Single-arm Observational Studies Research Articles

Use of vortioxetine in different neurological fields: a systematic review and future perspectives.

Vortioxetine is a multimodal antidepressant with a high tolerability profile. Recent evidence suggests a role for vortioxetine in improving cognitive function and reducing functional disability linked to depression. We conducted a systematic review on the use of vortioxetine in different neurological disorders. PubMed was searched for articles published from inception until June 2024. Article reference lists were screened, and relevant articles were retrieved for consultation. Clinical trials focused on the use of vortioxetine in cerebrovascular diseases, movement disorders and cognitive impairments were included. The systematic review protocol was developed using guidance from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Our search identified 236 citations, 8 of which ultimately met the criteria for inclusion in the synthesis. The included studies consisted of 3 randomized controlled trials, 1 nonrandomized clinical trial and 4 single-arm observational studies. Subsequently, we grouped these articles into three sections of neurological interest (cerebrovascular diseases, movement disorders and cognitive dysfunction). Through its multimodal mechanism of action, the antidepressant vortioxetine shows potential benefit in improving depressive symptoms in patients with depression and different, comorbid neurological condition. In addition, the pro-cognitive effect of this agent may represent a possible indication for its use in the treatment of adults with depression and/or neurological cognitive impairment. Future research is needed to explore and clarify other possible implications for a rational administration of this molecule in other neurological fields.

Organ-specific malperfusion in acute type A aortic dissection: epidemiological meta-analysis of incidence rates.

Acute type A aortic dissection is a life-threatening clinical emergency that necessitates immediate surgical intervention with an estimated mortality rate of approximately 1-2% per hour. When complicated by malperfusion, the perioperative mortality rate is reported to be increased by up to 39%. Malperfusion can affect many vascular beds with varying incidence and severity, resulting in coronary, cerebral, visceral, peripheral, renal or spinal malperfusion. The primary aim of this systematic review and meta-analysis is to investigate the epidemiology of specific types of organ malperfusion in acute type A aortic dissection and to analyse the impact on the survival outcomes associated with each malperfusion type. Electronic databases PubMed, MEDLINE and Embase were searched through to September 2024 to identify original studies that presented data on the incidence and the survival outcome of organ malperfusion in association with acute type A aortic dissection. The extracted data included patient characteristics and incidence of organ-specific malperfusion. Primary outcomes were the respective in-hospital mortality rate associated with each organ-specific malperfusion and a proportional meta-analysis was conducted to pool results. Quality assessment was performed using the modified National Institutes of Health quality assessment tool for single-arm observational studies. A total of 40 studies met the inclusion criteria, including a total of 35 361 patients. Peripheral limb malperfusion was the most prevalent with a pooled incidence of 12% (95% c.i. 10 to 14). This was followed by lower limb or iliofemoral with 11% (95% c.i. 9 to 14). Spinal malperfusion was the lowest with 1% (95% c.i. 1 to 2). The pooled mortality rate with organ malperfusion varied between 18 and 36%. Within this population the highest mortality rate was associated with mesenteric malperfusion with 36% (95% c.i. 28 to 45). Following this the highest mortality rate was found with coronary at 33% (95% c.i. 26 to 40) and cerebral at 28% (95% c.i. 24 to 33) malperfusion. Survival during hospital admission after acute type A aortic dissection can vary depending on the presence and type of malperfusion, with mesenteric, coronary and cerebral malperfusion being associated with the highest in-hospital mortality rates. Organ-specific malperfusion syndromes should be considered when assessing the perioperative risk and surgical planning of patients undergoing surgical repair for acute type A aortic dissection.

Patient-reported Outcome Measures for Peripheral Nerve Injuries: A Systematic Review.

The goal of managing patients with peripheral nerve injuries is to improve how a patient feels and functions. This goal is best assessed with patient-reported outcome measures (PROMs), which elicit patient concerns, treatment goals, and clinical progression. This study reviews existing PROMs for adult patients with peripheral nerve injuries to assess how comprehensively they measure outcomes important to patients. A systematic review of Ovid MEDLINE, Scopus, Web of Science, and Embase (from inception to August 13, 2022) was conducted to identify PROMs developed for adult patients with peripheral nerve injuries. Studies were included if (1) the study population involved traumatic or acquired peripheral nerve injuries; (2) they were randomized controlled trials, cohort studies, or single-arm observational studies; (3) participants were 18 years or older; and (4) PROMs were used to assess quality of life or patient satisfaction. A total of 378 studies were included in this systematic review. We identified 141 unique PROMs used in the adult peripheral nerve injury literature: 20 are disease-specific (14%), 10 are function-specific (7%), 19 are mental health and well-being-specific (13%), 11 are quality of life-specific (8%), 32 are body region-specific (23%), 29 are symptom-specific (21%), 3 are satisfaction-specific (2%), 15 are generic (11%), and 2 are other (1%). There exists considerable heterogeneity of PROMs used in research on patients with peripheral nerve injuries. None of the PROMs comprehensively assess this patient population. The need for the development of a comprehensive PROM for this patient population is highlighted.

Transcatheter Aortic Valve Replacement Versus Surgical Aortic Valve Replacement in Bicuspid Aortic Valve Stenosis-We Need a Well-Designed Randomized Control Trial.

Bicuspid aortic stenosis is a common pathology, typically seen in patients a decade younger than those with tricuspid valves. Surgical aortic valve replacement has been the mainstay treatment for bicuspid disease, especially considering the prevalence of concomitant aortic aneurysmal pathology. Transcatheter aortic valve replacement has shown equivalent results in bicuspid compared to tricuspid pathology in highly selected patient populations in single-arm registries and observational studies. For older patients with favorable bicuspid pathology, TAVR is reasonable. However, as younger patients with longer life expectancy are now being treated with TAVR, what is "best" is a question only answered by a well-designed randomized controlled trial. Herein, we describe the current evidence for treating bicuspid aortic stenosis and provide a framework for future trials. Yet, the question of equipoise remains, and who will we enroll?

Efficacy and Safety of Cardioband in Patients with Tricuspid Regurgitation: Systematic Review and Meta-Analysis of Single-Arm Trials and Observational Studies.

Background/Objectives: The incidence and prevalence of tricuspid regurgitation (TR) are increasing worldwide. "Traditional" drug therapy with diuretics is often ineffective and the identification of new strategies, including non-pharmacological ones, is an urgent need. The aim of this study was to summarize the results on the efficacy and safety of Cardioband, one of the few approved transcatheter tricuspid valve repair systems, in patients with TR. Methods: Three databases (Medline, Scopus, and CENTRAL) were searched to identify clinical trials and observational studies on the efficacy (primary outcome) and safety (secondary outcome) of Cardioband. A random-effects meta-analysis was performed with R software (version 4.3.3). Survival and freedom from heart failure (HF) hospitalization were estimated with the method of reconstructing individual patient data from Kaplan-Meier curves (IPDfromKM). Results: Eleven studies were included in this systematic review and meta-analysis. Cardioband significantly reduced annulus diameter (-9.31 mm [95% Confidence Interval, CI: -11.47; -7.15]), vena contracta (-6.41 mm [95% CI: -8.34; -4.49]), and effective regurgitant orifice area (EROA) (-0.50 cm2 [95% CI: -0.72; -0.28]) in patients with TR. Cardioband reduced the severity of TR and the extent of heart failure in 91% [95% CI: 85; 97] and 63% [95% CI: 52-75] of patients, respectively. Finally, Cardioband implantation was associated with prolonged survival and freedom from HF hospitalization (80.1% and 57.8% at 24 months, respectively). Conclusions: This study demonstrates that Cardioband implantation leads to cardiac remodeling and mechanical improvements, reduces the severity of TR, and improves quality of life. Therefore, Cardioband is an effective option for the non-pharmacological treatment of TR.

Persistence of COVID-19 Human Milk Antibodies After Maternal COVID-19 Vaccination: Systematic Review and Meta-Regression Analysis.

The World Health Organization (WHO) declared COVID-19 a pandemic. The Centers for Disease Control and Prevention (CDC), WHO, and American College of Obstetricians and Gynecologists (ACOG) recommend vaccination of pregnant and lactating women, aiming to protect both mothers and their infants through transplacental and human milk antibody transmission. This study aims to assess the quantity of antibodies in human milk and determine the effect of time, vaccine type, and dose on antibody level. Single-arm prospective observational studies reportingthe COVID-19-specific antibody level in human milk after COVID-19 vaccination during pregnancy or lactation were included. PubMed, Scopus, Cochrane, EBSCO, and Web of Science were searched from December 2019 to November22, 2022. Data were extracted in a uniform Google sheet.A total of 2657 studies were identified. After the removal of duplicates and screening, 24 studies were included in the systematic review and meta-regression. Human milk COVID-19-specific antibody levels increased with subsequent vaccine doses, as reflected by a positive relationship for the second (coefficient=0.91, P-value 0.043 for IgA and coefficient=1.77, P-value 0.009 for IgG) and third (coefficient=1.23, P-value 0.0029 for IgA and coefficient=3.73, P-value 0.0068 for IgG)doses. The antibody level exhibited a weak positive relationship with the follow-up time (coefficient=0.13, P-value 0.0029 for IgA and coefficient=0.18, P-value 0.016 for IgG). Only one of the 38 infants showed detectable COVID-19 IgM and IgA antibody levels in their blood. There wasan increase in the neutralizing activity of COVID-19 antibodies in human milk following the COVID-19 vaccination. From the analysis of published data, we found high positive levels of antibodies in human milk that increased with subsequent doses. Additionally, the human milk antibodies exhibit a positive neutralizing effect. Only one infant had detectable COVID-19 IgM+IgA antibodies in the blood. Further research is needed to discuss infant protection through a mother'svaccination.

Abstract PO1-01-04: The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis

Abstract Background In patients with the HR+/HER2+ breast cancer (BC) subtype, it can be more challenging to achieve pathological complete response (pCR) after neoadjuvant therapy compared with the HR-/HER2+ subtype. The importance of neoadjuvant therapy and the association of pCR with long-term clinical benefits have been widely demonstrated in HER2+ BC. This network meta-analysis aimed to identify the optimal anti-HER2 regimen, the role of endocrine therapy, and the better chemotherapy choice for the neoadjuvant treatment of HR+/HER2+ BC patients. Methods Literature for neoadjuvant clinical trials in HR+/HER2+ breast cancer was searched in Medline, EMBASE, Cochrane Library, and Web of Science for publications released before June 2023. Single-arm trials, retrospective studies, and observational studies were excluded, as well as studies containing no neoadjuvant phase and/or no anti-HER2 drugs. A network meta-analysis with the fixed-effect model in a Bayesian framework was performed. Odds ratios (ORs) with 95% confidence intervals (CI) for pathological complete response (pCR) analysis and hazard ratios (HRs) with 95% CI for event-free survival (EFS) were calculated. A ranking of treatment patterns was performed using SUCRA. (Registered in PROSPERO: CRD42023385644 Results 2,844 records were identified by the literature search, 60 trials were included after the screening, and valid data were extracted. 19 trials and 2,883 patients were included in the primary analysis of pCR. Compared with trastuzumab + chemotherapy (CT), three treatment regimens showed significantly higher pCR rates, T-DM1 based treatment (T-DM1, OR: 2.83, 95% CI: 1.90, 4.27; which includes T-DM1 alone, T-DM1 + pertuzumab or T-DM1 + endocrine therapy), trastuzumab + pertuzumab + CT (PH, OR: 2.57, 95% CI: 1.70, 3.94), and trastuzumab + tyrosine kinase inhibitor (TKI)+ CT (H+TKI, OR: 1.60, 95% CI: 1.22, 2.09; TKI includes lapatinib, neratinib and pyrotinib). The SUCRA ranking of pCR showed that T-DM1 was ranked first (SUCRA: 0.94), followed by PH (SUCRA: 0.85) and H+TKI (SUCRA: 0.60). PH came first in the SUCRA ranking of EFS (SUCRA: 0.74) as well as cumulative SUCRA combining pCR and EFS (SUCRA: 0.79). For chemotherapy strategies, platinum-containing regimens showed no significant increase in pCR rate compared to no platinum regimens (OR: 1.27, 95% CI: 0.95, 1.69), regimens with anthracycline also had no statistical difference from those without anthracycline (OR: 0.74, 95% CI: 0.51, 1.07). When assessing the impact of endocrine therapy, no significant difference in pCR rate was observed with or without endocrine therapy (OR: 1.18, 95% CI: 0.80, 1.73). Conclusions The PH regimen remains the best neoadjuvant treatment choice for HR+/HER2+ early BC patients considering pCR and EFS outcomes simultaneously. H+TKI did not show significant benefits, so it is not recommended to be given priority in clinical practice. The platinum-containing regimen’s potential benefit compared to the non-platinum regimen is uncertain and needs more clinical investigation. The necessity of adding endocrine therapy is not proven due to limited data availability. Funding: This study was sponsored by Shanghai Roche Pharmaceuticals Ltd. Disclosure: Hao Tang, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Yajing Feng, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Xin Yu, Shanghai Roche Pharmaceuticals Ltd.: Employee (Ongoing), Salary (Ongoing) Citation Format: Hao Wang, Shiwei Liu, Miao Yu, Kun Mi, Exian Mou, Li Xia, Weimin Xie, Hao Tang, Yajing Feng, Xin Yu. The optimal neoadjuvant treatment regimen for HR+/HER2+ breast cancer: a network meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-01-04.

The efficacy and safety of the novel combination lenvatinib and pembrolizumab in endometrial cancer: A systematic review and single-arm meta-analysis

ObjectiveEndometrial carcinoma is the most widespread gynecological cancer, with increasing morbidity and mortality. Pembrolizumab, a monoclonal antibody that targets PD1 receptor tumors, is approved for patients with microsatellite instability-high (MSI-H) solid tumors. Many clinical trials and observational studies have been conducted to assess the safety and efficacy of Lenvatinib and Pembrolizumab combination therapy in the setting of endometrial cancer. However, results have been inconsistent, and current data is based on a heterogeneous population. The primary objective was to assess the safety and efficacy of Lenvatinib plus Pembrolizumab for endometrial cancer. Data sourcesThe search was conducted from inception from four databases; PubMed, Google Scholar, the Cochrane Library, and ClinicalTrials.gov. The electronic database search was conducted from inception to August 20, 2023. Study eligibility criteriaWe considered randomized controlled trials and single-arm observational studies, i.e. cohort, case-control and cross-sectional studies. MethodologyWe performed a single-arm meta-analysis, involving 7 studies having a total of 495 patients with endometrial cancer were eventually included which had the following outcomes: Complete response, Partial response, Progression-free survival, stable disease, progressive disease, safety outcomes, Adverse events, and the total number of deaths. ResultsOur results showed that 88.6 % of the patients were positive for non-MSI-H/pMMR tumors (95 % CI = 0.825–0.927) whereas 6.5 % (95 % CI = 3.8–9.8 %) of the patients for MSI-H/dMMR tumors. The pooled objective response of endometrial cancer patients treated with Lenvatinib and Pembrolizumab was 36.5 % (95 % CI = 0.258–0.471), the pooled estimate of complete and partial response was 47 % (95 % CI = 0.024–0.070) and 31.3 % (95 % CI = 0.230–0.396). 38.2 % patients had stable disease (95 % CI = 0.329–0.435) and 24.0 % patients had progressive disease (95 % CI = 0.103–0.378). The pooled median progression-free survival was 5.97 (95 % CI 5.43–7.63) months and, whereas the median overall survival was 17.19 months (95 % CI 15.34–19.31). All grade adverse events occurred in 85 % and Grade 3 or worse adverse events occurred in 39 % of patients during the therapy whereas death occurred in 23.8 % during the treatment. ConclusionThe results of this meta-analysis concludes that although the combined treatment of a Lenvatinib and Pembrolizumab had a PFS and OS that was inferior to the standard therapy used to treat advanced and recurrent endometrial cancer, it is still a novel treatment and shows potential for further research with a greater sample size.

Trigeminal neuralgia pain outcomes following microsurgical resection versus stereotactic radiosurgery for petroclival meningiomas: a systematic review and meta-analysis.

Petroclival meningiomas (PCMs) are challenging lesions to treat because of their deep location and proximity to critical neurovascular structures. Patients with these lesions commonly present because of local mass effect. A symptom that proves challenging to definitively manage is trigeminal neuralgia (TN), which occurs in approximately 5% of PCM cases. To date, there is no consensus on whether microsurgical resection or stereotactic radiosurgery (SRS) leads to better outcomes in the treatment of TN secondary to PCM. In this systematic review and meta-analysis, the authors aimed to evaluate the available literature on the efficacy of microsurgical resection versus SRS for controlling TN secondary to PCM. The Embase, MEDLINE, Scopus, and Cochrane databases were queried from database inception to May 17, 2022, using the search terms "(petroclival AND meningioma) AND (trigeminal AND neuralgia)." Study inclusion criteria were as follows: 1) reports on patients aged ≥ 18 years and diagnosed with TN secondary to PCM, 2) cases treated with microsurgical resection or SRS, 3) cases with at least one posttreatment follow-up report of TN pain, 4) cases with at least one outcome of tumor control, and 5) publications describing randomized controlled trials, comparative or single-arm observational studies, case reports, or case series. Exclusion criteria were 1) literature reviews, technical notes, conference abstracts, or autopsy reports; 2) publications that did not clearly differentiate data on patients with PCMs from data on patients with different tumors or with meningiomas in different locations (other intracranial or spinal meningiomas); 3) publications that contained insufficient data on treatments and outcomes; and 4) publications not written in the English language. References of eligible studies were screened to retrieve additional relevant studies. Data on pain and tumor outcomes were compared between the microsurgical resection and SRS treatment groups. The DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction was used to pool estimates from the included studies. Two comparative observational studies and 6 single-arm observational studies describing outcomes after primary intervention were included in the analyses (138 patients). Fifty-seven patients underwent microsurgical resection and 81 underwent SRS for the management of TN secondary to PCM. By the last follow-up (mean 71 months, range 24-149 months), the resection group had significantly higher rates of pain resolution than the SRS group (82%, 95% CI 50%-100% vs 31%, 95% CI 18%-45%, respectively; p = 0.004). There was also a significantly longer median time to tumor recurrence following resection (43.75 vs 16.7 months, p < 0.01). The resection group showed lower rates of pain persistence (0%, 95% CI 0%-6% vs 25%, 95% CI 13%-39%, p = 0.001) and pain exacerbation (0% vs 12%, 95% CI 3%-23%, p = 0.001). The most common postintervention Barrow Neurological Institute pain score in the surgical group was I (66.7%) compared with III (27.2%) in the SRS group. Surgical reintervention was less frequently required following primary resection (1.8%, 95% CI 0%-37% vs 19%, 95% CI 1%-48%, p < 0.01). Microsurgical resection is associated with higher rates of TN pain resolution and lower rates of pain persistence and exacerbation than SRS in the treatment of PCM. SRS with further TN management is a viable alternative in patients who are not good candidates for microsurgical resection.

Safety of Ultrahypofractionated Pelvic Nodal Irradiation in the Definitive Management of Prostate Cancer: Systematic Review and Meta-analysis

Aim: This systematic review and meta-analysis aimed to evaluate the evidence for ultra-hypofractionated pelvic nodal irradiation in prostate cancer patients, with a focus on reported acute and late toxicities. Methods: A comprehensive search was conducted in five electronic databases (PubMed, Scopus, Web of Science, Cochrane Library, Clinicaltrials.gov) from inception until 23 March 2023. Eligible publications included patients with intermediate- and high-risk and node positive prostate cancer who underwent elective or therapeutic ultra-hypofractionated pelvic nodal irradiation. Primary outcomes included the presence of grade ≥2 rates of acute and late gastrointestinal and genitourinary toxicity based on the Common Terminology Criteria for Adverse Events (CTCAE) scale or Radiation Therapy Oncology Group (RTOG) scales. Quality assessment was performed using NIH tools for non-controlled before and after clinical trials, as well as single-arm observational studies. Since all outcomes were categorical variables, proportion was calculated to estimate the effect size and compare the outcomes after the intervention. Results: We identified 16 publications that reported the use of ultra-hypofractionated radiotherapy to treat the pelvis in prostate cancer. Seven publications met our criteria and were included in the meta-analysis, including 417 patients. The median total dose to the pelvic lymph nodes was 25 Gy (range: 25 - 28.5 Gy), with a median of 5 fractions. The prostate received a median dose of 40 Gy (range: 35 to 47.5 Gy). All studies utilized androgen deprivation therapy for a median duration of 18 months. The median follow-up period was 3 years (range: 0.5-5.6 years). The rates of acute grade ≥2 gastrointestinal and genitourinary toxicity were 8% (CI 95%: 1% to 15%) and 29% (CI 95%: 18% to 41%), respectively. For late grade ≥2 gastrointestinal and genitourinary toxicity, the rates were 13% (CI 95%: 5% to 21%) and 29% (CI 95%: 17% to 42%), respectively. Conclusion: Ultra-hypofractionated pelvic nodal irradiation appears to be a safe approach in terms of acute and late genitourinary and gastrointestinal toxicity.

Patient-reported outcome (PRO) instruments used in patients undergoing adoptive cell therapy (ACT) for the treatment of cancer: a systematic review

IntroductionAdoptive cell therapy (ACT) is a rapidly evolving field. Patient-reported outcomes (PROs) allow patients to report the impact of treatment on their quality of life during and after treatment. The systematic review aims to characterise the breadth of PROs utilised in ACT cancer care and provide guidance for the use of PROs in this patient population in the future.MethodsA systematic search was conducted (MEDLINE, PsycINFO, Embase and CINAHL) in August 2021 by two reviewers. Search terms covered the following: “adoptive cell therapy”, “patient-reported outcomes” and “cancer”. Studies were included if they used a PRO measure to report the impact of ACT. The methodological quality of PROs was assessed. Forward and backward reference searching was conducted of any relevant papers. A quality grading scale was applied based on Cochrane and Revenson criteria for classification of high-quality studies. Key data from the studies and the included PROs was extracted by two researchers and tabulated.ResultsOne-hundred nine papers were identified; 11 papers were included. The majority of studies were single-arm trials or observational studies. Twenty-two different PROs were identified; none was ACT specific. The PROMIS-29 and EQ-5D were most commonly used. Few studies collected PRO data in the first 1–2 weeks. Four studies followed patients up for over a year, and a further four studies followed patients for approximately 3 months.DiscussionNone of the PROs identified have been designed specifically for ACT. Appropriateness of existing instruments should be considered. It should be considered whether it is appropriate to collect data more frequently in the acute stage and then less frequently during follow-up. It should be considered if one tool is suitable at all time points or if the tool should be adapted depending on time since treatment. More research is needed to identify the exact timings of PRO assessments, and qualitative work with patients is needed to determine the most important issues for them throughout the treatment and follow-up.

Efficacy and safety of Water Vapor Thermal Therapy in the treatment of benign prostate hyperplasia: a systematic review and single-arm Meta-analysis

BackgroundBenign prostatic hyperplasia (BPH) is a common chronic condition among men aged 50 or older, causing voiding and obstructive lower urinary tract symptoms. Water vapor thermal therapy (WVTT) using the Rezūm® system is a new minimally invasive surgical technique that is increasingly reported as a treatment for BPH.MethodsThe protocol was submitted to the PROSPERO registry. We searched PubMed, Web of Science, Embase, Cochrane Library and ClinicalTrials.gov up to July 29, 2022. Quality assessment was carried out by a 20-item checklist form prepared by the Institute of Health Economics (IHE). Double arcsine transformation was performed to stabilize the variance of the original ratio. When I2 > 50%, the random effect model was used to calculate the pooled parameters. Otherwise, the fixed effect model was used. 95% confidence intervals (CIs) were calculated. A leave-one-out sensitivity analysis was performed to evaluate the impact of each study on the pooled outcomes, and finally, Egger’s test was used to assess publication bias.ResultsA total of seven single-arm observational studies and one random controlled trial, including 1015 patients, were included. One year after WVTT, the International Prostate Symptom Score decreased by 11.37 (95% CI: -12.53, -10.21), the IPSS Quality of Life scale decreased by 2.59 (95% CI: -2.92, -2.26), the maximum urine flow rate increased by 5.26 ml/s (95% CI: 4.53, 5.99), and the postvoid residual decreased by 13.18 ml (95% CI: -24.32, -2.03). The most common complication was dysuria, with a pooled incidence of 21% (95% CI: 14%, 29%), and the second most common complication was hematuria, with a pooled incidence of 14% (95% CI: 10%, 18%). The pooled incidence of retreatment was 3% (95% CI: 2%, 5%).ConclusionsWVTT is an attractive alternative to medication or more invasive surgical procedures and can serve as first-line therapy for men with BPH.

The impact of daptomycin therapeutic drug monitoring on clinical outcomes: a systematic review

AimDaptomycin therapeutic drug monitoring (TDM) is a potentially valuable intervention for a relatively new drug. The aim of this study was to determine whether daptomycin TDM, including dose adjustment where necessary, improves the clinical outcomes of adult patients with Gram-positive infections. MethodsA systematic review of English-language studies in MEDLINE (Ovid MEDLINE and Epub Ahead of Print, In-process, In-Data-Review & Other Non-Indexed Citations, Daily and Versions), EMBASE via OVID, Cochrane Central Register of Controlled Trials via the OVID platform, Scopus and Web of Science online databases was performed and conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. There was no discrimination on study type or time of publication. Study selectionAdults (age ≥18 years) with a Gram-positive infection requiring treatment with daptomycin who received TDM, with subsequent reporting of serum concentrations and dose adjustment where necessary, were included. ResultsIn total, 2869 studies were identified, of which nine met the inclusion criteria. No studies of daptomycin TDM including a relevant control arm have been published to date. All of the included studies were single-arm observational cohort studies. Broad heterogeneity was observed between the studies in terms of included pathogens, infection types, daptomycin TDM practices, reported clinical outcomes, and reporting of potential confounders. ConclusionsNo studies exploring the efficacy of routine daptomycin TDM on patient-centred outcomes in comparison with fixed dosing regimens have been published to date. This represents a key knowledge gap as opposed to an inherent lack of efficacy. Further well-designed, comparative studies are required to determine the role of daptomycin TDM in patients with Gram-positive infections.

World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) guideline update – XIII – Oral immunotherapy for CMA – Systematic review

BackgroundAllergy to cow's milk is the most common food allergy in infants and it is usually outgrown by 5 years of age. In some individuals it persists beyond early childhood. Oral immunotherapy (OIT, oral desensitization, specific oral tolerance induction) has been proposed as a promising therapeutic strategy for persistent IgE-mediated cow's milk allergy. We previously published the systematic review of OIT for cow's milk allergy (CMA) in 2010 as part of the World Allergy Organization (WAO) Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines. ObjectiveTo systematically synthesize the currently available evidence about OIT for IgE-mediated CMA and to inform the updated 2022 WAO guidelines. MethodsWe searched the electronic databases including PubMed, Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the websites of selected allergy organizations. We included all studies irrespective of the language of the original publication. The last search was conducted in February 2021. We registered the protocol on Open Science Framework (10.17605/OSF.IO/AH2DT). ResultsWe identified 2147 unique records published between 2010 and 2021, including 13 randomized trials and 109 observational studies addressing cow's milk OIT. We found low-certainty evidence that OIT with unheated cow's milk, compared to elimination diet alone, increased the likelihood of being able to consume ≥150 ml of cow's milk in controlled settings (risk ratio (RR): 12.3, 95% CI: 5.9 to 26.0; risk difference (RD): 25 more per 100, 95% CI 11 to 56) as well as accidently ingest a small amount (≥5 ml) of cow's milk (RR: 8.7, 95% CI: 4.7 to 16.1; RD: 25 more per 100, 95% CI 12 to 50). However, 2–8 weeks after discontinuation of a successful OIT, tolerance of cow's milk persisted in only 36% (range: 20%–91%) of patients. OIT increased the frequency of anaphylaxis (rate ratio: 60.0, 95% CI 15 to 244; rate difference 5 more anaphylactic reactions per 1 person per year, 95% CI: 4 to 6; moderate evidence) and the frequency of epinephrine use (rate ratio: 35.2, 95% CI: 9 to 136.5; rate difference 268 more events per 100 person-years, 95% CI: 203 to 333; high certainty). OIT also increased the risk of gastrointestinal symptoms (RR 6.9, 95% CI 1.6–30.9; RD 28 more per 100, CI 3 to 100) and respiratory symptoms (RR 49.0, 95% CI 3.12–770.6; RD 77 more per 100, CI 62 to 92), compared with avoidance diet alone. Single-arm observational studies showed that on average 6.9% of OIT patients (95% CI: 3.8%–10%) developed eosinophilic esophagitis (very low certainty evidence). We found 1 trial and 2 small case series of OIT with baked milk. ConclusionsModerate certainty evidence shows that OIT with unheated cow's milk in patients with IgE-mediated CMA is associated with an increased probability of being able to drink milk and, at the same time, an increased risk of serious adverse effects.

Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria.

Pyronaridine-artesunate for treating uncomplicated Plasmodium falciparum malaria.

Network Meta-analysis on Disconnected Evidence Networks When Only Aggregate Data Are Available: Modified Methods to Include Disconnected Trials and Single-Arm Studies while Minimizing Bias.

BackgroundNetwork meta-analysis (NMA) requires a connected network of randomized controlled trials (RCTs) and cannot include single-arm studies. Regulators or academics often have only aggregate data. Two aggregate data methods for analyzing disconnected networks are random effects on baseline and aggregate-level matching (ALM). ALM has been used only for single-arm studies, and both methods may bias effect estimates.MethodsWe modified random effects on baseline to separate RCTs connected to and disconnected from the reference and any single-arm studies, minimizing the introduction of bias. We term our modified method reference prediction. We similarly modified ALM and extended it to include RCTs disconnected from the reference. We tested these methods using constructed data and a simulation study.ResultsIn simulations, bias for connected treatments for ALM ranged from −0.0158 to 0.051 and for reference prediction from −0.0107 to 0.083. These were low compared with the true mean effect of 0.5. Coverage ranged from 0.92 to 1.00. In disconnected treatments, bias of ALM ranged from −0.16 to 0.392 and of reference prediction from −0.102 to 0.40, whereas coverage of ALM ranged from 0.30 to 0.82 and of reference prediction from 0.64 to 0.94. Under fixed study effects for disconnected evidence, bias was similar, but coverage was 0.81 to 1.00 for reference prediction and 0.18 to 0.76 for ALM. Trends of similar bias but greater coverage for reference prediction with random study effects were repeated in constructed data.ConclusionsBoth methods with random study effects seem to minimize bias in treatment connected to the reference. They can estimate treatment effects for disconnected treatments but may be biased. Reference prediction has greater coverage and may be recommended overall.HighlightsTwo methods were modified for network meta-analysis on disconnected networks and for including single-arm observational or interventional studies in network meta-analysis using only aggregate data and for minimizing the bias of effect estimates for treatments only in trials connected to the reference.Reference prediction was developed as a modification of random effects on baseline that keeps analyses of trials connected to the reference separately from those disconnected from the reference and from single-arm studies. The method was further modified to account for correlation in trials with more than 2 arms and, under random study effects, to estimate variance in heterogeneity separately in connected and disconnected evidence.Aggregate-level matching was extended to include trials disconnected from the reference, rather than only single-arm studies. The method was further modified to separately estimate treatment effects and heterogeneity variance in the connected and disconnected evidence and to account for the correlation between arms in trials with more than 2 arms.Performance was assessed using a constructed data example and simulation study.The methods were found to have similar, and sometimes low, bias when estimating the relative effects for disconnected treatments, but reference prediction with random study effects had the greatest coverage.The use of reference prediction with random study effects for disconnected networks is recommended if no individual patient data or alternative real-world evidence is available.

A meta-analysis of proportions of single arm observational series for anterior skull base meningiomas comparing supraorbital craniotomy to the endoscopic endonasal approach

IntroductionOlfactory groove (OG) and planum sphenoidale/tuberculum sella (PS/TS) meningiomas are frequently treated via supraorbital craniotomy (SOC) or endoscopic endonasal approach (EEA). Though previously compared, noncomparative studies comprising the majority of case series were excluded or analyses did not weight the study by sample size. We perform a meta-analysis taking these into consideration to understand relevant outcomes. MethodsA systematic literature search was performed from January 2000 to January 2020 for meningiomas treated by SOC or EEA utilizing PRISMA guidelines. Data was collected as binary variables. A meta-analysis of proportions for single-arm observational studies was performed in RStudios. ResultsA total of 42 studies were included consisting of 427 SOC and 524 EEA patients. In OG, SOC had greater gross total resection (GTR; 90% [95% CI 84–94]) than EEA (66% [55–75]) (p < 0.0001 with a slight advantage in PS/TS (82% [76–87]) over EEA (74% [69–79]) (p = 0.0542). EEA had more frequent CSF leak in both OG (EEA 31% [22–41], SOC 11% [7–17], p = 0.0003) and PS/TS (EEA 15% [11–20], SOC 6% [4–10], p = 0.0020). Visual improvement was borderline significant (p = 0.0468) for EEA (73% [65–79]), over SOC (61% [51–70]given the overlapping confidence intervals. There was no difference in stroke, seizure, or recurrence. DiscussionSOC is favored over EEA for OG meningiomas given the higher rate of GTR and lower CSF leak rate. For PS/TS meningiomas without visual deficit, there is a slight EOR advantage with SOC. In cases of visual deficit, EEA has a slight advantage in postoperative visual improvement.

Efficacy and Safety of Intravascular Lithotripsy in Calcified Coronary Lesions: A Systematic Review and Meta-Analysis

BackgroundIntravascular lithotripsy (IVL) is a recently introduced therapeutic modality in the management of calcified coronary lesions (CCAD). IVL delivers sonic pressure waves to modulate calcium, hence promote vessel compliance and optimize stent deployment. MethodsWe performed a comprehensive literature search for studies that evaluated the utility of adjunctive IVL. The primary outcomes of our study were the clinical success, defined as the ability of IVL to produce residual diameter stenosis <50% (RDS < 50%) after stenting with no evidence of in-hospital major adverse cardiac events, and the angiographic success, defined as success in facilitating stent delivery with RDS < 50% and without serious angiographic complications. The secondary outcomes included post-IVL and post-stenting changes in lumen area, calcium angle, and the maximum calcium thickness. Proportional analysis was used for binary data and mean difference was used for continuous data. All meta-analyses were conducted using a random-effect model and 95% confidence intervals (CIs) were included. ResultsA total of eight single-arm observational studies, including 980 patients (1011 lesions), were included. 48.8% of the patients presented with acute coronary syndrome. Severe calcifications were present in 97% of lesions. Clinical success was achieved in 95.4% of patients (95%CI:92.9%–97.9%). Angiographic success was achieved in 97% of patients (95%CI:95%–99%). There was an overall increase in postprocedural lumen area as well as significant reduction of calcium angle and maximum calcium thickness. ConclusionsIVL seems to have excellent efficacy and safety in the management of CCAD. However, adequately powered RCTs are needed to evaluate IVL compared to other calcium/plaque modifying techniques.

Appropriate Tourniquet Types in the Pediatric Population: A Systematic Review.

Trauma is the leading cause of mortality in those aged 1-19, with hemorrhage accounting for up to 40% of all trauma deaths. Manufactured tourniquets are recommended for the control of life-threatening extremity hemorrhage in adults but their use in the pediatric population requires further investigation. We performed a systematic review to evaluate the most appropriate tourniquet design for use in the pediatric population. A literature search of Embase and the Cochran databases of trials and systematic reviews on October 1, 2020 identified 454 unique references, of which 15 were included for full-text screening. Two single-arm observational studies with a high risk of bias evaluated the use of windlass tourniquets in the pediatric population (73 patients, age 2-16 years). The certainty of the evidence was very low. In both studies, conducted on uninjured extremities, the use of a manufactured windlass tourniquet, specifically the Combat Application Tourniquet (C-A-T®) Generation 7, led to the cessation of Doppler detected pulses in 71/71 (100%) of upper extremities and 69/73 (94.5%) of lower extremities. Of the four failures, one participant withdrew due to pain and three tourniquet applications failed to occlude pulses after three turns of the windlass. No controls were used for comparison. In conclusion, two observational studies demonstrated that windlass tourniquets were able to abolish distal pulses in children as young as two years of age and with a minimum limb circumference of 13 cm. These preliminary findings may be helpful for organizations in the creation of guidelines for the management of life-threatening extremity bleeding in children.

Second-generation antidepressants for treatment of seasonal affective disorder.

Seasonal affective disorder (SAD) is a seasonal pattern of recurrent depressive episodes that is often treated with second-generation antidepressants (SGAs), light therapy, or psychotherapy. To assess the efficacy and safety of second-generation antidepressants (SGAs) for the treatment of seasonal affective disorder (SAD) in adults in comparison with placebo, light therapy, other SGAs, or psychotherapy. This is an update of anearlier review first published in 2011. We searched the Cochrane Central Register of Controlled Trials(CENTRAL; 2020, Issue 1) in the Cochrane Library (all years), Ovid MEDLINE, Embase, and PsycINFO (2011 to January 2020), together with the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all available years), for reports of randomised controlled trials (RCTs). Wehand searchedthereference listsof all included studiesand other systematic reviews. We searched ClinicalTrials.gov for unpublished/ongoing trials.We ran a separate updatesearch for reports of adverse events in the Ovid databases. SELECTION CRITERIA: For efficacy we included RCTs of SGAs compared with other SGAs, placebo, light therapy, or psychotherapy in adult participants with SAD. For adverse events we also included non-randomised studies. Two review authors independently screened abstracts and full-text publications against the inclusion criteria. Data extraction and 'Risk of bias' assessment were conducted individually. We pooled data for meta-analysis where the participant groups were similar, and the studies assessed the same treatments with the same comparator and had similar definitions of outcome measures over a similar duration of treatment. In this update we identified no new RCT on the effectiveness of SGAs in SAD patients. We included 2 additional single-arm observational studies that reported on adverse events of SGAs. For efficacy we included three RCTs of between five and eight weeks' duration with a total of 204 participants. For adverse events we included two RCTs and five observational (non-randomised) studies of five to eight weeks' duration with a total of 249 participants. All participants met the DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for SAD. The average age ranged from 34 to 42 years, and the majority of participants were female (66% to 100%). Results from one trial with 68 participants showed that fluoxetine (20/36)was numerically superior to placebo (11/32)in achieving clinical response; however, the confidence interval (CI) included both a potential benefit as well as no benefit of fluoxetine (risk ratio (RR) 1.62, 95% CI 0.92 to 2.83, very low-certainty evidence). The number of adverse events was similar in both groups (very low-certainty evidence). Two trials involving a total of 136 participants compared fluoxetine versus light therapy. Meta-analysis showed fluoxetine and light therapy to be approximately equal in treating seasonal depression: RR of response 0.98 (95% CI 0.77 to 1.24, low-certainty evidence), RR of remission 0.81 (95% CI 0.39 to 1.71, very low-certainty evidence). The number of adverse events was similar in both groups (low-certainty evidence). We did not identify any eligible study comparing SGA with another SGA or with psychotherapy. Two RCTs and five non-randomised studies reported adverse event data on a total of 249 participants who received bupropion, fluoxetine, escitalopram, duloxetine, nefazodone, reboxetine, light therapy, or placebo. We were only able to obtain crude rates of adverse events, therefore caution is advised regarding interpretation of this information. Between 0% and 100% of participants who received an SGA suffered an adverse event, and between 0% and 25% of participants withdrew from the study due to adverse events. Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo showing a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy suggesting equivalence between the two interventions. The lack of available evidence precluded us from drawing any overall conclusions on the use of SGAs for SAD. Further, larger RCTs are required to expand and strengthen the evidence base on this topic, and should also include comparisons with psychotherapy and other SGAs. Data on adverse events were sparse, and a comparative analysis was not possible. The data we obtained on adverse events is therefore not robust, and our confidence in the data is limited. Overall, up to 25% of participants treated with SGAs for SAD withdrew from the study early due to adverse events.