Mutagenesis enhances gellan gum production by a novel Sphingomonas spp: upstream optimization, kinetic modeling, and structural and physico-functional evaluation / La mutagénesis mejora la producción de goma gellan mediante una nueva especie de Sphingomonas: optimización ascendente, modelado cinético y evaluación estructural y físico-funcional

Gellan gum (GG) has gained tremendous attention owing to its diversified applications. However, its high production and hence market cost are still a bottleneck in its widespread utilization. In the present study, high GG producing mutant of Sphingomonas spp. was developed by random mutagenesis using ethyl methylsulphonate (EMS) for industrial fermentation and identified as Sphingomonas trueperi after 16S rRNA and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF–MS) analysis. The fermentation conditions such as pH, temperature, and inoculum ratio were optimized by one factor at a time (OFAT) followed by screening of medium components by the Plackett–Burman statistical design. The most critical nutrients were further optimized by response surface methodology for maximizing GG production. The effect of dissolved oxygen tension in bioreactor on cell growth, substrate consumption, GG production, and batch productivity was elucidated. The highest GG titer (23 ± 2.4 g/L) was attained in optimized medium at 10% inoculum (6.45 ± 0.5 log cfu/mL) under controlled fermentation conditions of pH (7), temperature (30 °C), agitation (300–600 rpm), and aeration (0.5–2.0 SLPM) at 22 ± 2% dissolved oxygen tension in a 10-L bioreactor. Kinetic modeling of optimized batch process revealed that logistic growth model could best explain biomass accumulation, while GG formation and substrate consumption were best explained by Luedeking-Piret and exponential decay model, respectively. Structural and physico-functional features of GG produced by mutant Sphingomonas spp. were characterized by HPLC, FTIR, NMR, DSC, TGA, GPC, SEM, and rheological analysis. The higher productivity (0.51 g/L/h) under optimized fermentation conditions suggests potential consideration of mutant and process for commercial utilization.(AU)

Local Recurrence-Free Survival After TaTME: A Canadian Institutional Experience.

BACKGROUND: Transanal total mesorectal excision is a novel surgical treatment for mid to low rectal cancers. Norwegian population data have raised concerns about local recurrence in patients treated with transanal total mesorectal excision. OBJECTIVE: This study aimed to analyze local recurrence and disease-free survival in patients treated by transanal total mesorectal excision for rectal cancer at a high-volume tertiary center. DESIGN: This retrospective study used a prospectively maintained institutional transanal total mesorectal excision database. Patient demographics, treatment, and outcomes data were analyzed. Local recurrence, disease-free survival, and overall survival were analyzed using Kaplan-Meier analysis. SETTINGS: The study was conducted at a single academic institution in Vancouver, Canada. PATIENTS: All patients treated by transanal total mesorectal excision for rectal adenocarcinoma between 2014 and 2022 were included. MAIN OUTCOME MEASURES: The primary outcome was local recurrence-free survival. RESULTS: Between 2014 and 2022, 306 patients were treated by transanal total mesorectal excision at St. Paul's Hospital. Of these, 279 patients met the inclusion criteria. The mean age was 62 years (SD ± 12.3), and 66.7% of patients were men. Restorative resection was achieved in 97.5% of patients, with a conversion rate from laparoscopic to open surgery of 6.8%. The composite optimal pathological outcome was 93.9%. The median follow-up was 26 months (interquartile range, 12-47), and 82.8% of patients achieved reestablishment of GI continuity to date. The overall local recurrence rate was 4.7% (n = 13). The estimated 2-year local recurrence-free survival rate was 95.0% (95% CI, 92-98) and the estimated 5-year local recurrence-free survival rate was 94.5% (95% CI, 91-98). LIMITATIONS: Limitations include the retrospective nature of the study and the generalizability of a Canadian population. CONCLUSIONS: Recent European data have challenged the presumed oncologic safety of transanal total mesorectal excision. Although the learning curve for this procedure is challenging and poor outcomes are associated with low volume, this high-volume single-center study confirms acceptable oncologic outcomes consistent with the current standard. See Video Abstract . SOBREVIDA SIN RECIDIVA DESPUS DE TATME EXPERIENCIA INSTITUCIONAL CANADIENSE: ANTECEDENTES:La excisión total del mesorecto por vía transanal es un tratamiento quirúrgico novedoso para los cánceres de recto medio a bajo. Estudios sobre la población noruega han generado preocupación debido a la recidiva local en pacientes tratados con excisión total del mesorecto por vía transanal.OBJETIVO:Nuestra finalidad fué de analizar la recidiva local y la sobrevida libre de enfermedad en pacientes tratados mediante la excisión total del mesorecto por vía transanal, debido a un cáncer de recto en un centro terciario de alto volúmen.DISEÑO:El presente estudio retrospectivo, utiliza una base de datos institucional sobre la excisión total del mesorecto por vía transanal mantenida prospectivamente. Se analizaron los datos demográficos, de tratamiento y los resultados de los pacientes sometidos a la técnica mencionada. La recidiva local, la sobrevida libre de enfermedad y la sobrevida global se analizaron mediante el modelo de Kaplan-Meier.AJUSTES:El estudio se llevó a cabo en una sola institución académica en Vancouver, Canadá.PARTICIPANTES:Se incluyeron todos los pacientes tratados mediante excisión total del mesorecto por vía transanal causado por adenocarcinomas de recto entre 2014 y 2022.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la sobrevida libre de recidiva local.RESULTADOS:Entre 2014 y 2022, 306 pacientes fueron tratados mediante la excisión total del mesorecto por vía transanal en el Hospital St. Paul. De estos, 279 pacientes cumplieron los criterios de inclusión. La edad media fue de 62 años (DE ± 12,3) y el 66,7% de los pacientes eran varones. La resección restauradora se logró en el 97,5% de los pacientes con una tasa de conversión de cirugía laparoscópica en laparotomía del 6,8%. El resultado patológico óptimo combinado fué del 93,9%. La mediana de seguimiento fue de 26 meses (rango intercuartil 12-47) y el 82,8% logró el restablecimiento de la continuidad gastrointestinal hasta la fecha. La tasa global de recidiva local fué del 4,7% (n = 13). La sobrevida libre de recidiva local estimada a los 2 años fué del 95,0% (IC del 95%: 92-98) y del 94,5% a los 5 años (IC del 95%: 91-98).LIMITACIONES:Las limitaciones incluyen la naturaleza retrospectiva del estudio y la generalización de una población canadiense.CONCLUSIONES:Datos europeos recientes han cuestionado la supuesta seguridad oncológica de la excisión total del mesorecto por vía transanal. Si bien la curva de aprendizaje de este procedimiento es muy desafiante y los malos resultados se asocian con un volumen bajo, el presente estudio, unicéntrico de gran volumen confirma los resultados oncológicos aceptables consistentes con el estándar actual. (Traducción-Dr. Xavier Delgadillo ).

Mutagenesis enhances gellan gum production by a novel Sphingomonas spp.: upstream optimization, kinetic modeling, and structural and physico-functional evaluation.

Gellan gum (GG) has gained tremendous attention owing to its diversified applications. However, its high production and hence market cost are still a bottleneck in its widespread utilization. In the present study, high GG producing mutant of Sphingomonas spp. was developed by random mutagenesis using ethyl methylsulphonate (EMS) for industrial fermentation and identified as Sphingomonas trueperi after 16S rRNA and matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF-MS) analysis. The fermentation conditions such as pH, temperature, and inoculum ratio were optimized by one factor at a time (OFAT) followed by screening of medium components by the Plackett-Burman statistical design. The most critical nutrients were further optimized by response surface methodology for maximizing GG production. The effect of dissolved oxygen tension in bioreactor on cell growth, substrate consumption, GG production, and batch productivity was elucidated. The highest GG titer (23 ± 2.4 g/L) was attained in optimized medium at 10% inoculum (6.45 ± 0.5 log cfu/mL) under controlled fermentation conditions of pH (7), temperature (30 °C), agitation (300-600 rpm), and aeration (0.5-2.0 SLPM) at 22 ± 2% dissolved oxygen tension in a 10-L bioreactor. Kinetic modeling of optimized batch process revealed that logistic growth model could best explain biomass accumulation, while GG formation and substrate consumption were best explained by Luedeking-Piret and exponential decay model, respectively. Structural and physico-functional features of GG produced by mutant Sphingomonas spp. were characterized by HPLC, FTIR, NMR, DSC, TGA, GPC, SEM, and rheological analysis. The higher productivity (0.51 g/L/h) under optimized fermentation conditions suggests potential consideration of mutant and process for commercial utilization.

Surgical Outcomes in Total Neoadjuvant Therapy for Rectal Cancer Versus Standard Long-course Chemoradiation: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: This systematic review and meta-analysis seeks to evaluate the impact of total neoadjuvant therapy (TNT) for rectal cancers on surgical complications and surgical pathology when compared with standard long-course chemoradiotherapy (LCRT). BACKGROUND: The oncological benefits of TNT are well published in previous meta-analyses, but there is little synthesized information on how it affects surgical outcomes. A recent study has suggested an increase in local recurrence and higher rates of breached total mesorectal excision (TME) plane in TNT patients. METHODS: This study conformed to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A search was performed in Medline (via PubMed), Cochrane databases, EMBASE and CINAHL to identify relevant randomized controlled trials (RCTs) comparing outcomes between TNT and LCRT. Meta-analyses of pooled proportions between TNT and LCRT were performed, comparing primary outcomes of surgical mortality, morbidity and all reported complications; surgical-pathology differences, namely mesorectal quality, R0 resection rates, circumferential resection margin positive rates, and sphincter preservation rates. Death and progression of disease during neoadjuvant treatment period was also compared. Risk of bias of RCTs was performed using the Cochrane risk-of-bias tool by 2 independent reviewers. RESULTS: A total of 3185 patients with rectal cancer from 11 RCTs were included in the analysis: 1607 received TNT and 1578 received LCRT, of which 1422 (TNT arm) and 1391 (LCRT arm) underwent surgical resection with curative intent. There was no significant difference in mortality [risk ratio (RR)=0.86, 95% CI: 0.13-5.52, P =0.88, I2 =52%] or major complications (RR=1.04, 95% CI: 0.86-1.26, P =0.70, I2 =0%) between TNT and LCRT. There was a significantly higher risk of breached TME in TNT group on pooled analysis (RR=1.49, 95% CI: 1.03-12.16, P =0.03, I2 =0%), and on subgroup analysis there is higher risk of breached TME in those receiving extended duration of neoadjuvant treatment (>17 weeks from start of treatment to surgery) when compared with LCRT (RR=1.61, 95% CI: 1.06-2.44, P =0.03). No difference in R0 resection rates (RR=0.85, 95% CI: 0.66-1.10, P =0.21, I2 =15%), circumferential resection margin positive rates (RR=0.87, 95% CI: 0.65-1.16, P =0.35, I2 =10%) or sphincter preservation rates (RR=1.02, 95% CI: 0.83-1.25, P =0.88, I2 =57%) were observed. There was a significantly lower risk of progression of disease to an unresectable stage during the neoadjuvant treatment period in TNT patients (RR=0.60, 95% CI: 0.39-0.92, P =0.03, I2 =18%). On subgroup analysis, it appears to favor those receiving extended duration of neoadjuvant treatment (RR=0.44, 95% CI: 0.26-0.80, P =0.002), and those receiving induction-type chemotherapy in TNT (RR=0.25, 95% CI: 0.07-0.88, P =0.03). CONCLUSIONS: TNT increases rates of breached TME which can contribute to higher local recurrence rates. TNT, however, improves systemic control by reducing early progression of disease during neoadjuvant treatment period. Further research is warranted to identify patients that will benefit from this strategy.

Antioxidant and Antiproliferative Activities of Several Garlic Forms.

It is hypothesized that garlic, Allium sativum, might protect against oxidative stress that causes damage to cells and tissues leading to the development of various health conditions including cancer. However, it is not known whether garlic's potential anticancer benefits differ by form of garlic consumed. This study aimed to quantify and compare the in vitro antioxidant and antiproliferative activity of several garlic forms in water and alcohol extracts including fresh garlic, fresh garlic set aside, heated garlic, heated garlic set aside, garlic powder, black garlic, two commercially available garlic supplements. Antioxidant activity of different garlic forms were measured using three assays: DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) assay, superoxide assay, and hydroxyl assay. In vitro effects of garlic extracts were investigated against the most common lung cancer subtypes: H520, H1975, and A549 cell lines using the sulforhodamine B (SRB) assay. Among free radical scavenging assays, Garlicin®, a commercially available supplement, displayed high antioxidant activity in water and alcohol extracts (DPPH assay: 2.02 mg AAE (mg ascorbic acid equivalent)/g garlic and 3.53 mg AAE/g garlic, respectively; superoxide assay: 6.73 mg AAE/g garlic and 7.13 mg AAE/g garlic, respectively). In the hydroxyl assay, water extract of fresh garlic crushed and set aside for 10 min showed the highest antioxidant activity. Garlicin® alcohol extract and fresh garlic water extracts strongly inhibited the proliferation of H1975, A549 and H520 cells. Other forms of garlic including garlic powder and black garlic exhibited low antioxidant and antiproliferative activity. Our results demonstrate that the preparation and processing methods of garlic may lead to different antioxidant benefits.

Local versus radical surgery for early rectal cancer with or without neoadjuvant or adjuvant therapy.

BACKGROUND: Total mesorectal excision is the standard of care for stage I rectal cancer. Despite major advances and increasing enthusiasm for modern endoscopic local excision (LE), uncertainty remains regarding its oncologic equivalence and safety relative to radical resection (RR). OBJECTIVES: To assess the oncologic, operative, and functional outcomes of modern endoscopic LE compared to RR surgery in adults with stage I rectal cancer. SEARCH METHODS: We searched CENTRAL, Ovid MEDLINE, Ovid Embase, Web of Science - Science Citation Index Expanded (1900 to present), four trial registers (ClinicalTrials.gov, ISRCTN registry, the WHO International Clinical Trials Registry Platform, and the National Cancer Institute Clinical Trials database), two thesis and proceedings databases, and relevant scientific societies' publications in February 2022. We performed handsearching and reference checking and contacted study authors of ongoing trials to identify additional studies. SELECTION CRITERIA: We searched for randomized controlled trials (RCTs) in people with stage I rectal cancer comparing any modern LE techniques to any RR techniques with or without the use of neo/adjuvant chemoradiotherapy (CRT). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We calculated hazard ratios (HR) and standard errors for time-to-event data and risk ratios for dichotomous outcomes, using generic inverse variance and random-effects methods. We regrouped surgical complications from the included studies into major and minor according to the standard Clavien-Dindo classification. We assessed the certainty of evidence using the GRADE framework. MAIN RESULTS: Four RCTs were included in data synthesis with a combined total of 266 participants with stage I rectal cancer (T1-2N0M0), if not stated otherwise. Surgery was performed in university hospital settings. The mean age of participants was above 60, and median follow-up ranged from 17.5 months to 9.6 years. Regarding the use of co-interventions, one study used neoadjuvant CRT in all participants (T2 cancers); one study used short-course radiotherapy in the LE group (T1-T2 cancers); one study used adjuvant CRT selectively in high-risk patients undergoing RR (T1-T2 cancers); and the fourth study did not use any CRT (T1 cancers). We assessed the overall risk of bias as high for oncologic and morbidity outcomes across studies. All studies had at least one key domain with a high risk of bias. None of the studies reported separate outcomes for T1 versus T2 or for high-risk features. Low-certainty evidence suggests that RR may result in an improvement in disease-free survival compared to LE (3 trials, 212 participants; HR 1.96, 95% confidence interval (CI) 0.91 to 4.24). This would translate into a three-year disease-recurrence risk of 27% (95% CI 14 to 50%) versus 15% after LE and RR, respectively. Regarding sphincter function, only one study provided objective results and reported short-term deterioration in stool frequency, flatulence, incontinence, abdominal pain, and embarrassment about bowel function in the RR group. At three years, the LE group had superiority in overall stool frequency, embarrassment about bowel function, and diarrhea. Local excision may have little to no effect on cancer-related survival compared to RR (3 trials, 207 participants; HR 1.42, 95% CI 0.60 to 3.33; very low-certainty evidence). We did not pool studies for local recurrence, but the included studies individually reported comparable local recurrence rates for LE and RR (low-certainty evidence). It is unclear if the risk of major postoperative complications may be lower with LE compared with RR (risk ratio 0.53, 95% CI 0.22 to 1.28; low-certainty evidence; corresponding to 5.8% (95% CI 2.4% to 14.1%) risk for LE versus 11% for RR). Moderate-certainty evidence shows that the risk of minor postoperative complications is probably lower after LE (risk ratio 0.48, 95% CI 0.27 to 0.85); corresponding to an absolute risk of 14% (95% CI 8% to 26%) for LE compared to 30.1% for RR. One study reported an 11% rate of temporary stoma after LE versus 82% in the RR group. Another study reported a 46% rate of temporary or permanent stomas after RR and none after LE. The evidence is uncertain about the effect of LE compared with RR on quality of life. Only one study reported standard quality of life function, in favor of LE, with a 90% or greater probability of superiority in overall quality of life, role, social, and emotional functions, body image, and health anxiety. Other studies reported a significantly shorter postoperative period to oral intake, bowel movement, and off-bed activities in the LE group. AUTHORS' CONCLUSIONS: Based on low-certainty evidence, LE may decrease disease-free survival in early rectal cancer. Very low-certainty evidence suggests that LE may have little to no effect on cancer-related survival compared to RR for the treatment of stage I rectal cancer. Based on low-certainty evidence, it is unclear if LE may have a lower major complication rate, but probably causes a large reduction in minor complication rate. Limited data based on one study suggest better sphincter function, quality of life, or genitourinary function after LE. Limitations exist with respect to the applicability of these findings. We identified only four eligible studies with a low number of total participants, subjecting the results to imprecision. Risk of bias had a serious impact on the quality of evidence. More RCTs are needed to answer our review question with greater certainty and to compare local and distant metastasis rates. Data on important patient outcomes such as sphincter function and quality of life are very limited. Results of currently ongoing trials will likely impact the results of this review. Future trials should accurately report and compare outcomes according to the stage and high-risk features of rectal tumors, and evaluate quality of life, sphincter, and genitourinary outcomes. The role of neoadjuvant or adjuvant therapy as an emerging co-intervention for improving oncologic outcomes after LE needs to be further defined.

Safety and Efficacy of Iltamiocel Cellular Therapy for the Treatment of Fecal Incontinence. Results of a Phase 1/2 Study.

OBJECTIVE: To examine the safety and efficacy of iltamiocel, an investigational cellular therapy of autologous muscle-derived cells, as a treatment for fecal incontinence (FI) in adults. BACKGROUND: Limited therapeutic options are available for patients with FI refractory to conservative treatments. Cell therapy using autologous muscle-derived cells represents a promising, minimally invasive approach for restoring anal sphincter function. METHODS: In this multicenter, prospective, non-randomized study, 48 participants were treated with a single iltamiocel dose of 250×10 6 cells. The primary outcome was the incidence of product or procedure-related adverse events (AEs) and serious AEs. Secondary outcomes were changes in the number of FI episodes, Cleveland Clinic Incontinence Score, Fecal Incontinence Quality of Life, and anorectal manometry at 3, 6, and 12 months compared to baseline. RESULTS: No serious AEs and only one product-related AE of inflammation at the injection site were reported. At 12 months, there was a reduction in median FI episodes (-6.0; 95% confidence interval (CI): -10.0, -1.0) and days with episodes (-4.0; 95% CI: -8.0, -1.0). A ≥50% reduction in FI episodes was observed in 53.7% of participants, and 24.4% had complete restoration of continence. Symptom severity and quality of life improved with mean Cleveland Clinic Incontinence Score reduction (-2.9; 95% CI: -3.7, -2.1), and Fecal Incontinence Quality of Life increased (2.2; 95% CI:1.4, 2.9). No significant changes were detected in anorectal manometry measurements. A history of episiotomy was significantly associated with treatment response in multivariate analysis. CONCLUSION: The administration of iltamiocel cellular therapy is safe. Iltamiocel shows promise for significantly improving fecal incontinence symptoms and quality of life.

Management of rectal neuroendocrine tumours by transanal endoscopic microsurgery.

AIM: The objective of this study was to evaluate the safety and effectiveness of transanal endoscopic microsurgery for rectal neuroendocrine tumours. METHOD: A retrospective cohort study of all pathology-confirmed rectal neuroendocrine tumours treated by transanal endoscopic microsurgery from April 2007 to December 2020 at a tertiary care centre was performed. Demographic, clinical, radiographic and pathological data were collected. Characteristics of patients with recurrence were examined. Descriptive statistics were performed. RESULTS: There were 58 patients treated by transanal endoscopic microsurgery excision. Referrals were for primary excision (15, 25.9%), completion re-excision after incomplete endoscopic removal (38, 65.5%) or locally recurrent rectal neuroendocrine tumours (5, 8.6%). The mean age of patients was 56.4 ± 11.9 years and 26 patients were women (44.8%). Mean tumour size was 7.4 ± 3.8 mm (range 1.0-15.0 mm). Most (86.4%) were Grade 1 tumours. Mean operative time was 37.2 ± 17.2 min and 56 patients (96.6%) were discharged on the same day. All patients had negative margins on final pathology. Of the 38 patients who were referred for completion re-excision after incomplete endoscopic removal, eight (21.1%) had residual tumour on final pathology. Three recurrences were diagnosed at 2.1, 4.5 and 12.5 years after excision. All recurrences were from Grade 1 or 2 primary tumours, less than 2 cm, and diagnosed radiographically. CONCLUSION: To date, this is the largest North American study looking at transanal endoscopic microsurgery for rectal neuroendocrine tumours. This technique is effective in managing primary, incompletely excised and recurrent tumours with good clinical and oncological outcomes.

A comparison of perineal stapled prolapse resection and the Altemeier procedure at 2 Canadian academic hospitals.

BACKGROUND: The preferred perineal repair method for full-thickness rectal prolapse is the Altemeier procedure, a perineal proctosigmoidectomy with handsewn anastomosis. A recently described variant of this procedure combines the resection and anastomosis into 1 step by means of linear and transverse stapling. There are few published data comparing the characteristics and outcomes of these 2 approaches. METHODS: This retrospective review, performed at 2 Canadian academic hospitals, compares surgical and cost outcomes between the perineal stapled prolapse resection (PSPR) and the Altemeier procedure. All patients who underwent these procedures between 2015 and 2019 were included. RESULTS: There were 25 patients in the PSPR group and 19 in the Altemeier group. Patients in the PSPR group were significantly older than those in the Altemeier group (81 [95% confidence interval (CI) 70-92] yr v. 74 [95% CI 63-85] yr; p = 0.047), had a lower body mass index (21.4 [95% CI 17.7-25.1] v. 24.4 [95% CI 18.5-30.3]; p = 0.042) and had equivalent American Society of Anesthesiologists scores (2.84 [95% CI 2.09-3.59] v. 2.68 [95% CI 1.93-3.43]; p = 0.49). The operative time for PSPR was significantly less (30.3 [95% CI 16.3-44.3] min v. 67 [95% CI 43-91] min; p < 0.001), as were the operative costs. Recurrence (28.0% v. 36.8%; p = 0.53) and complication rates were equivalent. CONCLUSION: PSPR is a safe, efficient and effective approach to perineal proctosigmoidectomy. It is associated with surgical outcomes comparable to those of the Altemeier procedure, but with a significant reduction in operative time and cost.

Social support, educational, and behavioral modification interventions for improving household disaster preparedness in the general community-dwelling population: a systematic review and meta-analysis.

Background: The efficacy of household emergency preparedness interventions for community-dwelling, non-institutionalized people is largely unknown. Objective: To ascertain the state of the science on social support, educational, and behavioral modification interventions to improve all-hazard household disaster preparedness. Design: Systematic review and meta-analysis. Methods: Databases, trial registers, reports, and websites were searched, and citation trails followed utilizing replicable methods. Individual, cluster, and cross-over randomized controlled trials of non-institutionalized, community-dwelling populations and non-randomized controlled trials, controlled before-after, and program evaluation studies were included. At least two review authors independently screened each potentially relevant study for inclusion, extracted data, and assessed the risk of bias. Risk of bias was assessed using Cochrane's RoB2 tool for randomized studies and ROBINS-I tool for nonrandomized studies. Meta-analyses were applied using a random-effects model. Where meta-analysis was not indicated, results were synthesized using summary statistics of intervention effect estimates and vote counting based on effect direction. The evidence was rated using GRADE. Results: 17 studies were included with substantial methodological and clinical diversity. No intervention effect was observed for preparedness supplies (OR = 6.12, 95% 0.13 to 284.37) or knowledge (SMD = 0.96, 95% CI -0.15 to 2.08) outcomes. A small positive effect (SMD = 0.53, 95% CI 0.16 to 0.91) was observed for preparedness behaviors, with very low certainty of evidence. No studies reported adverse effects from the interventions. Conclusion: Research designs elucidating the efficacy of practical yet complex and multi- faceted social support, educational, and behavioral modification interventions present substantial methodological challenges where rigorous study design elements may not match the contextual public health priority needs and resources where interventions were delivered. While the overall strength of the evidence was evaluated as low to very low, we acknowledge the valuable and informative work of the included studies. The research represents the seminal work in this field and provides an important foundation for the state of the science of household emergency preparedness intervention effectiveness and efficacy. The findings are relevant to disaster preparedness practice and research, and we encourage researchers to continue this line of research, using these studies and this review to inform ongoing improvements in study designs.

Gabapentin to treat acute alcohol withdrawal in hospitalized patients: A systematic review and meta-analysis.

BACKGROUND: Gabapentin is an antiepileptic medication with evidence of benefit in alcohol use disorder patients. The mechanism of action of gabapentin may also benefit patients suffering from acute alcohol withdrawal syndrome (AWS). METHODS: A systematic review and meta-analysis were conducted to examine if gabapentin can effectively replace/reduce the use of benzodiazepines for the treatment of acute alcohol withdrawal symptoms in hospitalized patients. Time to alcohol withdrawal symptom resolution, amount of benzodiazepines administered, rate of resolution of alcohol withdrawal symptoms, serious withdrawal-related complications, and hospital length of stay (LOS) were examined. RESULTS: Eight retrospective studies (n = 2030) were included in this meta-analysis. There were no studies that examined study outcomes for patients who received only gabapentin and no benzodiazepines; in all studies, gabapentin-treated patients may have received benzodiazepines prior to gabapentin. There were no significant differences between gabapentin-treated and benzodiazepine-treated groups in time to symptom resolution, amount benzodiazepines administered, withdrawal-related complications, or LOS. There was a significant difference in the rate of symptom resolution favoring gabapentin-treated patients (p = 0.05); however, this analysis included only one study. Subgroup analyses of severe AWS patients revealed a significant decrease in LOS (p = 0.04) and a decrease in amount of benzodiazepines administered (p = 0.02) in gabapentin-treated patients, but these analyses included only one study. Subgroup analysis of patients receiving only gabapentin without benzodiazepines found a significantly decreased LOS in the gabapentin group compared to the benzodiazepine group (p < 0.001), but this analysis included only two studies. CONCLUSIONS: There is insufficient evidence to support the widespread use of gabapentin to treat inpatients suffering AWS. All studies included in this meta-analysis are retrospective with high risk of confounding. Well-designed, randomized, controlled studies of gabapentin to treat patients with AWS are required.

Patterns of Healthcare Utilization Leading to Diagnosis of Young-Onset Colorectal Cancer (yCRC): Population-Based Case-Control Study.

Background: The increasing risk of young-onset colorectal cancer (yCRC) in adults < 50 years has called for better understanding of patients' pathways to diagnosis. This study evaluated patterns of healthcare utilization before diagnosis of yCRC. Methods: Using linked administrative health databases in British Columbia, Canada, we identified yCRC cases and cancer-free controls matched (1:10) on age, sex, and healthcare utilization. The index date was the date of diagnosis for yCRC cases and matched date for controls. Outpatient visits, emergency department visits, and hospitalizations over a 5-year prediagnosis period (e.g., year-1 to year-5) were compared using descriptive statistics and Poisson regression models. Results: The study included 2567 yCRC cases (49.6% females, 43.0 ± 5.8 years) and 25,455 controls (48.6% females, 43.0 ± 5.8 years). We observed an increasing number of outpatient visits from prediagnosis year-5 (median = 3) to year-1 (median = 8) for yCRC cases. Among controls, outpatient visits were stable and did not have a pattern of increase. Poisson regression models indicated higher adjusted count ratios for outpatient visits for yCRC cases compared to controls in the year before diagnosis (1.11; 95% CI, 1.07 to 1.15). In the year before diagnosis, 35.1% of yCRC cases had potentially related visits to CRC (e.g., nausea, vomiting) and 16.9% had potentially red flag visits (e.g., gastrointestinal hemorrhage or iron deficiency anemia). Conclusions: Using population-based data, we found that individuals with yCRC did not have higher healthcare utilization than individuals without in the prediagnosis period except for the year before diagnosis.

Leukotriene inhibitors with dexamethasone show promise in the prevention of death in COVID-19 patients with low oxygen saturations.

Introduction: COVID-19 is a major health threat around the world causing hundreds of millions of infections and millions of deaths. There is a pressing global need for effective therapies. We hypothesized that leukotriene inhibitors (LTIs), that have been shown to lower IL6 and IL8 levels, may have a protective effect in patients with COVID-19. Methods: In this retrospective controlled cohort study, we compared death rates in COVID-19 patients who were taking a LTI with those who were not taking an LTI. We used the Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW) to create a cohort of COVID-19-positive patients and tracked their use of LTIs between November 1, 2019 and November 11, 2021. Results: Of the 1,677,595 cohort of patients tested for COVID-19, 189,195 patients tested positive for COVID-19. Forty thousand seven hundred one were admitted. 38,184 had an oxygen requirement and 1214 were taking an LTI. The use of dexamethasone plus a LTI in hospital showed a survival advantage of 13.5% (CI: 0.23%-26.7%; p < 0.01) in patients presenting with a minimal O2Sat of 50% or less. For patients with an O2Sat of <60 and <50% if they were on LTIs as outpatients, continuing the LTI led to a 14.4% and 22.25 survival advantage if they were continued on the medication as inpatients. Conclusions: When combined dexamethasone and LTIs provided a mortality benefit in COVID-19 patients presenting with an O2 saturations <50%. The LTI cohort had lower markers of inflammation and cytokine storm.

Neutralizing COVID-19 Convalescent Plasma in Adults Hospitalized With COVID-19: A Blinded, Randomized, Placebo-Controlled Trial.

BACKGROUND: Convalescent plasma has been one of the most common treatments for COVID-19, but most clinical trial data to date have not supported its efficacy. RESEARCH QUESTION: Is rigorously selected COVID-19 convalescent plasma with neutralizing anti-SARS-CoV-2 antibodies an efficacious treatment for adults hospitalized with COVID-19? STUDY DESIGN AND METHODS: This was a multicenter, blinded, placebo-controlled randomized clinical trial among adults hospitalized with SARS-CoV-2 infection and acute respiratory symptoms for < 14 days. Enrolled patients were randomly assigned to receive one unit of COVID-19 convalescent plasma (n = 487) or placebo (n = 473). The primary outcome was clinical status (disease severity) 14 days following study infusion measured with a seven-category ordinal scale ranging from discharged from the hospital with resumption of normal activities (lowest score) to death (highest score). The primary outcome was analyzed with a multivariable ordinal regression model, with an adjusted odds ratio (aOR) < 1.0 indicating more favorable outcomes with convalescent plasma than with placebo. In secondary analyses, trial participants were stratified according to the presence of endogenous anti-SARS-CoV-2 antibodies ("serostatus") at randomization. The trial included 13 secondary efficacy outcomes, including 28-day mortality. RESULTS: Among 974 randomized patients, 960 were included in the primary analysis. Clinical status on the ordinal outcome scale at 14 days did not differ between the convalescent plasma and placebo groups in the overall population (aOR, 1.04; one-seventh support interval [1/7 SI], 0.82-1.33), in patients without endogenous antibodies (aOR, 1.15; 1/7 SI, 0.74-1.80), or in patients with endogenous antibodies (aOR, 0.96; 1/7 SI, 0.72-1.30). None of the 13 secondary efficacy outcomes were different between groups. At 28 days, 89 of 482 (18.5%) patients in the convalescent plasma group and 80 of 465 (17.2%) patients in the placebo group had died (aOR, 1.04; 1/7 SI, 0.69-1.58). INTERPRETATION: Among adults hospitalized with COVID-19, including those seronegative for anti-SARS-CoV-2 antibodies, treatment with convalescent plasma did not improve clinical outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT04362176; URL: www. CLINICALTRIALS: gov.

Venous and arterial thrombosis in COVID-19: An updated narrative review.

Hospitalized patients with coronavirus disease 2019 (COVID-19), particularly those admitted to the intensive care unit (ICU) are at high risk of morbidity and mortality. Several observational studies have described hemostatic derangements and thrombotic complications in patients with COVID-19. The aim of this review article is to summarize the current evidence on pathologic findings, pathophysiology, coagulation and hemostatic abnormalities, D-dimer's role in prognostication epidemiology and risk factors of thrombotic complications, and the role of prophylactic and therapeutic anticoagulation in patients with COVID-19. While existing evidence is limited in quality, COVID-19 appears to increase micro-and macro-vascular thrombosis rates in hospitalized and critically ill patients, which may contribute to the burden of disease. D-dimer can be used for risk stratification of hospitalized patients, but its role to guide anticoagulation therapy remains unclear. Evidence of higher quality is needed to address the role of therapeutic anticoagulation or high-intensity venous thromboembolism prophylaxis in COVID-19 patients. TAKE-HOME POINTS.

Advances in fermentative production, purification, characterization and applications of gellan gum.

Multiple microbial exopolysaccharides have been reported in recent decade with their structural and functional features. Gellan gum (GG) is among these emerging biopolymers with versatile properties. Low production yield, high downstream cost, and abundant market demand have made GG a high cost material. Hence, an understanding on the various possibilities to develop cost-effective gellan gum bioprocess is desirable. This review focuses on details of upstream and downstream process of GG from an industrial perspective. It emphasizes on GG producing Sphingomonas spp., updates on biosynthesis, strain and media engineering, kinetic modeling, bioreactor design and scale-up considerations. Details of the downstream operations with possible modifications to make it cost-effective and environmentally sustainable have been discussed. The updated regulatory criteria for GG as a food ingredient and analytical tools required to validate the same have been briefly discussed. Derivatives of GG and their applications in various industrial segments have also been highlighted.

Proteomic Network Analysis of Bronchoalveolar Lavage Fluid in Ex-Smokers to Discover Implicated Protein Targets and Novel Drug Treatments for Chronic Obstructive Pulmonary Disease.

Bronchoalveolar lavage of the epithelial lining fluid (BALF) can sample the profound changes in the airway lumen milieu prevalent in chronic obstructive pulmonary disease (COPD). We compared the BALF proteome of ex-smokers with moderate COPD who are not in exacerbation status to non-smoking healthy control subjects and applied proteome-scale translational bioinformatics approaches to identify potential therapeutic protein targets and drugs that modulate these proteins for the treatment of COPD. Proteomic profiles of BALF were obtained from (1) never-smoker control subjects with normal lung function (n = 10) or (2) individuals with stable moderate (GOLD stage 2, FEV1 50−80% predicted, FEV1/FVC < 0.70) COPD who were ex-smokers for at least 1 year (n = 10). After identifying potential crucial hub proteins, drug−proteome interaction signatures were ranked by the computational analysis of novel drug opportunities (CANDO) platform for multiscale therapeutic discovery to identify potentially repurposable drugs. Subsequently, a literature-based knowledge graph was utilized to rank combinations of drugs that most likely ameliorate inflammatory processes. Proteomic network analysis demonstrated that 233 of the >1800 proteins identified in the BALF were significantly differentially expressed in COPD versus control. Functional annotation of the differentially expressed proteins was used to detail canonical pathways containing the differential expressed proteins. Topological network analysis demonstrated that four putative proteins act as central node proteins in COPD. The drugs with the most similar interaction signatures to approved COPD drugs were extracted with the CANDO platform. The drugs identified using CANDO were subsequently analyzed using a knowledge-based technique to determine an optimal two-drug combination that had the most appropriate effect on the central node proteins. Network analysis of the BALF proteome identified critical targets that have critical roles in modulating COPD pathogenesis, for which we identified several drugs that could be repurposed to treat COPD using a multiscale shotgun drug discovery approach.

Pirfenidone in Progressive Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.

Background: The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax convened to update clinical practice guidelines for interstitial lung disease (ILD). Objective: To conduct a systematic review to evaluate existing ILD literature to determine whether patients with progressive pulmonary fibrosis (PPF) should be treated with the antifibrotic pirfenidone. Data Sources: A literature search was conducted across MEDLINE, EMBASE, and Cochrane databases through December 2020 for studies using pirfenidone to treat patients with PPF. Data Extraction: Mortality, disease progression, lung function, and adverse event data were extracted. Meta-analyses were performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation Working Group approach was used to assess the quality of evidence. Synthesis: Two studies met inclusion criteria. Meta-analyses revealed that changes in forced vital capacity (FVC) percent predicted (mean difference [MD], 2.3%; 95% confidence interval [CI], 0.5-4.1%), the FVC in milliliters (MD, 100.0 ml; 95% CI, 98.1-101.9 ml), and the 6-minute-walk distance in meters (MD, 25.2 m; 95% CI, 8.3-42.1 m) all favored pirfenidone over placebo. The changes in the diffusing capacity of the lung for carbon monoxide (DLCO) in millimoles per kilopascal per minute (MD, 0.40 mmol/kPa/min; 95%, CI 0.10-0.70 mmol/kPa/min) and risk of DLCO declining more than 15% (relative risk [RR], 0.27; 95% CI, 0.08-0.95) also favored pirfenidone. The risks of gastrointestinal discomfort (RR, 1.83; 95% CI, 1.29-2.60) and photosensitivity (RR, 4.88; 95% CI, 1.09-21.83) were higher with pirfenidone. The quality of the evidence was low or very low according to the Grading of Recommendations, Assessment, Development and Evaluation criteria, depending on the outcome. Conclusions: Pirfenidone use in patients with PPF is associated with a statistically significant decrease in disease progression and with protection of lung function. However, there is very low certainty in the estimated effects because of limitations in the available evidence. Primary Source of Funding: Funded by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.

Nintedanib in Progressive Pulmonary Fibrosis: A Systematic Review and Meta-Analysis.

Background: The American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax convened to update clinical practice guidelines for interstitial lung disease (ILD). Objective: To conduct a systematic review to evaluate existing ILD literature to determine whether patients with progressive pulmonary fibrosis (PPF) should be treated with the antifibrotic nintedanib. Data Sources: A literature search was conducted across MEDLINE, EMBASE, and Cochrane databases through December 2020 for studies using nintedanib to treat patients with PPF. Data Extraction: Mortality, disease progression, and adverse event data were extracted, and meta-analyses performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group approach was used to assess the quality of evidence. Synthesis: Two relevant studies were selected. The annual decline in forced vital capacity was less in the nintedanib arm in the overall study population (mean difference [MD], 107 ml/yr; 95% confidence interval [CI], 65.4 to 148.5 ml/yr) and in the subgroups with usual interstitial pneumonia (UIP) pattern of pulmonary fibrosis (MD, 128.2 ml/yr; 95% CI, 70.8 to 185.6 ml/yr), non-UIP patterns of pulmonary fibrosis (MD, 75.3 ml/yr; 95% CI, 15.5 to 135.0 ml/yr), fibrotic connective tissue disease-related ILD (MD, 106.2 ml/yr; 95% CI, 10.6 to 201.9 ml/yr), fibrotic idiopathic nonspecific interstitial pneumonia (MD, 141.7 ml/yr; 95% CI, 46.0 to 237.4 ml/yr), and fibrotic occupational ILD (MD, 252.8 ml/yr; 95% CI, 79.2 to 426.5 ml/yr), but not fibrotic hypersensitivity pneumonitis (MD, 72.9 ml/yr; 95% CI, -8.9 to 154.7 ml/yr), fibrotic sarcoidosis (MD, -20.5 ml/yr; 95% CI, -337.1 to 296.1 ml/yr), or unclassified fibrotic ILD (MD, 68.5 ml/yr; 95% CI, -31.3 to 168.4 ml/yr) when compared with placebo. Gastrointestinal side effects were common. Quality of evidence for the outcomes ranged from very low to moderate GRADE. Conclusions: Nintedanib use in patients with PPF is associated with a statistically significant decrease in disease progression but increase in gastrointestinal side effects regardless of the radiographic pattern of pulmonary fibrosis. However, limitations in the available evidence lead to low certainty in these effect estimates and make definitive conclusions about the differential effects by subtype of ILD difficult to determine. Primary Source of Funding: Funded by the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax.

Transbronchial Lung Cryobiopsy in Patients with Interstitial Lung Disease: A Systematic Review.

Rationale: In 2018, a systematic review evaluating transbronchial lung cryobiopsy (TBLC) in patients with interstitial lung disease (ILD) was performed to inform American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax clinical practice guidelines on the diagnosis of idiopathic pulmonary fibrosis. Objectives: To perform a new systematic review to inform updated guidelines. Methods: Medline, Excerpta Medica Database, and the Cochrane Central Register of Controlled Trials (CCTR) were searched through June 2020. Studies that enrolled patients with ILD and reported the diagnostic yield or complication rates of TBLC were selected for inclusion. Data was extracted and then pooled across studies via meta-analysis. The quality of the evidence was appraised using the grading of recommendations, assessment, development, and evaluation approach. Results: Histopathologic diagnostic yield (number of procedures that yielded a histopathologic diagnosis divided by the total number of procedures performed) of TBLC was 80% (95% confidence interval [CI], 76-83%) in patients with ILD. TBLC was complicated by bleeding and pneumothorax in 30% (95% CI, 20-41%) and 8% (95% CI, 6-11%) of patients, respectively. Procedure-related mortality, severe bleeding, prolonged air leak, acute exacerbation, respiratory failure, and respiratory infection were rare. The quality of the evidence was very low owing to the uncontrolled study designs, lack of consecutive enrollment, and inconsistent results. Conclusions: Very low-quality evidence indicated that TBLC has a diagnostic yield of approximately 80% in patients with ILD, with manageable complications.