D3/Penta 21 clinical trial design: A randomised non-inferiority trial with nested drug licensing substudy to assess dolutegravir and lamivudine fixed dose formulations for the maintenance of virological suppression in children with HIV-1 infection, aged 2 to 15 years.

BACKGROUND: There is increasing interest in utilising two-drug regimens for HIV treatment with the goal of reducing toxicity and improve acceptability. The D3 trial evaluates the efficacy and safety of DTG/3TC in children and adolescents and includes a nested pharmacokinetics(PK) substudy for paediatric drug licensing. METHODS: D3 is an ongoing open-label, phase III, 96-week non-inferiority randomised controlled trial(RCT) conducted in South Africa, Spain, Thailand, Uganda and the United Kingdom. D3 has enrolled 386 children aged 2- < 15 years, virologically suppressed for ≥6 months, with no prior treatment failure. Participants were randomised 1:1 to receive DTG/3TC or DTG plus two nucleoside reverse transcriptase inhibitors(NRTIs), stratified by region, age (2- < 6, 6- < 12, 12- < 15 years) and DTG use at enrolment (participants permitted to start DTG at enrolment). The primary outcome is confirmed HIV-1 RNA viral rebound ≥50 copies/mL by 96-weeks. The trial employs the Smooth Away From Expected(SAFE) non-inferiority frontier, which specifies the non-inferiority margin and significance level based on the observed event risk in the control arm. The nested PK substudy evaluates WHO weight-band-aligned dosing in the DTG/3TC arm. DISCUSSION: D3 is the first comparative trial evaluating DTG/3TC in children and adolescents. Implications of integrating a PK substudy and supplying data for prompt regulatory submission, were carefully considered to ensure the integrity of the ongoing trial. The trial uses an innovative non-inferiority frontier for the primary analysis to allow for a lower-than-expected confirmed viral rebound risk in the control arm, while ensuring interpretability of results and maintaining the planned sample size in an already funded trial. TRIAL REGISTRATION: International Standard Randomised Clinical Trial Number Register: ISRCTN17157458. European Clinical Trials Database: 2020-001426-57. CLINICALTRIALS: gov: NCT04337450.

Totally intracorporeal colorectal anastomosis (TICA) versus classical mini-laparotomy for specimen extraction, after segmental bowel resection for deep endometriosis: a single-center experience.

PURPOSE: The surgical approach to bowel endometriosis is still unclear. The aim of the study is to compare TICA to conventional specimen extractions and extra-abdominal insertion of the anvil in terms of both complications and functional outcomes. METHODS: This is a single-center, observational, retrospective study conducted enrolling symptomatic women underwent laparoscopic excision of deep endometriosis with segmental bowel resection between September 2019 and June 2022. Women who underwent TICA were compared to classical technique (CT) in terms of intra- and postoperative complications, moreover, functional outcomes relating to the pelvic organs were assessed using validated questionnaires [Knowles-Eccersley-Scott-Symptom (KESS) questionnaire and Gastro-Intestinal Quality of Life Index (GIQLI)] for bowel function. Pain symptoms were assessed using Visual Analogue Scale (VAS) scores. RESULTS: The sample included 64 women. TICA was performed on 31.2% (n = 20) of the women, whereas CT was used on 68.8% (n = 44). None of the patients experienced rectovaginal, vesicovaginal, ureteral or vesical fistula, or ureteral stenosis and uroperitoneum, and in no cases was it necessary to reoperate. Regarding the two surgical approaches, no significant difference was observed in terms of complications. As concerns pain symptoms at 6-month follow-up evaluations on stratified data, except for dysuria, all VAS scales reported showed significant reductions between median values, for both surgery interventions. As well, significant improvements were further observed in KESS scores and overall GIQLI. Only the GIQLI evaluation was significantly smaller in the TICA group compared to CT after the 6-month follow-up. CONCLUSIONS: We did not find any significant differences in terms of intra- or post-operative complications compared TICA and CT, but only a slight improvement in the Gastro-Intestinal Quality of Life Index in patients who underwent the CT compared to the TICA technique.

Preoperative diagnosis of ureteral medial deviations secondary to deep endometriosis using transvaginal ultrasound examinations: Can we predict the need for ureterolysis during laparoscopic surgery?

OBJECTIVE: To evaluate ureteral involvement using transvaginal sonography (TVS) regarding the distortion of the course of the ureters caused by deep endometriosis (DE), which can facilitate predicting the need for ureterolysis during surgery, even in the absence of ureteral stenosis or dilatation. METHODS: This is a single-center, observational, retrospective pilot study of 88 consecutive patients who later underwent surgery for DE that used ultrasound preoperative diagnosis of ureteral medial deviation of one or both ureters between January 2019 and January 2022. At TVS, the course of the ureter was considered medialized if, in longitudinal and transversal section, any distance was detectable between the ureter and the cervix at the point where the ureter crosses the uterine artery. The primary end point was to determine sensitivity, specificity, and positive and negative predictive values of "ureteral medial deviation" diagnosed using TVS, in order to predict the need for ureterolysis. RESULTS: Our series included 88 women with a median age of 39 (interquartile range 33-43) years. Ureteral medialization showed a relatively low false-positive rate (10.9%), with a specificity of 89.1% (95% confidence interval [CI] 81.4%-96.7%) and a sensitivity of 86.6% (95% CI 80.3%-92.9%), along with a high positive predictive value of 93.3% (95% CI 88.4%-98.1%), and a lower negative predictive value of 79.1% (95% CI 69.8%-88.5%), respectively. CONCLUSIONS: This study introduced a new ultrasound sign with a high degree of accuracy to predict ureterolysis and this may have positive implications in the management and surgical planning of patients with ureteral endometriosis.

Comparison of clinical and ultrasound examinations in assessing the parametria in patients with deep infiltrating endometriosis: a multicentre prospective study.

RESEARCH QUESTION: How do clinical rectovaginal examination and transvaginal ultrasound examination perform in the diagnosis of parametrial infiltration in patients with endometriosis? DESIGN: This was a multicentre prospective observational study. Patients with suspected deep endometriosis at clinical examination and/or at ultrasound evaluation and scheduled for surgery were included. Following multicentre multidisciplinary meetings, consensus was obtained on terms and methodology to define the parametrium at pelvic anatomy, ultrasound and surgery. Sensitivity, specificity, accuracy, and positive and negative likelihood ratios were calculated for clinical and ultrasound examinations with respect to surgery. RESULTS: In total, 195 women were selected for the present study and 164 were included in the analysis. Ultrasound examination had good to high specificity (>80%) for all parameters, except the left lateral parametrium (78.8%). The sensitivity of ultrasound examination was good to high for fixity of the right and left ovaries, uterosacral ligaments, retrocervix and rectovaginal space; and low for the anterior and lateral parametria, vagina, bladder and bowel. Clinical examination had good to high specificity for fixity of the left ovary, anterior parametrium, right uterosacral ligament, retrocervix and vagina; and low specificity for fixity of the right ovary, lateral parametrium, left uterosacral ligament and rectovaginal space. The sensitivity of clinical examination was good for the uterosacral ligaments and rectovaginal space, and low for the remaining parameters. CONCLUSION: Ultrasound examination provided good specificity for all the parameters, but sensitivity was low for the anterior and lateral parametria. Clinical examination provided good specificity for the anterior and posterior parametria, but sensitivity was low for the anterior and lateral parametria. Further prospective studies are needed to validate this methodology and confirm the results.

Vascular- and nerve-sparing bowel resection for deep endometriosis: A retrospective single-center study.

OBJECTIVE: Surgical management of bowel endometriosis is still controversial. Recently, many authors have pointed out the potential benefits of preserving the superior rectal artery, thus ensuring better perfusion of the anastomosis. The aim of this study was to evaluate the complication rate and functional outcomes of a bowel resection technique for deep endometriosis (DE) involving a nerve- and vascular-sparing approach. METHODS: A single-center retrospective study was conducted by enrolling patients who underwent segmental resection of the rectus sigmoid for DE in our department between September 2019 and April 2022. Intraoperative and postoperative complications were recorded for each woman, and functional outcomes relating to the pelvic organs were assessed using validated questionnaires (Knowles-Eccersley-Scott-Symptom [KESS] questionnaire and Gastro-Intestinal Quality of Life Index [GIQLI] for bowel function, Bristol Female Lower Urinary Tract Symptoms [BFLUTS] for urinary function, and Female Sexual Function Index [FSFI] for sexual function). These were evaluated preoperatively and postoperatively after 6 months from surgery. RESULTS: Sixty-one patients were enrolled. No patients had Clavien-Dindo grade 3 or 4 complications, there were no rectovaginal fistulas or ureteral lesions, and in no cases was it necessary to reoperate. Temporary bladder voiding deficits were reported in 8.2% of patients, which were treated with self-catheterizations, always resolving within 45 days of surgery. Gastrointestinal function evaluated by KESS and GIQLI improved significantly after surgery, whereas sexual function appeared to worsen, although without reaching the level of statistically significant validity. CONCLUSION: Our vascular- and nerve-sparing segmental bowel resection technique for DE had a low intraoperative and postoperative complication rate and produced an improvement in gastrointestinal function after surgery.

Challenges in the Implementation of the NeoOBS Study, a Global Pragmatic Observational Cohort Study, to Investigate the Aetiology and Management of Neonatal Sepsis in the Hospital Setting.

Neonatal sepsis is a significant cause of mortality and morbidity in low- and middle-income countries. To deliver high-quality data studies and inform future trials, it is crucial to understand the challenges encountered when managing global multi-centre research studies and to identify solutions that can feasibly be implemented in these settings. This paper provides an overview of the complexities faced by diverse research teams in different countries and regions, together with actions implemented to achieve pragmatic study management of a large multi-centre observational study of neonatal sepsis. We discuss specific considerations for enrolling sites with different approval processes and varied research experience, structures, and training. Implementing a flexible recruitment strategy and providing ongoing training were necessary to overcome these challenges. We emphasize the attention that must be given to designing the database and monitoring plans. Extensive data collection tools, complex databases, tight timelines, and stringent monitoring arrangements can be problematic and might put the study at risk. Finally, we discuss the complexities added when collecting and shipping isolates and the importance of having a robust central management team and interdisciplinary collaborators able to adapt easily and make swift decisions to deliver the study on time and to target. With pragmatic approaches, appropriate training, and good communication, these challenges can be overcome to deliver high-quality data from a complex study in challenging settings through a collaborative research network.

Are ureterolysis for deep endometriosis really all the same? An anatomical classification proposal for ureterolysis: A single-center experience.

OBJECTIVE: Ureteral endometriosis has an incidence of 0.1% to 1%. The type of surgery required is either conservative (ureterolysis) or radical treatment, depending on the degree of ureter infiltration. The incidence of intraoperative and postoperative complications is heterogeneous. Thus, the aim of the current study was to propose a classification of ureterolysis based on the anatomical structure of the ureter and differing complication rates with procedures. METHODS: A total of 139 ureterolysis procedures were included in the study. Patients were divided into three groups according to the depth of ureterolysis required. Differences were recorded across the three types of ureterolysis in terms of intraoperative and postoperative complications. RESULTS: The incidence of ureteral fistula was reported in 0.7% of cases, with postoperative ureteral stenosis in 2% of type 2 ureterolysis. In the case of type 3 ureterolysis, after conservative procedures, 52.9% of patients required an ureteroneocystostomy to solve the ureteral stenosis. CONCLUSION: The risk of ureteral injury and ureteroneocystostomy after conservative procedures appears to be associated with type 3 ureterolysis, probably due to excessive devascularization, secondary to the incision of adventitia. Obviously, these data should be confirmed through a prospective study of a larger number, but our proposed classification can provide the basis for making data from future studies more comparable.

Empirical treatment against cytomegalovirus and tuberculosis in HIV-infected infants with severe pneumonia: study protocol for a multicenter, open-label randomized controlled clinical trial.

BACKGROUND: Pneumonia is the primary cause of death among HIV-infected children in Africa, with mortality rates as high as 35-40% in infants hospitalized with severe pneumonia. Bacterial pathogens and Pneumocystis jirovecii are well known causes of pneumonia-related death, but other important causes such as cytomegalovirus (CMV) and tuberculosis (TB) remain under-recognized and undertreated. The immune response elicited by CMV may be associated with the risk of developing TB and TB disease progression, and CMV may accelerate disease caused both by HIV and TB. Minimally invasive autopsies confirm that CMV and TB are unrecognized causes of death in children with HIV. CMV and TB may also co-infect the same child. The aim of this study is to compare the impact on 15-day and 1-year mortality of empirical treatment against TB and CMV plus standard of care (SoC) versus SoC in HIV-infected infants with severe pneumonia. METHODS: This is a Phase II-III, open-label randomized factorial (2 × 2) clinical trial, conducted in six African countries. The trial has four arms. Infants from 28 to 365 days of age HIV-infected and hospitalized with severe pneumonia will be randomized (1:1:1:1) to (i) SoC, (ii) valganciclovir, (iii) TB-T, and (iv) TB-T plus valganciclovir. The primary endpoint of the study is all-cause mortality, focusing on the short-term (up to 15 days) and long-term (up to 1 year) mortality. Secondary endpoints include repeat hospitalization, duration of oxygen therapy during initial admission, severe and notable adverse events, adverse reactions, CMV and TB prevalence at enrolment, TB incidence, CMV viral load reduction, and evaluation of diagnostic tests such as GeneXpert Ultra on fecal and nasopharyngeal aspirate samples and urine TB-LAM. DISCUSSION: Given the challenges in diagnosing CMV and TB in children and results from previous autopsy studies that show high rates of poly-infection in HIV-infected infants with respiratory disease, this study aims to evaluate a new approach including empirical treatment of CMV and TB for this patient population. The potential downsides of empirical treatment of these conditions include toxicity and medication interactions, which will be evaluated with pharmacokinetics sub-studies. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03915366, Universal Trial Number U111-1231-4736, Pan African Clinical Trial Registry PACTR201994797961340.

Infiltrating T lymphocytes and programmed cell death protein-1/programmed death-ligand 1 expression in endometriosis-associated ovarian cancer.

OBJECTIVE: To characterize T lymphocyte infiltration and programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) expression in early-stage endometriosis-associated ovarian cancer (EAOC), ovarian endometriosis (OE), atypical endometriosis (AE), and deep endometriosis (DE). DESIGN: Case-control, retrospective study. SETTING: Research University Hospital. PATIENT(S): A total of 362 patients with a histologic diagnosis of EAOC, OE, AE, or DE were identified between 2000 and 2019 from Fondazione Policlinico Universitario Agostino Gemelli IRCCS and Gemelli Molise SpA tissue data banks. A 1:1 propensity score-matched method yielded matched pairs of 55 subjects with EAOC, 55 patients with OE, 12 patients with AE, and 42 patients with DE, resulting in no differences in family history of cancer, parity, and use of oral contraceptives. INTERVENTION(S): Immunohistochemistry assays using the following primary antibodies: CD3+; CD4+; CD8+; PD-1; and PD-L1. MAIN OUTCOME MEASURE(S): To characterize T lymphocyte infiltration and PD-1/PD-L1 expression in 4 different endometriosis-related diseases. RESULT(S): Endometriosis-associated ovarian cancer cases displayed significantly higher levels of PD-1/PD-L1 expression compared with all other endometriosis-related diseases (vs. OE vs. AE vs. DE). Moreover, a significantly lower count of infiltrating T lymphocytes was observed in EAOC cases compared with OE ones. Finally, one-third of OE cases showed a cancer-like PD-1/PD-L1 expression profile. CONCLUSION(S): Endometriosis-associated ovarian cancer is characterized by higher levels of PD-1/PD-L1 expression compared with benign endometriosis-related diseases. This profile was found in one-third of clinically benign cases, suggesting that it develops early in the carcinogenesis process.

Alpha-Lipoic Acid Plays a Role in Endometriosis: New Evidence on Inflammasome-Mediated Interleukin Production, Cellular Adhesion and Invasion.

Endometriosis is an estrogen-linked gynecological disease defined by the presence of endometrial tissue on extrauterine sites where it forms invasive lesions. Alterations in estrogen-mediated cellular signaling seems to have an essential role in the pathogenesis of endometriosis. Higher estrogen receptor (ER)-ß levels and enhanced ER-ß activity were detected in endometriotic tissues. It is well known that ER-ß interacts with components of the cytoplasmic inflammasome-3 (NALP-3), the NALP-3 activation increases interleukin (IL)-1ß and IL-18, enhancing cellular adhesion and proliferation. Otherwise, the inhibition of ER-ß activity suppresses the ectopic lesions growth. The present study aims to investigate the potential effect of α-lipoic acid (ALA) on NALP-3 and ER-ß expression using a western blot analysis, NALP-3-induced cytokines production by ELISA, migration and invasion of immortalized epithelial (12Z) and stromal endometriotic cells (22B) using a 3D culture invasion assay, and matrix-metalloprotease (MMPs) activity using gelatin zymography. ALA significantly reduces ER-ß, NALP-3 protein expression/activity and the secretion of IL-1ß and IL-18 in both 12Z and 22B cells. ALA treatment reduces cellular adhesion and invasion via a lower expression of adhesion molecules and MMPs activities. These results provide convincing evidence that ALA might inhibit endometriosis progression.

Laparoscopic Ethanol Sclerotherapy for Ovarian Endometriomas: Preliminary Results.

STUDY OBJECTIVE: The purpose of this study was to evaluate the laparoscopic aspiration of endometriomas through 95% ethanol sclerotherapy. DESIGN: A single-center, retrospective study. SETTING: Endometriosis outpatient clinic of a tertiary university hospital, gynecology department of Agostino Gemelli University Foundation Polyclinic IRCCS, Rome, Italy. PATIENTS: Fifty-three women with 64 identified endometriomas measuring 4 to 10 cm with no suspected malignancy. INTERVENTIONS: Laparoscopic aspiration and 95% ethanol sclerotherapy of endometriomas were completed in the patients between September 2013 and September 2017. MEASUREMENTS AND MAIN RESULTS: Using standard laparoscopy, the ovarian endometriomas were aspirated and washed to remove all cystic material. A 95% ethanol solution was instilled in the cysts and left for 15 minutes, then removed. The patients were followed by ultrasound at 3, 6, 9, and 12 months, and then annually to identify recurrence. All patients were administered postoperative hormone therapy, suspended only in those desiring pregnancy or experiencing adverse effects. The mean age was 32 years (range 19-40 years), and the mean cyst diameter was 6 cm (range 4-10 cm). Thirteen of the 53 patients (25%) had had previous surgery for endometriomas. Forty-one patients (77%) had associated deep endometriosis, treated during the same laparoscopic procedure. No major ethanol-related complications were recorded. The mean length of follow-up was 31 months. Recurrence of endometriomas was observed in 5 patients (9%). Overall, pregnancy occurred in 16 of 28 patients (57%) desiring pregnancy. CONCLUSION: Laparoscopic aspiration and ethanol sclerotherapy as treatment for endometriomas, even in patients with bilateral endometriomas or with associated deep endometriosis, resulted in <10% recurrence and no major complications.