PPAR agonists as add-on treatment with metformin in management of type 2 diabetes: a systematic review and meta-analysis.

The combination of metformin and the peroxisome proliferator-activated receptors (PPAR) agonists offers a promising avenue for managing type 2 diabetes (T2D) through their potential complementary mechanisms of action. The results from randomized controlled trials (RCT) assessing the efficacy of PPAR agonists plus metformin versus metformin alone in T2D are inconsistent, which prompted the conduct of the systematic review and meta-analysis. We searched MEDLINE and EMBASE from inception (1966) to March 2023 to identify all RCTs comparing any PPAR agonists plus metformin versus metformin alone in T2D. Categorical variables were summarized as relative risk along with 95% confidence interval (CI). Twenty RCTs enrolling a total of 6058 patients met the inclusion criteria. The certainty of evidence ranged from moderate to very low. Pooled results show that using PPAR agonist plus metformin, as compared to metformin alone, results in lower concentrations of fasting glucose [MD = - 22.07 mg/dl (95% CI - 27.17, - 16.97), HbA1c [MD = - 0.53% (95% CI - 0.67, - 0.38)], HOMA-IR [MD = - 1.26 (95% CI - 2.16, - 0.37)], and fasting insulin [MD = - 19.83 pmol/L (95% CI - 29.54, - 10.13)] without significant increase in any adverse events. Thus, synthesized evidence from RCTs demonstrates the beneficial effects of PPAR agonist add-on treatment versus metformin alone in T2D patients. In particular, novel dual PPARα/γ agonist (tesaglitazar) demonstrate efficacy in improving glycaemic and lipid concentrations, so further RCTs should be performed to elucidate the long-term outcomes and safety profile of these novel combined and personalized therapeutic strategies in the management of T2D.PROSPERO registration no. CRD42023412603.

Efficacy of Intravenous Iron in Patients with Heart Failure with Reduced Ejection Fraction and Iron Deficiency: A Systematic Review and Meta-Analysis of Randomized Control Trials.

BACKGROUND: The European Society of Cardiology (ESC) provided a focused update to the 2021 Guideline for the Management of Heart Failure, now providing a 1A recommendation for intravenous iron in patients with heart failure with reduced ejection fraction (HFrEF) and iron deficiency (ID). However, the findings from randomized controlled trials (RCT) are mixed. This systematic review of RCTs aims to provide an update and synthesize the evidence addressing the association of intravenous iron with patient-based outcomes in patients with HFrEF and ID. METHODS: Any RCT evaluating the effect of intravenous iron in patients with HFrEF and ID was eligible for inclusion. A complete search of the EMBASE and PubMed databases was conducted from inception until 15 September 2023. The primary outcome was the composite of the quality of life (QoL) questionnaires, while the secondary outcomes included first heart failure (HF) hospitalizations and all-cause mortality. Data extraction was performed independently by two reviewers. Data were pooled using a random-effects model. RESULTS: Of the 1035 references, 15 RCTs enrolling 6649 patients were included in this study. Intravenous iron was associated with significant improvement in the composite of QoL (standardized mean difference - 1.36, 95% confidence interval [CI] - 2.24 to - 0.48; p = 0.002), a significant reduction in first HF hospitalizations (hazard ratio [HR] 0.73, 95% CI 0.56-0.95; p = 0.02), and with no change in all-cause mortality (HR 0.90, 95% CI 0.79-1.03; p = 0.12). The certainty of the evidence ranged from moderate to very low. CONCLUSION: Intravenous iron is possibly associated with improved QoL and reduced HF hospitalizations, without impacting all-cause mortality. These findings not only support the use of intravenous iron in patients with HFrEF but also emphasize the need for well-designed and executed RCTs with granular outcome reporting and powered sufficiently to address the impact of intravenous iron on mortality in patients with HFrEF and ID. REGISTRATION: PROSPERO identifier number CRD42023389.

Efficacy of Autologous and Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Promyelocytic Leukemia: Results of a Systematic Review and Meta-Analysis.

Despite therapeutic advances for acute promyelocytic leukemia (APL) with the emergence of all-trans retinoic acid, arsenic trioxide, and gemtuzumab-ozogamycin, approximately 10% of patients still experience disease relapse, typically occurring within 24 to 36 months following completion of front-line treatment. Traditionally, both allogeneic (allo) and autologous (auto) hematopoietic cell transplantation (HCT) have been considered reasonable treatment options for relapsed APL; however, no randomized controlled studies have been conducted comparing allo-HCT and auto-HCT in patients with relapsed APL. We performed a systematic review/meta-analysis to assess the totality of evidence pertaining to allo-HCT or auto-HCT in relapsed APL. Our search identified 1158 references, of which 23 met our inclusion criteria. While acknowledging the limitations of comparing these 2 treatment modalities indirectly, based on results from separate meta-analyses, it appears that pooled rates of event-free survival (71% versus 54%), progression-free survival (63% versus 43%), and overall survival (82% versus 58%) are higher after auto-HCT. This difference can be explained in part by the higher risk of pooled nonrelapse mortality (NRM) in patients undergoing allo-HCT (29% versus 5%), owing to inherent risks associated with this modality. In the absence of a randomized prospective clinical trial comparing allo-HCT and auto-HCT, our results show that both modalities are acceptable in patients with relapsed APL. The higher pooled NRM rate with allo-HCT is an important consideration when choosing this option. Additionally, the comparable pooled relapse rate for auto-HCT and allo-HCT (24% versus 23%) provides a rationale for evaluating post-HCT consolidative strategies to mitigate this risk.

A systematic critical appraisal of clinical practice guidelines of antithrombotic agents in gastrointestinal endoscopy using the AGREE II tool.

BACKGROUND AND AIM: The quality of clinical practice guidelines (CPGs) for the management of antithrombotic agents in patients undergoing gastrointestinal (GI) endoscopy has not been systematically appraised. The goal of this study was to evaluate the methodological quality of CPGs for the management of antithrombotic agents in periendoscopic period published within last 6 years. METHODS: A systematic search of PubMed and Embase databases was performed to identify eligible CPGs published between January 1, 2016, and April 14, 2022, addressing the management of antithrombotic agents in the periendoscopic period. The quality of the CPG was independently assessed by six reviewers using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Domain scores were considered of sufficient quality when > 60% and of good quality when > 80%. RESULTS: The search yielded 343 citations, of which seven CPGs published by the gastroenterology associations in Asia (n = 3), Europe (n = 2), and North America (n = 2) were included for the critical appraisal. The overall median score for the AGREE II domains was 93% (interquartile range [IQR] 11%) for scope and purpose, 79% (IQR 61%) for stakeholder involvement, 79% (IQR 36%) for rigor of development, 100% (IQR 14%) for clarity of presentation, 32% (IQR 36%) for applicability, 93% (IQR 29%) for editorial independence, and 86% (IQR 29%) for overall assessment. CONCLUSIONS: The findings show that the overall methodological quality of the CPGs for the management of antithrombotic agents in the periendoscopic period varies across the domains. There is significant scope for improvement in the methodological rigor and applicability of CPGs.

Efficacy of Decision Aids in The Use of Left Ventricular Assist Device in Patients With Advanced Heart Failure: A Systematic Review and Meta-Analysis of Randomized Control Trials.

Although left ventricular assist device (LVAD) implantation can improve survival in patients with end-stage heart failure, it is not without risk. Numerous complications are possible, and durable support requires substantial lifestyle changes. The use of various knowledge-assessment tools may allow for more informed patient decisions. To synthesize the totality of the evidence, we conducted a systematic review and meta-analysis to summarize the efficacy of decision aid (DA) use in patients with advanced heart failure who are eligible for LVAD. Any randomized controlled trial (RCT) evaluating the efficacy of DAs in patients considering LVAD was eligible for inclusion. A complete search of EMBASE and PubMed was conducted from the start until June 8, 2023. The primary outcome was patients' LVAD knowledge. Data extraction was performed independently by 2 reviewers. Data were pooled using a random-effects model. Of the 575 references, 2 RCTs randomizing 490 patients were included in this study. DAs were associated with no significant change in LVAD knowledge (standardized mean difference 0.07, 95% confidence interval -0.24 to 0.39, p = 0.64) or decisional conflict (mean difference -1.48, 95% confidence interval -5.28 to 2.32, p = 0.45). The certainty of the evidence ranged from moderate to very low. The use of DAs in LVAD-eligible patients with advanced heart failure resulted in no difference in patients' knowledge of LVAD after LVAD education. The findings from this study will aid in the power analysis of a well-designed RCT to evaluate and encourage further investigation into the efficacy and relevance of DAs in preparing patients for a life with LVAD.

Quality of Pancreatic Cyst Clinical Practice Guidelines.

BACKGROUND: There are various published clinical practice guidelines (CPGs) for the management of pancreatic cystic lesions. However, the quality of these guidelines has not been systematically appraised. This study aimed to evaluate the quality of CPGs published in the last 5 years for the management of pancreatic cysts. METHODS: A systematic search of the PubMed database for eligible CPGs published between January 1, 2016 and November 17, 2021, using a sensitive filter. The quality of the CPGs was independently evaluated using the Appraisal of Guidelines for Research & Evaluation II instrument, with domain scores considered sufficient quality if >60% and good quality if >80%. RESULTS: The search yielded 4 eligible CPGs out of 426 citations. The scores varied for different domains for each CPG, with the overall median score being 79% for scope and purpose, 26% for stakeholder involvement, 51% for rigor of development, 69% for clarity of presentation, 14% for applicability, and 75% for editorial independence. CONCLUSIONS: The study revealed that the quality of the CPGs for pancreatic cyst management in adults remains moderate at best. Patient representatives were not involved in any of the CPG development process. There is a significant scope for improvement in methodological rigor and clarity of presentation.

A Systematic Critical Appraisal of Clinical Practice Guidelines in Heart Failure Using the AGREE II Tool.

Multiple clinical practice guidelines (CPGs) for heart failure management have been published to provide the best practices regarding the use of foundational therapies to reduce morbidity and mortality in this patient population. However, a critical appraisal of these heart failure guidelines has not been performed. This systematic review aimed to assess the methodological quality of current CPGs in the management of patients with heart failure. A comprehensive search of EMBASE and PubMed was conducted to identify CPGs published between January 1, 2021 and September 8, 2022. Any CPGs published in the last 2 years addressing the management of heart failure were eligible for inclusion. The methodological quality of the CPGs was assessed using the AGREE II (Appraisal of Guidelines for Research & Evaluate II) instrument. The initial search yielded 3,269 citations, of which, 6 CPGs were included. A total of 2 CPGs were each published by the cardiology associations in North America and Asia and 1 each in Europe and South America. The overall median score for the AGREE II domains were 100% for scope and purpose, 71% for stakeholder involvement, 71% for the rigor of development, 100% for clarity of presentation, 43% for applicability, 100% for editorial independence, and 64% for overall assessment. CPG developers would benefit from the use of a standardized approach to the development of CPGs and use the contents of the AGREE II tool to improve the methodological rigor, reporting, and applicability of CPGs.

Effects of combined treatment of probiotics and metformin in management of type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Lifestyle changes and dietary intervention, including the use of probiotics, can modulate dysbiosis of gut microbiome and contribute to the management of type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis aim to assess the efficacy of metformin plus probiotics versus metformin alone on outcomes in patients with T2DM. METHODS: We searched MEDLINE and EMBASE from inception to February 2023 to identify all randomized controlled trials (RCTs), which compared the use of metformin plus probiotics versus metformin alone in adult patients with T2DM. Data were summarized as mean differences (MD) with 95 % confidence interval (CI) and pooled under the random effects model. FINDINGS: Fourteen RCTs (17 comparisons, 1009 patients) were included in this systematic review. Pooled results show a significant decrease in fasting glucose (FG) (MD = -0.64, 95 % CI = -1.06, -0.22) and HbA1c (MD = -0.29, 95 % CI = -0.47, -0.10) levels in patients with T2DM treated with metformin plus probiotics versus metformin alone. The addition of probiotics to metformin resulted in lower odds of gastrointestinal adverse events (Odds ratio = 0.18, 95 % CI = 0.09, 0.3.8; I2 = 0 %). CONCLUSIONS: The addition of probiotics to metformin therapy is associated with improvement in T2DM outcomes. However, high-quality and adequately reported RCTs are needed in the future to confirm our findings.

Endothelial glycocalyx-associated molecules as potential serological markers for sepsis-associated encephalopathy: A systematic review and meta-analysis.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is characterized by a diffuse cerebral dysfunction that accompanies sepsis in the absence of direct central nervous system infection. The endothelial glycocalyx is a dynamic mesh containing heparan sulfate linked to proteoglycans and glycoproteins, including selectins and vascular/intercellular adhesion molecules (V/I-CAMs), which protects the endothelium while mediating mechano-signal transduction between the blood and vascular wall. During severe inflammatory states, components of the glycocalyx are shed into the circulation and can be detected in soluble forms. Currently, SAE remains a diagnosis of exclusion and limited information is available on the utility of glycocalyx-associated molecules as biomarkers for SAE. We set out to synthesize all available evidence on the association between circulating molecules released from the endothelial glycocalyx surface during sepsis and sepsis-associated encephalopathy. METHODS: MEDLINE (PubMed) and EMBASE were searched since inception until May 2, 2022 to identify eligible studies. Any comparative observational study: i) evaluating the association between sepsis and cognitive decline and ii) providing information on level of circulating glycocalyx-associated molecules was eligible for inclusion. RESULTS: Four case-control studies with 160 patients met the inclusion criteria. Meta-analysis of biomarkers ICAM-1 (SMD 0.41; 95% CI 0.05-0.76; p = 0.03; I2 = 50%) and VCAM-1 (SMD 0.55; 95% CI 0.12-0.98; p = 0.01; I2 = 82%) revealed higher pooled mean concentration in patients with SAE compared to the patients with sepsis alone. Single studies reported elevated levels of P-selectin (MD 0.80; 95% CI -17.77-19.37), E-selectin (MD 96.40; 95% Cl 37.90-154.90), heparan sulfate NS2S (MD 19.41; 95% CI 13.37-25.46), and heparan sulfate NS+NS2S+NS6S (MD 67.00; 95% CI 31.00-103.00) in patients with SAE compared to the patients with sepsis alone. CONCLUSION: Plasma glycocalyx-associated molecules are elevated in SAE and may be useful for early identification of cognitive decline in sepsis patients.

Putting the pieces together to understand anger in combat veterans and service members: Psychological and physical contributors.

Dysregulated anger can result in devastating health and interpersonal consequences for individuals, families, and communities. Compared to civilians, combat veterans and service members (C-V/SM) report higher levels of anger and often have risk factors for anger including posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), pain, alcohol use, and impaired sleep. The current study examined the relative contributions of established variables associated with anger (e.g., combat exposure, current PTSD symptoms, history of TBI, pain interference, and hazardous alcohol use) in 1263 C-V/SM. Sleep impairments, represented by poor sleep quality and obstructive sleep apnea (OSA) risk, were also evaluated as potential mediators of the relationships between established risk factors and anger, and therefore potential modifiable treatment targets. Multiple regression model results revealed that PTSD symptoms (ß = 0.517, p < .001), OSA risk (ß = 0.057, p = .016), pain interference (ß = 0.214, p < .001), and hazardous alcohol use (ß = 0.054, p = .009) were significantly associated with anger. Results of the mediation models revealed that OSA risk accounted for the association between PTSD and anger, in addition to the association between pain interference and anger. The current study extends previous literature by simultaneously examining factors associated with anger using a multivariable model in a large sample of C-V/SM. Additionally, treating OSA may be a novel way to reduce anger in C-V/SM who have PTSD and/or pain interference.

Associations Between Sociodemographic, Mental Health, and Mild Traumatic Brain Injury Characteristics With Lifetime History of Criminal Justice Involvement in Combat Veterans and Service Members.

INTRODUCTION: Veterans and service members (V/SM) may have more risk factors for arrest and felony incarceration (e.g., posttraumatic stress disorder and at-risk substance use) but also more protective factors (e.g., access to health care) to mitigate behaviors that may lead to arrest. As such, understanding which factors are associated with criminal justice involvement among V/SM could inform prevention and treatment efforts. The current study examined relationships between lifetime history of arrests and felony incarceration and sociodemographic, psychological, and brain injury characteristics factors among combat V/SM. MATERIALS AND METHODS: The current study was a secondary data analysis from the Chronic Effects of Neurotrauma Consortium multicenter cohort study, approved by local institutional review boards at each study site. Participants were V/SM (N = 1,540) with combat exposure (19% active duty at time of enrollment) who were recruited from eight Department of Veterans Affairs and DoD medical centers and completed a baseline assessment. Participants were predominantly male (87%) and white (72%), with a mean age of 40 years (SD = 9.7). Most (81%) reported a history of at least one mild traumatic brain injury, with one-third of those experiencing three or more mild traumatic brain injuries (33%). Participants completed a self-report measure of lifetime arrest and felony incarceration history, a structured interview for all potential concussive events, the post-traumatic stress disorder checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and the Alcohol Use Disorders Identification Test-Consumption. Three groups were compared on self-reported level of lifetime history of criminal justice system involvement: (1) no history of arrest or incarceration (65%); (2) history of arrest but no felony incarceration (32%); and (3) history of felony incarceration (3%). RESULTS: Ordinal regression analyses revealed that hazardous alcohol consumption (ß = .44, P < .001; odds ratio = 1.56) was positively associated with increased criminal justice involvement after adjusting for all other variables. Being married or partnered (ß = -.44, P < .001; odds ratio = 0.64) was negatively associated with decreased criminal justice involvement. CONCLUSIONS: The rate of lifetime arrest (35%) in this V/SM sample was consistent with rates of arrests in the U.S. general population. One modifiable characteristic associated with lifetime arrest and felony incarceration was hazardous alcohol consumption. Alcohol use should be a top treatment target for V/SM at risk for arrest and those with history of criminal justice involvement.

Efficacy of SGLT2 inhibitors in patients with heart failure: An overview of systematic reviews.

AIMS: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to have benefit in patients with heart failure (HF). Multiple systematic reviews and meta-analyses (SRs and MAs) of randomized control trials (RCTs) comparing SGLT2i to placebo have been performed. However, there is uncertainty in the quality of the evidence and associated efficacy. We performed an overview of SRs and MAs of RCTs to summarize the evidence related to the efficacy of SGLT2i for the management of HF. METHODS AND RESULTS: A comprehensive search of three databases (the Cochrane Library, EMBASE, and PubMed) was conducted until February 21, 2021. All SRs of RCTs evaluating the efficacy of SGLT2i in patients with HF were eligible for inclusion. The primary outcome was all-cause mortality. Methodological quality was evaluated using the AMSTAR-2 assessment tool. The overall quality of evidence was summarized using the Grading of Recommendations Assessment, Development, and Evaluation method. The initial search yielded 3431 references, of which, eight SRs and MAs met the inclusion criteria. The methodological quality ranged from critically low to high. The overall quality of evidence ranged from very low to moderate. Most of the SRs and MAs showed benefits in all-cause mortality, HF-related hospitalizations, and KCCQ score change. CONCLUSIONS: SGLT2i are possibly beneficial in patients with HF, however, none of the SRs and MAs compared the efficacy between different types of SGLT2i. Furthermore, this paper emphasizes the need for consistent reproducible conduct and reporting of SRs to generate high-quality evidence and facilitate clinical decision-making.

Autologous hematopoietic cell transplantation versus whole-brain radiotherapy consolidation in primary central nervous system lymphoma: A systematic review and meta-analysis.

The management of newly diagnosed primary central nervous system lymphoma (PCNSL) includes administration of high-dose methotrexate based regimens followed by consolidation therapy to minimize the risk of relapse. However, the best consolidation strategy (autologous hematopoietic cell transplant [auto-HCT] vs. whole-brain radiotherapy [WBRT]) is controversial. Hence, we performed a systematic review and meta-analysis of all randomized controlled trials that compared auto-HCT versus WBRT consolidation for patients with PCNSL after first-line treatment.The primary outcome was overall survival (OS), while the secondary outcomes included progression-free survival (PFS), response rates (overall response rate [ORR] and complete remission [CR]), relapse rate, treatment-related mortality (TRM), and neuropsychological adverse events. We performed a pooled analysis of the single-arm studies that incorporated auto-HCT or WBRT consolidation and evaluated neurocognitive outcomes. Only two studies met the inclusion criteria (n = 240). There was no significant difference in OS (HR = 1.50; 95% CI = 0.95-2.36), PFS (HR = 0.99; 95% CI = 0.44-2.22), ORR (RR = 1.48; 95% CI = 0.90-2.44), CR rate (RR = 1.21; 95% CI = 0.90-1.63), relapse rate (RR = 0.46; 95% CI = 0.05-4.28), and TRM (RR = 5.67; 95% CI = 1.01-31.91). The neuropsychological tests to assess neurocognitive domains were different and inconsistently reported in the two studies and therefore we were unable to perform a meta-analysis but provide a descriptive assessment. Both the studies showed a significant decline in the attention/executive function (based on the trail making test A and trail making test B) in those receiving WBRT compared to auto-HCT. We found 9 single-arm phase II studies that reported data on outcomes associated with either auto-HCT (5 studies) or WBRT (4 studies) consolidation. Of these, two studies (n = 43) reported data on neurocognitive decline following auto-HCT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 6% (95% CI, 0%-17%) for those receiving auto-HCT and there was no heterogeneity between studies (I2  = 0%). Three studies (n = 122) reported data on neurocognitive decline following WBRT consolidation. Pooled proportion of patients with neurocognitive decline in these studies was 43% (95% CI, 11%-78%) for those receiving WBRT and there was high heterogeneity between studies (I2  = 94%). There was significant heterogeneity between subgroups (p = 0.035). The outcomes were not significantly different in patients with PCNSL receiving auto-HCT or WBRT consolidation therapies, however, there is a higher degree of neurocognitive decline associated with WBRT compared to auto-HCT consolidation. The decision to choose a consolidation strategy needs to be individualized based on age, frailty, and co-morbidities.

Resident duty hours and resident and patient outcomes: Systematic review and meta-analysis.

OBJECTIVES: The policies regarding resident physician work hours are constantly being evaluated and changed. However, the results of randomised control trials (RCTs) are mixed. This systematic review of RCTs aims to synthesise the evidence associated with resident duty hour restrictions and its impact on resident- and patient-based outcomes. METHODS: A comprehensive search of the Cochrane Library, EMBASE and PubMed was conducted from inception until 31 July 2020. Any RCT evaluating the impact of longer resident physician work hours compared to shorter resident physician work hours on resident- and patient-based outcomes was eligible for inclusion. Two reviewers extracted data independently. The primary outcome was the impact of resident duty hour restrictions on emotional exhaustion, depersonalisation and personal accomplishment, as defined by the Maslach Burnout Inventory. The secondary patient-related outcomes were patient hospital length of stay, serious medical errors and preventable adverse events. Data were pooled using a random-effects model. RESULTS: Of the 873 references, nine RCTs met the inclusion criteria. A shorter shift length compared with longer shift length was associated with significantly less emotional exhaustion (standardised mean difference [SMD] = -0.11, 95% CI = -0.21, -0.00) and less dissatisfaction with overall well-being (OR = 0.61, 95% CI 0.38, 0.99) but not with hospital length of stay (SMD = -0.01, 95% CI = -0.05, 0.02, p = 0.45) and serious medical errors per 1000 patient hours (OR = 1.07, 95% CI = 0.52, 2.21; p = 0.86). CONCLUSIONS: Shorter resident duty hours is possibly associated with improvement in resident-based outcomes, specifically, emotional exhaustion, dissatisfaction with overall well-being, sleep duration and sleepiness. These findings may inform the policy change in support of reduced shift hours resulting in overall well-being for the residents with possible reduction in burnout without adverse impact on patient-based outcomes.

Efficacy of a Second Allogeneic Hematopoietic Cell Transplant in Relapsed Acute Myeloid Leukemia: Results of a Systematic Review and Meta-Analysis.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only known treatment modality that can offer the possibility of cure for acute myeloid leukemia (AML). Unfortunately, relapse and disease progression still occur in more than one third of cases even when patients are allografted in complete hematologic remission (CR). Treatment of AML relapsing after a first allo-HCT is particularly challenging. A second allo-HCT is offered to patients considered fit for the procedure, but reported outcomes have been conflicting. To perform a systematic review and meta-analysis to assess the totality of evidence on the role of a second allo-HCT in patients with AML, we performed a comprehensive literature search using PUBMED/MEDLINE and EMBASE on August 25, 2021, and extracted clinical outcome data relating to benefits (CR, overall survival [OS], and progression-free/disease-free survival [PFS/DFS]) and harms (acute and chronic graft-versus-host disease, non-relapse mortality [NRM], and relapse). The search identified 821 studies. Only 20 studies (n = 2772 patients) met our inclusion criteria. A second allo-HCT resulted in pooled CR, OS, PFS/DFS, NRM and relapse rates of 67%, 34%, 30%, 27%, and 51%, respectively. OS was 2-fold higher when the second allo-HCT was performed in CR (38% versus 17%) and 3-fold higher in patients who had a later relapse from the first allo-HCT (34% versus 10%). There was no apparent difference in pooled OS (hazard ratio = 1.01; 95% confidence interval, 0.78-1.31; P = .94) whether the same original donor or a different one was used. Notwithstanding several limitations apart from the high heterogeneity among included studies, this analysis shows that a second allo-HCT is a reasonable treatment option for relapsed AML. The procedure appears to be more effective when performed in CR and in patients who had a later relapse from the first allo-HCT. The high pooled relapse rates exceeding 50%, even when receiving the second allo-HCT in CR is worrisome and emphasizes the need to incorporate new therapies whether as post-transplantation maintenance or consolidation to mitigate relapse risk. This analysis was limited to patients receiving a second allo-HCT for the sole purpose of treating AML relapse. Accordingly, we caution against extrapolating these findings to other indications such as treatment of graft failure, poor graft function, or mixed donor chimerism.

Evidence-based surgical guidelines for treating children with Wilms tumor in low-resource settings.

BACKGROUND: Survival of Wilms tumor (WT) is > 90% in high-resource settings but < 30% in low-resource settings. Adapting a standardized surgical approach to WT is challenging in low-resource settings, but a local control strategy is crucial to improving outcomes. OBJECTIVE: Provide resource-sensitive recommendations for the surgical management of WT. METHODS: We performed a systematic review of PubMed and EMBASE through July 7, 2020, and used the GRADE approach to assess evidence and recommendations. RECOMMENDATIONS: Initiation of treatment should be expedited, and surgery should be done in a high-volume setting. Cross-sectional imaging should be done to optimize preoperative planning. For patients with typical clinical features of WT, biopsy should not be done before chemotherapy, and neoadjuvant chemotherapy should precede surgical resection. Also, resection should include a large transperitoneal laparotomy, adequate lymph node sampling, and documentation of staging findings. For WT with tumor thrombus in the inferior vena cava, neoadjuvant chemotherapy should be given before en bloc resection of the tumor and thrombus and evaluation for viable tumor thrombus. For those with bilateral WT, neoadjuvant chemotherapy should be given for 6-12 weeks. Neither routine use of complex hilar control techniques during nephron-sparing surgery nor nephron-sparing resection for unilateral WT with a normal contralateral kidney is recommended. When indicated, postoperative radiotherapy should be administered within 14 days of surgery. Post-chemotherapy pulmonary oligometastasis should be resected when feasible, if local protocols allow omission of whole-lung irradiation in patients with nonanaplastic histology stage IV WT with pulmonary metastasis without evidence of extrapulmonary metastasis. CONCLUSION: We provide evidence-based recommendations for the surgical management of WT, considering the benefits/risks associated with limited-resource settings.

Perioperative Carcinoid Crisis: A Systematic Review and Meta-Analysis.

BACKGROUND: Surgery is the only curative option for patients with neuroendocrine tumors (NET) and is also indicated for debulking of liver metastasis. Intraoperative carcinoid crisis (CC) is thought to be a potentially lethal complication. Though perioperative octreotide is often recommended for prevention, recent NET society guidelines raised concerns regarding limited data supporting its use. We sought to evaluate existing evidence characterizing CC and evaluating the efficacy of prophylactic octreotide. METHODS: A systematic review was performed on studies including patients having surgery for well-differentiated NET and/or NET liver metastasis (2000-2021), and reporting data on the incidence, risk factors, or prognosis of CC, and/or use of prophylactic octreotide. Meta-analysis was performed using random-effects models. RESULTS: Eight studies met inclusion criteria (n = 943 operations). The pooled incidence of CC was 19% (95% CI [0.06-0.36]). Liver metastasis (odds ratio 2.85 [1.49-5.47]) and gender (male 0.58 [0.34-0.99]) were the only significant risk factors. The occurrence of CC was associated with increased risk of major postoperative complications (2.12 [1.03-4.35]). The use of prophylactic octreotide was not associated with decreased risk of CC (0.73 [0.32-1.66]). Notably, there was no standard prophylactic octreotide strategy used. CONCLUSIONS: Intraoperative carcinoid crisis is a common complication occurring in up to 20% of patients with midgut NET and/or liver metastasis undergoing surgery. Prophylactic octreotide may not provide an efficient way to prevent this complication. Future studies should focus on prospective evaluation of well-defined prophylactic protocols using a standardized definition for CC.

Is inguinal hernia associated with an increased risk of colon cancer? A systematic review and meta-analysis.

BACKGROUND: The presence of an inguinal hernia has been associated with an increased risk of identifying colon cancer, and therefore colonoscopy is recommended prior to inguinal hernia repair. However, the evidence on the association between the presence of an inguinal hernia and colon cancer is conflicting and uncertain. We performed a systematic review and meta-analysis to synthesize all available evidence on this topic. METHODS: A comprehensive search of PubMed and EMBASE was performed. Any comparative study (case-control or cohort study) comparing the rate of colon cancer detection in patients with and without inguinal hernias who underwent screening colonoscopy or flexible sigmoidoscopy was eligible for inclusion. Data were extracted and pooled under a random effects model. RESULTS: The initial search identified 692 references, of which 4 comparative studies (1462 patients) met the inclusion criteria. The overall risk of bias in the included studies was low. Pooled results showed a statistically non-significant difference in the incidence of detection of colon cancer, with patients with inguinal hernia having a 1.26 times increased likelihood of colon cancer diagnosis compared with patients without inguinal hernia (odds ratio (OR) 1.26; 95% confidence interval (CI) 0.63-2.51; P = 0.51). Although patients with inguinal hernia were also 1.23 times more likely to be diagnosed with colon polyps compared to patients without inguinal hernia, this difference was statistically non-significant (OR 1.23; 95% CI 0.94-1.60; P = 0.12). CONCLUSION: The findings from this first systematic review and meta-analysis show that there is no difference in the incidence of either colon cancer or colon polyps in patients presenting with inguinal hernias compared to those without. Nevertheless, larger prospective studies are needed to further investigate the relationship between the risk of colon cancer or polyps and the presence of inguinal hernia.

Efficacy of Allogeneic Hematopoietic Cell Transplantation in Patients With Chronic Phase CML Resistant or Intolerant to Tyrosine Kinase Inhibitors.

Approximately 15-20% of chronic myeloid leukemia (CML) patients fail tyrosine kinase inhibitor (TKI) therapy secondary to resistance or intolerance. In the pre-TKI era, front-line allogeneic hematopoietic cell transplantation (allo- HCT) represented the standard approach for patients with chronic phase-CML (CP-CML) who were deemed fit to tolerate the procedure and had a human leukocyte antigen compatible donor available. Currently, CP-CML patients are eligible for allo-HCT only if they fail more than one TKI and/or are intolerant to the drug. We performed a systematic review/meta-analysis of the available literature to assess the evidence regarding allo-HCT efficacy in CP-CML patients. Data from eligible studies were extracted in relation to benefits (overall survival [OS], progression-free survival, disease-free survival [DFS], complete remission [CR], and molecular response [MR]) and harms (nonrelapse mortality [NRM], relapse, and acute and chronic graft-versus-host disease), and stratified by age into adult and pediatric groups. For adult allo-HCT recipients, the pooled OS, DFS, CR and, MR were 84% [95% confidence interval (CI) 59-99%], 66% (95% CI 59-73%), 56% (95% CI 30-80%), and 88% (95% CI 62-98%), respectively. Pooled NRM and relapse were 20% (95% CI 15-26%) and 19% (95% CI 10-28%), respectively. For the pediatric group, the OS rate was reported in one study and was 91% (95% CI 72-99%). Our results suggest that allo-HCT is an effective treatment for TKI-resistant or TKI-intolerant CP-CML. Post-transplant strategies are still needed to further mitigate the risk of relapse.

Downregulation of collagen XI during late postnatal corneal development is followed by upregulation after injury.

Collagen XI plays a role in nucleating collagen fibrils and in controlling fibril diameter. The aim of this research was to elucidate the role that collagen XI plays in corneal fibrillogenesis during development and following injury. The temporal and spatial expression of collagen XI was evaluated in C57BL/6 wild-type mice. For wound-healing studies in adult mice, stromal injuries were created using techniques that avoid caustic chemicals. The temporal expression and spatial localization of collagen XI was studied following injury in a Col11a1 inducible knockout mouse model. We found that collagen XI expression occurs during early maturation and is upregulated after stromal injury in areas of regeneration and remodeling. Abnormal fibrillogenesis with new fibrils of heterogeneous size and shape occurs after injury in a decreased collagen XI matrix. In conclusion, collagen XI is expressed in the stroma during development and following injury in adults, and is a regulator of collagen fibrillogenesis in regenerating corneal tissue.