Preclinical safety and efficacy of a therapeutic antibody that targets SARS-CoV-2 at the sotrovimab face but is escaped by Omicron

The recurrent emerging of novel viral variants of concern (VOCs) with evasion of preexisting antibody immunity upholds severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case numbers and maintains a persistent demand for updated therapies. We selected the patient-derived antibody CV38-142 based on its potency and breadth against the VOCs Alpha, Beta, Gamma, and Delta for preclinical development into a therapeutic. CV38-142 showed in vivo efficacy in a Syrian hamster VOC infection model after post-exposure and therapeutic application and revealed a favorable safety profile in a human protein library screen and tissue cross-reactivity study. Although CV38-142 targets the same viral surface as sotrovimab, which maintains activity against Omicron, CV38-142 did not neutralize the Omicron lineages BA.1 and BA.2. These results highlight the contingencies of developing antibody therapeutics in the context of antigenic drift and reinforce the need to develop broadly neutralizing variant-proof antibodies against SARS-CoV-2

Effectiveness and acceptability of progestogens in combined oral contraceptives – a systematic review

BACKGROUND: The progestogen component of oral contraceptives (OCs) has undergone changes since it was recognized that their chemical structure can influence the spectrum of minor adverse and beneficial effects. METHODS: The objective of this review was to evaluate currently available low-dose OCs containing ethinylestradiol and different progestogens in terms of contraceptive effectiveness, cycle control, side effects and continuation rates. The Cochrane Controlled Trials Register, MEDLINE and EMBASE databases were searched. Randomized trials reporting clinical outcomes were considered for inclusion and were assessed for methodological quality and validity. RESULTS: Twenty–two trials were included in the review. Eighteen were sponsored by pharmaceutical companies and in only 5 there was an attempt for blinding. Most comparisons between different interventions included one to three trials, involving usually less than 500 women. Discontinuation was less with second-generation progestogens compared to first–generation (RR 0.79; 95% CI 0.69–0.91). Cycle control appeared to be better with second-compared to first-generation progestogens for both, mono-and triphasic preparations (RR 0.69; 95% CI 0.52–0.91) and (RR 0.61; 95% CI 0.43–0.85), respectively. Intermenstrual bleeding was less with third- compared to second-generation pills (RR 0.71; 95% CI 0.55–0.91). Contraceptive effectiveness of gestodene (GSD) was comparable to that of levonorgestrel (LNG), and had similar pattern of spotting, breakthrough bleeding and absence of withdrawal bleeding). Drospirenone (DRSP) was similar compared to desogestrel (DSG) regarding contraceptive effectiveness, cycle control and side effects. CONCLUSION: The third- and second-generation progestogens are preferred over first generation in all indices of acceptability. Current evidence suggests that GSD is comparable to LNG in terms of contraceptive effectiveness and for most cycle control indices. GSD is also comparable to DSG. DRSP is comparable to DSG. Future research should focus on independently conducted well designed randomized trials comparing particularly the third- with second-generation progestogens

Preclinical safety and efficacy of a therapeutic antibody that targets SARS-CoV-2 at the sotrovimab face but is escaped by Omicron

The recurrent emerging of novel viral variants of concern (VOCs) with evasion of preexisting antibody immunity upholds severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) case numbers and maintains a persistent demand for updated therapies. We selected the patient-derived antibody CV38-142 based on its potency and breadth against the VOCs Alpha, Beta, Gamma, and Delta for preclinical development into a therapeutic. CV38-142 showed in vivo efficacy in a Syrian hamster VOC infection model after post-exposure and therapeutic application and revealed a favorable safety profile in a human protein library screen and tissue cross-reactivity study. Although CV38-142 targets the same viral surface as sotrovimab, which maintains activity against Omicron, CV38-142 did not neutralize the Omicron lineages BA.1 and BA.2. These results highlight the contingencies of developing antibody therapeutics in the context of antigenic drift and reinforce the need to develop broadly neutralizing variant-proof antibodies against SARS-CoV-2

Osteogenesis imperfecta

Osteogenesis imperfecta is an inherited disorder of the connective tissue. The extreme bone fragility seen in patients suffering from osteogenesis imperfecta pose a series of problems with regard to behavior management and rendering of quality dental treatment. Presented here a case of a four year old child suffering from osteogenesis imperfecta

UPDATING the CLINICAL-EXPERIENCE in ENDOMETRIOSIS - the BRAZILIAN PERSPECTIVE

In an open-label, multicentre, randomized, parallel group study, 164 women with endometriosis were assigned to treatment. Out of these women, 81 received danazol (600 mg daily for 8 weeks, then 400 mg for 16 weeks) and 83 were given gestrinone (2.5 mg twice a week for 24 weeks). Five weeks before the start of treatment clinical evaluation and diagnostic laparoscopy were performed during the screening visit. Drug assignment and laboratory data assessment were carried out within 3 days of the estimated onset of the menstrual cycle at baseline visit. the response to treatment was assessed during visits at weeks 2, 4, 8, 12, 16, 20 and 24; at the last visit a second laparoscopy was performed. Therapeutic efficacy was evaluated by analysis of the laparoscopic scores assessed according to the revised American Fertility Society classification. Symptomatic response was measured by clinical scores and laboratory data. in one centre, bone mineral density was also recorded. One patient in the danazol group discontinued treatment due to a cutaneous rash as a probable adverse reaction at the beginning of the study. the therapeutic efficacy of danazol and gestrinone did not differ significantly when the revised American Fertility Society scores were compared. the symptomatic response also showed no statistical difference when clinical examination scores were analysed. There was no significant difference between the drugs in laboratory data, including bone mineral density, with respect to adverse events. Analysis of clinical scores showed that danazol was superior to gestrinone with respect to acne and irregular bleeding. Based on these data, we conclude that both danazol and gestrinone are reliable in the treatment of endometriosis and offer similar results.UNIV São Paulo,SCH MED,DEPT OBSTET & GYNECOL,São Paulo,SP,BRAZILFED SCH MED SCI,DEPT OBSTET & GYNECOL,PORTO ALEGRE,RS,BRAZILFED UNIV São Paulo,SCH MED,DEPT TOCOGYNECOL,São Paulo,BRAZILFED UNIV São Paulo,SCH MED,DEPT TOCOGYNECOL,São Paulo,BRAZILWeb of Scienc

Reasons why patients fail screening in Indian breast cancer trials

Introduction: An increased number of screen failure patients in a clinical trial increases time and cost required for the recruitment. Assessment of reasons for screen failure can help reduce screen failure rates and improve recruitment. Materials and Methods: We collected retrospective data of human epidermal growth factor receptor (HER2) positive Indian breast cancer patients, who failed screening for phase 3 clinical trials and ascertained their reasons for screen failure from screening logs. Statistical comparison was done to ascertain if there are any differences between private and public sites. Results: Of 727 patients screened at 14 sites, 408 (56.1%) failed screening. The data on the specific reasons for screen failures was not available at one of the public sites (38 screen failures out of 83 screened patients). Hence, after excluding that site, further analysis is based on 644 patients, of which 370 failed screening. Of these, 296 (80%) screen failure patients did not meet selection criteria. The majority -266 were HER2 negative. Among logistical issues, 39 patients had inadequate breast tissue sample. Sixteen patients withdrew their consent at private sites as compared to six at public sites. The difference between private and public sites for the above three reasons was statistically significant. Conclusion: Use of prescreening logs to reduce the number of patients not meeting selection criteria and protocol logistics, and patient counseling to reduce consent withdrawals could be used to reduce screen failure rate

Coupling of a distributed stakeholder-built system dynamics socio-economic model with SAHYSMOD for sustainable soil salinity management. Part 2: Model coupling and application

Many simulation models focus on simulating a single physical process and do not constitute balanced representations of the physical, social and economic components of a system. The present study addresses this challenge by integrating a physical (P) model (SAHYSMOD) with a group (stakeholder) built system dynamics model (GBSDM) through a component modeling approach based on widely applied tools such as MS Excel, Python and Visual Basic for Applications (VBA). The coupled model (P-GBSDM) was applied to test soil salinity management scenarios (proposed by stakeholders) for the Haveli region of the Rechna Doab Basin in Pakistan. Scenarios such as water banking, vertical drainage, canal lining, and irrigation water reallocation were simulated with the integrated model. Spatiotemporal maps and economic and environmental trade-off criteria were used to examine the effectiveness of the selected management scenarios. After 20 years of simulation, canal lining reduced soil salinity by 22% but caused an initial reduction of 18% in farm income, which requires an initial investment from the government. The government-sponsored Salinity Control and Reclamation Project (SCARP) is a short-term policy that resulted in a 37% increase in water availability with a 12% increase in farmer income. However, it showed detrimental effects on soil salinity in the long term, with a 21% increase in soil salinity due to secondary salinization. The new P-GBSDM was shown to be an effective platform for engaging stakeholders and simulating their proposed management policies while taking into account socioeconomic considerations. This was not possible using the physically based SAHYSMOD model alone