In silico and in vitro assessment of an optimized QbD-guided myoinositol and metformin-loaded mucus-penetrating particle-based gel for the amelioration of PCOS.

Polycystic ovarian syndrome (PCOS) is a multi-factorial endocrine disorder affecting women of reproductive age. However, its high prevalence and the unsuccessful translation of conventional modalities have made PCOS a pharmaco-therapeutic challenge. In the present study, we explored bi-formulations (comprising metformin-loaded mucus-penetrating nanoparticles, MTF-MPPs, and myoinositol-loaded mucus-penetrating particles, MI-MPPs) incorporated in a carbomer gel tailored for intravaginal administration. For the development and optimization of the MPPs-gel, a QbD (quality by design) approach was employed, including the initial and final risk assessment, central composite design of experts, and method validation. The optimized MTF-MPPs and MI-MPPs possessed an optimum nanometric particle size (195.0 nm and 178.8 nm, respectively) and a PDI of 0.150 and 0.123, respectively, together with a negligible negative zeta potential (-5.19 mV and -6.19 mV, respectively) through the vaginal mucus. It was observed that the MPPs are small and monodisperse with a neutral surface charge. It was observed that the MPPs-gel formulations released approximately 69.86 ± 4.65% of MTF and 67.14 ± 5.74% of MI within 120 h (5 days), which was observed to be sustained unlike MFT-MI-gel with approximately 94.89 ± 4.17% of MTF and 90.91 ± 15% of MI drugs released within 12 h. The confocal microscopy study of rhodamine-loaded MPPs indicated that they possessed a high fluorescence intensity at a depth of 15 µm, while as the penetration trajectory in the vaginal tissue increased to 35 µm, their intensity was reduced, appearing to be more prominent in the blood vessels. The analyzed data of MPPs-gel suggest that the optimized MPPs-gel formulation has potential to reach the targeted area via the uterovaginal mucosa, which has a wide network of blood vessels. Subsequently, in vivo studies were conducted and the results revealed that the proposed MPPs-gel formulation could regulate the estrous cycle of the reproductive system compared to the conventional formulation. Moreover, the formulation significantly reduced the weight of the ovaries compared to the control and conventional vaginal gel. Biochemical estimation showed improved insulin and sex hormone levels. Thus, the obtained data revealed that the deep penetration and deposition of MTF and MI on the targeted area through intravaginal delivery resulted in better therapeutic effects than the conventional vaginal gel. The obtained results confirmed the amelioration of PCOS upon treatment using the prepared MPPs-gel formulation. According to the relevant evaluation studies, it was concluded that MPPs-gel was retained in the vaginal cavity for systemic effects. Also, the sustained and non-irritating therapeutic effect meets the safety aspects. This work serves as a promising strategy for intravaginal drug delivery.

Assessment of Postoperative Pain after Single-Visit Root Canal Treatment using Wave One® and One Shape® Single File System: A Clinical Study.

BACKGROUND: Wave One® (WO) and One Shape® (OS) are among the common endodontic file systems having rotary and reciprocating movement of instrument, respectively. The study evaluated the postoperative pain after single-visit root canal treatment using single file rotary and reciprocating system. MATERIALS AND METHODS: The present study was conducted in the department of conservative dentistry and endodontics on 68 teeth of patients aged between 20 and 45 years. Sixty-eight teeth were divided into two study groups. In Group A, instrumentation with OS file systems (n = 34) was done with subgroup A1 having patients without periapical lesion (n = 17) and subgroup A2 having patients with periapical lesion (n = 17). In Group B, instrumentation with WO file systems (n = 34) was done with subgroup B1 having patients without periapical lesion (n = 17) and subgroup B2 having patients with periapical lesion (n = 17). The root canal shaping procedures were performed according to the manufacturer's instructions for each instrument system. Presence of postobturation pain was accessed by visual analog scale (VAS) scale (0-10), where 0 showed no pain, 1-3 mild pain, 4-6 moderate pain, 7-9 severe pain, and 10 worst possible pain. RESULTS: The intensity of pain was measured with VAS score in patients without periapical lesions and with periapical lesions using WO and OS file system on the 1st, 2nd, 3rd, and 7th day. VAS score was found to be nonsignificant on the 1st, 2nd, 3rd, and 7th day in both groups (P > 0.05). Intergroup comparison of VAS score was found to be nonsignificant (P > 0.05). CONCLUSION: Both systems were found to have similar effect with respect to postoperative pain. However, WO single file system presented less pain as compared to OS system in cases with periapical lesion. Large sample studies are required to substantiate the result obtained in this study.

Socioeconomic position during pregnancy and DNA methylation signatures at three stages across early life: epigenome-wide association studies in the ALSPAC birth cohort.

BACKGROUND: Socioeconomic experiences are recognized determinants of health, and recent work has shown that social disadvantages in early life may induce sustained biological changes at molecular level that are detectable later in life. However, the dynamics and persistence of biological embedding of socioeconomic position (SEP) remains vastly unexplored. METHODS: Using the data from the ALSPAC birth cohort, we performed epigenome-wide association studies of DNA methylation changes at three life stages (birth, n = 914; childhood at mean age 7.5 years, n = 973; and adolescence at mean age 15.5 years, n = 974), measured using the Illumina HumanMethylation450 Beadchip, in relation to pregnancy SEP indicators (maternal and paternal education and occupation). RESULTS: Across the four early life SEP metrics investigated, only maternal education was associated with methylation levels at birth, and four CpGs mapped to SULF1, GLB1L2 and RPUSD1 genes were identified [false discovery rate (FDR)-corrected P-value <0.05]. No epigenetic signature was found associated with maternal education in child samples, but methylation levels at 20 CpG loci were found significantly associated with maternal education in adolescence. Although no overlap was found between the differentially methylated CpG sites at different ages, we identified two CpG sites at birth and during adolescence which are 219 bp apart in the SULF1 gene that encodes an heparan sulphatase involved in modulation of signalling pathways. Using data from an independent birth cohort, the ENVIRONAGE cohort, we were not able to replicate these findings. CONCLUSIONS: Taken together, our results suggest that parental SEP, and particularly maternal education, may influence the offspring's methylome at birth and adolescence.

Work satisfaction, burnout and gender-based inequalities among ophthalmologists in India: A survey.

BACKGROUND: Ophthalmology is a rapidly evolving branch of medicine and advancing technology has raised the bar of patient expectations and outcomes. However, studies that assess physician stress and satisfaction especially in developing countries are limited in literature. OBJECTIVE: This index study aims at looking at the levels of job satisfaction, burnout and perception of gender disparity among ophthalmologists in India. METHODS: An Internet-based survey was sent out to ophthalmologists. 297 respondents replied with responses, which were anonymized and analyzed. RESULTS: Of the 297 respondents, 101 were female and 196 were male ophthalmologists. The mean duration of practice of the respondents was 14.66 years. 54.21% (161/297) responded affirmatively when asked if they were satisfied with their careers. 19% (56/297) were not satisfied. 26.94% (80/297) replied that although they were satisfied, they wished they had more time for family. A quarter (25.2%; 63 out of 250) of the respondents felt burnt-out at that stage of their careers. 68.35% (203/297) of the respondents felt that being a woman ophthalmologist in India was more challenging than being a male ophthalmologist. This perception was significantly more amongst women respondents (p < 0.0002). Greater family responsibility, long working hours, and having to work harder were the challenges faced by female ophthalmologists. There was a significant difference in perception between male and female ophthalmologists regarding the presence of disparity in earnings given equal qualifications and experience with more women responding in the affirmative. CONCLUSIONS: Indian ophthalmologists have personally and professionally satisfying careers with low rates of burnout. While good family support and an understanding partner help ophthalmologists achieve good work-life balance, women ophthalmologists perceive a gender-based disparity when it comes to proving their worth and getting suitably remunerated.

Update on Gender Equity in Immunology, 2001 to 2016.

In 2001, The American Association of Immunologists Committee on the Status of Women conducted a survey examining the percentage of women faculty members within immunology departments or women in immunology graduate programs across 27 institutions in the United States, comparing it to the percentage of women receiving a Ph.D. Here, we examine the representation of women across these same 27 immunology departments and programs to examine changes in gender equity over the last 15 years.

Optimizing collimator margins for isotoxically dose-escalated conformal radiation therapy of non-small cell lung cancer.

PURPOSE: Isotoxic dose escalation schedules such as IDEAL-CRT [isotoxic dose escalation and acceleration in lung cancer chemoradiation therapy] (ISRCTN12155469) individualize doses prescribed to lung tumors, generating a fixed modeled risk of radiation pneumonitis. Because the beam penumbra is broadened in lung, the choice of collimator margin is an important element of the optimization of isotoxic conformal radiation therapy for lung cancer. METHODS AND MATERIALS: Twelve patients with stage I-III non-small cell lung cancer (NSCLC) were replanned retrospectively using a range of collimator margins. For each plan, the prescribed dose was calculated according to the IDEAL-CRT isotoxic prescription method, and the absolute dose (D99) delivered to 99% of the planning target volume (PTV) was determined. RESULTS: Reducing the multileaf collimator margin from the widely used 7 mm to a value of 2 mm produced gains of 2.1 to 15.6 Gy in absolute PTV D99, with a mean gain ± 1 standard error of the mean of 6.2 ± 1.1 Gy (2-sided P<.001). CONCLUSIONS: For NSCLC patients treated with conformal radiation therapy and an isotoxic dose prescription, absolute doses in the PTV may be increased by using smaller collimator margins, reductions in relative coverage being offset by increases in prescribed dose.

Assessment of the role in protection and pathogenesis of the Chlamydia muridarum V-type ATP synthase subunit A (AtpA) (TC0582).

A novel Chlamydia muridarum antigen (TC0582) was used to vaccinate BALB/c mice. Mice were also immunized with other components of the ATP synthase complex (TC0580, TC0581, and TC0584), or with the major outer membrane protein (MOMP). TC0582 was also formulated in combination with TC0580, TC0581 or MOMP. TC0582 alone, or in combination with the other antigens, elicited strong Chlamydia-specific humoral and cellular immune responses. Vaccinated animals were challenged intranasally and the course of the infection was followed for 10 days. Based on percentage change in body weight, lung weight, and number of Chlamydia inclusion forming units recovered from the lungs, mice immunized with TC0582, TC0581 or MOMP, as single antigens, showed significant protection. Mice immunized with combinations of two antigens were also protected but the level of protection was not additive. TC0582 has sequence homology with the eukaryotic ATP synthase subunit A (AtpA). Therefore, to determine if immunization with TC0582, or with Chlamydia, elicited antibodies that cross-reacted with the mouse AtpA, the two proteins were printed on a microarray. Sera from mice immunized with TC0582 and/or live Chlamydia, strongly reacted with TC0582 but did not recognize the mouse AtpA. In conclusion, TC0582 may be considered as a Chlamydia vaccine candidate.