production of recombinant proteins in plants, describing the current efforts for addressing these limitations, and we include an extensive list of recent patents generated with the intention of solving these limitations.