A Semi-Mechanistic Model of Immune Tolerance Induction to Support Preclinical Development of a Human Monoclonal Antibody

Administration of human monoclonal antibodies (mAb) in preclinical species often triggers an immunogenic response, leading to the formation of anti-drug antibodies (ADA). ADA can bind to the mAb and reduce their systemic exposure by enhancing immune-complex mediated clearance. Thus, ADA complicates the accurate assessment of preclinical pharmacokinetics and toxicology studies. To mitigate this effect, we explored short-term immunosuppressive therapy (methotrexate or combination of tacrolimus and sirolimus) to induce prolonged immune tolerance towards a human mAb, erenumab, in rats. The results demonstrated that tacrolimus/sirolimus but not the methotrexate regimens prevented ADA formation in all treated animals relative to the non-immunocompromised control group. A semi-mechanistic model of immune tolerance induction was developed to support model-based simulations of ADA responses to prolonged erenumab exposures following initial immune tolerance induction with tacrolimus/sirolimus. The model adequately described the observed ADA magnitude-time profiles in both the control and tacrolimus/sirolimus groups and reasonably simulated the kinetics of selected immune cells (CD4+ T-helper and T-regulatory) responsible for ADA formation. The model successfully captured the impact of tacrolimus/sirolimus treatment on ADA formation, demonstrating that the regimen effectively suppressed ADA responses and induced tolerance. Simulation of a 6-month toxicology study suggested that immune tolerance induced with an initial treatment cycle of tacrolimus/sirolimus can maintain a T-regulatory cell-mediated tolerance with continued antigen challenge, thereby facilitating the conductance of chronic toxicology studies for 6 months of duration without ADA formation. This work demonstrates the utility of modeling approaches in prospective planning of long-term toxicology studies to support preclinical development of mAbs

Colposcopic evaluation in cases of persistent inflammatory Pap smear

Background: The aim of the study was to assess the colposcopic evaluation in cases of persistant inflammatory Papanicolaou (Pap) smear.Methods: This was a prospective analytical study, conducted amongst 78 women attending the outpatient department of obstetrics and gynaecology at Subharti Medical College. Pap smear was performed by the conventional method and colposcopy was done for all 78 sexually active women who came with complaints of pain abdomen, irregular cycles, white discharge per vaginum and urinary tract infections. Final correlation of Pap smear and colposcopy were based on histopathology and human papillomavirus deoxyribonucleic acid (HPV DNA).Results: In this study of 78 women, 21% of women had normal colposcopic findings whereas 79% had abnormal colposcopic findings. Histopathological examination (HPE) findings revealed that 69% women had cervical intraepithelial neoplasia (CIN) 1, 23% had CIN II, 6% had CIN III and 3% had SCC. 25% women tested positive for HPV DNA and 75% women tested negative for HPV DNA.Conclusions: Patients with persistent inflammatory Pap smear despite undergoing treatment show changes on Colposcopic directed biopsies.

Feeding Interventions for Infants with Growth Failure in the First Six Months of Life: A Systematic Review.

(1) Introduction: Current evidence on managing infants under six months with growth failure or other nutrition-related risk is sparse and low quality. This review aims to inform research priorities to fill this evidence gap, focusing on breastfeeding practices. (2) Methods: We searched PubMed, CINAHL Plus, and Cochrane Library for studies on feeding interventions that aim to restore or improve the volume or quality of breastmilk and breastfeeding when breastfeeding practices are sub-optimal or prematurely stopped. We included studies from both low- and middle-income countries and high-income countries. (3) Results: Forty-seven studies met the inclusion criteria. Most were from high-income countries (n = 35, 74.5%) and included infants who were at risk of growth failure at birth (preterm infants/small for gestational age) and newborns with early growth faltering. Interventions included formula fortification or supplementation (n = 31, 66%), enteral feeds (n = 8, 17%), cup feeding (n = 2, 4.2%), and other (n = 6, 12.8%). Outcomes included anthropometric change (n = 40, 85.1%), reported feeding practices (n = 16, 34%), morbidity (n = 11, 23.4%), and mortality (n = 5, 10.6%). Of 31 studies that assessed formula fortification or supplementation, 30 reported anthropometric changes (n = 17 no effect, n = 9 positive, n = 4 mixed), seven morbidity (n = 3 no effect, n = 2 positive, n = 2 negative), five feeding (n = 2 positive, n = 2 no effect, n = 1 negative), and four mortality (n = 3 no effect, n = 1 negative). Of eight studies that assessed enteral feed interventions, seven reported anthropometric changes (n = 4 positive, n = 3 no effect), five feeding practices (n = 2 positive, n = 2 no effect, n = 1 negative), four morbidity (n = 4 no effect), and one reported mortality (n = 1 no effect). Overall, interventions with positive effects on feeding practices were cup feeding compared to bottle-feeding among preterm; nasogastric tube feed compared to bottle-feeding among low birth weight preterm; and early progressive feeding compared to delayed feeding among extremely low birth weight preterm. Bovine/cow milk feeding and high volume feeding interventions had an unfavourable effect, while electric breast pump and Galactagogue had a mixed effect. Regarding anthropometric outcomes, overall, macronutrient fortified formula, cream supplementation, and fortified human milk formula had a positive effect (weight gain) on preterm infants. Interventions comparing human breastmilk/donor milk with formula had mixed effects. Overall, only human milk compared to formula intervention had a positive effect on morbidity among preterm infants, while none of the interventions had any positive effect on mortality. Bovine/cow milk supplementation had unfavourable effects on both morbidity and mortality. (4) Conclusion: Future research should prioritise low- and middle-income countries, include infants presenting with growth failure in the post-neonatal period and record effects on morbidity and mortality outcomes

A SURVEY OF KNOWLEDGE AND AWARENESS REGARDING ANTIBIOTICS USE AND RESISTANCE AMONG NEPALESE PATIENTS

Introduction: Antimicrobial resistance is an under-appreciated threat to public health in nations around the globe. The unchecked usage of antibiotics in dentistry can also contribute to emerging antibiotic resistance. With the current rampant usage of antibiotics in the global scenario, it is important to know about the knowledge and awareness of patients regarding various aspects of antibiotics. However, relatively few works have been published on the effect of knowledge of antibiotics on its use, even lesser in context to Nepalese dental patients. This study aims to assess the knowledge about antibiotic treatment and awareness of antibiotic resistance among dental patients. Materials and Methods: A cross-sectional study was carried out during world antibiotic awareness week from November 13-19, 2017 in dental patients visiting Kantipur Dental College Teaching Hospital, Kathmandu, Nepal. We explained the aim of the study. Patients seeking dental services who were willing to participate signed an informed written consent were enrolled in the study. Pretested questionnaires were distributed among patients attending dental OPD. The responses in the questionnaire were used to assess the knowledge about various aspects of antibiotic treatment and antibiotic resistance in dental patients. The data were analyzed using SPSS version 20. Results: In this study, 136 patients responded out of 203 (with a response rate of 66.7%) that were valid for analysis. The knowledge about antibiotics use was found significantly low based on their actual practice though they had followed doctors and medical professional’s instructions. Our study showed that patient’s knowledge of antibiotics had a positive association with their attitude and had a negative association on awareness of the importance of the public education about antimicrobial resistance. Conclusion: The dental patients did not have adequate knowledge of antibiotic treatment, use, and resistance. To prevent antibiotic resistance, more efforts should be made to educate the general public regarding the appropriate dispensing of antibiotics

Effectiveness of Breastfeeding Support Packages in Low- and Middle-Income Countries for Infants under Six Months: A Systematic Review.

Small and nutritionally at-risk infants under six months, defined as those with wasting, underweight, or other forms of growth failure, are at high-risk of mortality and morbidity. The World Health Organisation 2013 guidelines on severe acute malnutrition highlight the need to effectively manage this vulnerable group, but programmatic challenges are widely reported. This review aims to inform future management strategies for small and nutritionally at-risk infants under six months in low- and middle-income countries (LMICs) by synthesising evidence on existing breastfeeding support packages for all infants under six months. We searched PubMed, CINAHL, Cochrane Library, EMBASE, and Global Health databases from inception to 18 July 2018. Intervention of interest were breastfeeding support packages. Studies reporting breastfeeding practices and/or caregivers'/healthcare staffs' knowledge/skills/practices for infants under six months from LMICs were included. Study quality was assessed using NICE quality appraisal checklist for intervention studies. A narrative data synthesis using the Synthesis Without Meta-analysis (SWiM) reporting guideline was conducted and key features of successful programmes identified. Of 15,256 studies initially identified, 41 were eligible for inclusion. They were geographically diverse, representing 22 LMICs. Interventions were mainly targeted at mother-infant pairs and only 7% (n = 3) studies included at-risk infants. Studies were rated to be of good or adequate quality. Twenty studies focused on hospital-based interventions, another 20 on community-based and one study compared both. Among all interventions, breastfeeding counselling (n = 6) and education (n = 6) support packages showed the most positive effect on breastfeeding practices followed by breastfeeding training (n = 4), promotion (n = 4) and peer support (n = 3). Breastfeeding education support (n = 3) also improved caregivers' knowledge/skills/practices. Identified breastfeeding support packages can serve as "primary prevention" interventions for all infants under six months in LMICs. For at-risk infants, these packages need to be adapted and formally tested in future studies. Future work should also examine impacts of breastfeeding support on anthropometry and morbidity outcomes. The review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO 2018 CRD42018102795)