Evaluation of clinical practice guidelines (CPG) on the management of female chronic pelvic pain (CPP) using the AGREE II instrument.

INTRODUCTION AND HYPOTHESIS: Variations in guidelines may result in differences in treatments and potentially poorer health-related outcomes. We aimed to systematically review and evaluate the quality of national and international guidelines and create an inventory of CPG recommendations on CPP. METHODS: We searched EMBASE and MEDLINE databases from inception till August 2020 as well as websites of professional organizations and societies. We selected national and international CPGs reporting on the diagnosis and management of female CPP. We included six CPGs. Five researchers independently assessed the quality of included guidelines using the AGREE II tool and extracted recommendations. RESULTS: Two hundred thirty-two recommendations were recorded and grouped into six categories: diagnosis, medical treatment, surgical management, behavioural interventions, complementary/alternative therapies and education/research. Thirty-nine (17.11%) recommendations were comparable including: a comprehensive pain history, a multi-disciplinary approach, attributing muscular dysfunction as a cause of CPP and an assessment of quality of life. Two guidelines acknowledged sexual dysfunction associated with CPP and recommended treatment with pelvic floor exercises and behavioural interventions. All guidelines recommended surgical management; however, there was no consensus regarding adhesiolysis, bilateral salpingo-oophorectomy during hysterectomy, neurectomy and laparoscopic uterosacral nerve ablation. Half of recommendations (106, 46.49%) were unreferenced or made in absence of good-quality evidence or supported by expert opinion. Based on the AGREE II assessment, two guidelines were graded as high quality and recommended without modifications (EAU and RCOG). Guidelines performed poorly in the "Applicability", "Editorial Independence" and "Stakeholder Involvement" domains. CONCLUSION: Majority of guidelines were of moderate quality with significant variation in recommendations and quality of guideline development

Effect of a Proposed Trastuzumab Biosimilar Compared With Trastuzumab on Overall Response Rate in Patients With ERBB2 (HER2)–Positive Metastatic Breast Cancer. A Randomized Clinical Trial

IMPORTANCE Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)–positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy. OBJECTIVE To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred. INTERVENTIONS Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane. MAIN OUTCOMES AND MEASURES The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and −15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events. RESULTS Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, −3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; −1.7%; 95% CI, −11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; −0.4%; 95% CI, −9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, −2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%). CONCLUSIONS AND RELEVANCE Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier: 2011-001965-4

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial

Background Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. Methods FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. Findings Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839–1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26–6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38–2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. Interpretation Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. Funding UK Stroke Association and NIHR Health Technology Assessment Programme

Ultrasound Irradiated Polymerization of Styrene under Heterogeneous Condition-A Kinetic Study

The kinetics of multi-site phase-transfer catalyzed free radical polymerization of Styrene (STY) using potassium peroxy disulphate (PDS) as water soluble initiator and newly synthesized 1,4-dihexadecylbenzopyrazine-1,4-diium dibromide as multi-site phase-transfer catalyst (MPTC) has been investigated in ethyl acetate / water two phase system at constant temperature 65 + 1°C under nitrogen atmosphere and ultrasound irradiation conditions. The rate of polymerization increases with an increase in concentrations of STY, MPTC and PDS. The order with respect to monomer, initiator and MPTC were found to be 2.0, 1.0 and 0.5 respectively. Based on the observed results a suitable mechanism has been proposed to account for the experimental observations and its significance was discussed

Triazophos toxicity induced histological abnormalities in Heteropneustes fossilis Bloch 1794 (Siluriformes: Heteropneustidae) organs and assessment of recovery response

Abstract Background Agricultural pesticides have toxic effects in the aquatic ecosystem, and their persistence poses a hazard to aquatic life, as seen by fish poisoning, both acute and chronic. Triazophos, a broad-spectrum organophosphate insecticide, is used to control agricultural crops from insect pests. For a period of 10 days, Heteropneustes fossilis, a fish of great economic and therapeutic value, was exposed to various levels of triazophos toxicity (5, 10 and 15 ppm), after which they were sacrificed. For recovery tests, the treated fish were switched to clean tap water after 10 days of exposure to the toxicant, examined for another 10 days, and then sacrificed. The histological changes in the tissues of the sacrificed fishes' gill, liver, intestine, kidney, brain, and muscle (treatment and recovery) were investigated. Results The histology investigations revealed that the toxicant was hazardous, with histopathological changes increasing as the concentration of the toxicant increased. The gills had the most damage, with fusion of secondary lamella and epithelial hyperplasia; liver had vacuolization, pyknotic nuclei, and focal necrosis; intestine had degenerated, necrotic villi, degeneration of epithelial cells, and atropy; kidney had narrowing of the tubular lumen, pyknotic nuclei, hypertrophy, degeneration; swelling, haemorrhage, larger neuronal cells, and karyolysis were observed in the brain, whereas infiltration of leucocytes, loss of striated muscles, and an increase in intra fibril area were observed in the muscle. When compared to the treated fishes, the 10-day recovery research demonstrated tissue damage and a slower recovery pattern. Conclusions Triazophos caused histological changes in the gill, liver, intestine, kidney, brain and muscle of the test fish Heteropneustes fossilis. With reference to recovery response, a slow recovery was observed. Furthermore, this is the first investigation into the effects of triazophos on the recovery response in Heteropneustes fossilis

Implications of an extensive salt water barrage on the distribution of black clam in a tropical estuarine system, Southwest coast of India

Based on a monthly field sampling over a year in the Kochi backwaters (KBW), this study presents the larval ecology of black clam and discusses how an extensive saltwater barrage [Thannermukkom barrage (TB)] impacted the natural black clam resource distribution. Spatial variations in salinity were found minimal during the Southwest Monsoon (June—September) due to the predominance of the freshwater associated with heavy monsoonal rainfall. Conversely, significant spatial changes in salinity were evident during the Pre-Southwest Monsoon (March—May) and Post-Southwest Monsoon (October—February). Monthly sampling exercises revealed that the black clam stock in the KBW breeds throughout the year, as their larvae were found (8 indiv. m—3—494 indiv. m—3) in all the locations. This observation is the modification of the traditional belief that black clam in the KBW breeds only twice a year. Mesohaline condition (salinity 5—18) is the most conducive for peak spawning and larval production. There were two peaks of larval production in the KBW over a year, mainly associated with the prevalence of the optimum salinity conditions on different spatial scales. The closing of the TB after the Southwest Monsoon (September) causes shrinkage of the area of the oligohaline and mesohaline conditions, the most conducive environment for the peak spawning and larval production of black clam in the KBW. This study presents a clear case of how human alterations of the natural environment impact valuable biological resources, which may apply to many similar aquatic ecosystems across the globe

Chronic Nicotine Exposure In Vivo and In Vitro Inhibits Vitamin B1 (Thiamin) Uptake by Pancreatic Acinar Cells.

Thiamin (vitamin B1), a member of the water-soluble family of vitamins, is essential for normal cellular functions; its deficiency results in oxidative stress and mitochondrial dysfunction. Pancreatic acinar cells (PAC) obtain thiamin from the circulation using a specific carrier-mediated process mediated by both thiamin transporters -1 and -2 (THTR-1 and THTR-2; encoded by the SLC19A2 and SLC19A3 genes, respectively). The aim of the current study was to examine the effect of chronic exposure of mouse PAC in vivo and human PAC in vitro to nicotine (a major component of cigarette smoke that has been implicated in pancreatic diseases) on thiamin uptake and to delineate the mechanism involved. The results showed that chronic exposure of mice to nicotine significantly inhibits thiamin uptake in murine PAC, and that this inhibition is associated with a marked decrease in expression of THTR-1 and THTR-2 at the protein, mRNA and hnRNAs level. Furthermore, expression of the important thiamin-metabolizing enzyme, thiamin pyrophosphokinase (TPKase), was significantly reduced in PAC of mice exposed to nicotine. Similarly, chronic exposure of cultured human PAC to nicotine (0.5 μM, 48 h) significantly inhibited thiamin uptake, which was also associated with a decrease in expression of THTR-1 and THTR-2 proteins and mRNAs. This study demonstrates that chronic exposure of PAC to nicotine impairs the physiology and the molecular biology of the thiamin uptake process. Furthermore, the study suggests that the effect is, in part, mediated through transcriptional mechanism(s) affecting the SLC19A2 and SLC19A3 genes

Chronic Nicotine Exposure In Vivo and In Vitro Inhibits Vitamin B1 (Thiamin) Uptake by Pancreatic Acinar Cells.

Thiamin (vitamin B1), a member of the water-soluble family of vitamins, is essential for normal cellular functions; its deficiency results in oxidative stress and mitochondrial dysfunction. Pancreatic acinar cells (PAC) obtain thiamin from the circulation using a specific carrier-mediated process mediated by both thiamin transporters -1 and -2 (THTR-1 and THTR-2; encoded by the SLC19A2 and SLC19A3 genes, respectively). The aim of the current study was to examine the effect of chronic exposure of mouse PAC in vivo and human PAC in vitro to nicotine (a major component of cigarette smoke that has been implicated in pancreatic diseases) on thiamin uptake and to delineate the mechanism involved. The results showed that chronic exposure of mice to nicotine significantly inhibits thiamin uptake in murine PAC, and that this inhibition is associated with a marked decrease in expression of THTR-1 and THTR-2 at the protein, mRNA and hnRNAs level. Furthermore, expression of the important thiamin-metabolizing enzyme, thiamin pyrophosphokinase (TPKase), was significantly reduced in PAC of mice exposed to nicotine. Similarly, chronic exposure of cultured human PAC to nicotine (0.5 μM, 48 h) significantly inhibited thiamin uptake, which was also associated with a decrease in expression of THTR-1 and THTR-2 proteins and mRNAs. This study demonstrates that chronic exposure of PAC to nicotine impairs the physiology and the molecular biology of the thiamin uptake process. Furthermore, the study suggests that the effect is, in part, mediated through transcriptional mechanism(s) affecting the SLC19A2 and SLC19A3 genes

Evaluation of clinical practice guidelines (CPG) on the management of female chronic pelvic pain (CPP) using the AGREE II instrument

Introduction and hypothesis Variations in guidelines may result in differences in treatments and potentially poorer health-related outcomes. We aimed to systematically review and evaluate the quality of national and international guidelines and create an inventory of CPG recommendations on CPP. Methods We searched EMBASE and MEDLINE databases from inception till August 2020 as well as websites of professional organizations and societies. We selected national and international CPGs reporting on the diagnosis and management of female CPP. We included six CPGs. Five researchers independently assessed the quality of included guidelines using the AGREE II tool and extracted recommendations. Results Two hundred thirty-two recommendations were recorded and grouped into six categories: diagnosis, medical treatment, surgical management, behavioural interventions, complementary/alternative therapies and education/research. Thirty-nine (17.11%) recommendations were comparable including: a comprehensive pain history, a multi-disciplinary approach, attributing muscular dysfunction as a cause of CPP and an assessment of quality of life. Two guidelines acknowledged sexual dysfunction associated with CPP and recommended treatment with pelvic floor exercises and behavioural interventions. All guidelines recommended surgical management; however, there was no consensus regarding adhesiolysis, bilateral salpingo-oophorectomy during hysterectomy, neurectomy and laparoscopic uterosacral nerve ablation. Half of recommendations (106, 46.49%) were unreferenced or made in absence of good-quality evidence or supported by expert opinion. Based on the AGREE II assessment, two guidelines were graded as high quality and recommended without modifications (EAU and RCOG). Guidelines performed poorly in the “Applicability”, “Editorial Independence” and “Stakeholder Involvement” domains. Conclusion Majority of guidelines were of moderate quality with significant variation in recommendations and quality of guideline development