Long-Term Outcome of Transcutaneous Posterior Tibial Nerve Stimulation in the Treatment of Functional Non-Retentive Fecal Incontinence in Children.

BACKGROUND: Functional non-retentive fecal incontinence (FNRFI) is a psychologically upsetting and embarrassing issue and affects children's quality of life negatively. AIM OF THIS STUDY: Evaluation of the short and long-term effect of Bilateral transcutaneous posterior tibial nerve stimulation (BTPTNS) in the treatment of FNRFI in children and its impact on the quality of life (QoL). Methodology: The current randomized controlled study included 94 Children with FNRFI who were randomly allocated into two equal groups. Group A received BTPTNS and Group B Received Sham BTPTNS. Follow-up was planned for 24 months for manometric findings, incontinence score, Incontinence episodes, and the QoL. RESULTS: The incontinence score was significantly decreases in Group A more than what was reported in Group B at 6, 12, 24 months follow up . In group A 53.2% of the included children who received BTPTNS showed a decrease in the incontinence episodes more than 75% and among them, 23.4% were fully continent. All the QoL domains were significantly improved in Group A after 6, 12, and 24 months when compared with Group B. CONCLUSION: BTPTNS can be a good modality in the treatment of FNRFI with favorable long-term maintenance of its effect together with a remarkable positive impact on all domains of QoL.

Expert consensus on the role of supplementation in obstetrics and gynecology using modified delphi method.

PURPOSE: To reach a consensus among obstetrics and gynecology experts on the effects of micronutrient supplementation on fertility and pregnancy to aid clinicians in decision-making and create a unified approach to managing micronutrient deficiencies in women, by performing a modified Delphi study. METHODS: A three-round modified Delphi process was conducted among a Delphi panel of 38 Egyptian experts to define recommendations regarding the role of supplementation on fertility and pregnancy in women of reproductive age. A literature review was performed and supporting evidence was graded to help guide the recommendations based on available evidence. RESULTS: A total of 62 statements were developed for discussion and voting. Out of the 62 statements, 60 statements reached expert consensus. Statements were divided into two domains. The first domain discussed the role of supplementation in fertility: optimizing natural fertility, polycystic ovary syndrome (PCOS), in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI), unexplained infertility, and endometriosis, whereas the second domain was concerned with the role of supplementation in pregnancy during the prenatal, antenatal, and postnatal periods. CONCLUSION: In this work, a modified Delphi methodology was implemented to reach a consensus on the use of micronutrient supplementation in women of reproductive age. These recommendations can help clinicians in their practice, guide future research, and identify gaps in the market for the pharmaceutical industry. This clinical guidance can be extrapolated to similar communities.

ß-caryophyllene oxide induces apoptosis and inhibits proliferation of A549 lung cancer cells.

One of the most common cancers that result in death is lung cancer. There is new hope in the fight against lung cancer thanks to the chemopreventive properties of natural dietary substances like ß-caryophyllene oxide (CPO), and research is currently being done to test this theory. CPO, a sesquiterpene isolated from medicinal plant essential oils, inhibits carcinogenesis and has been effective in treating many cancers. This study examined how CPO affected proliferation of human lung cancer A549 cells. CPO was found to have an inhibitory concentration (IC50) of 124.1 g/ml. The proliferative markers Ki67 and PCNA were significantly inhibited after cells were treated with CPO at a concentration of 50 g/ml compared to controls. CPO-treated cells expressed more P21, P53, and DNA strand breaks than controls. This was accompanied by a significant cell cycle arrest in the S and G2/M phases. In treated A549 cells, this was also associated with a significant induction of apoptosis, as shown by the upregulation of the expression of caspases 3, 7, and 9, as well as Bax, and the downregulation of Bcl-2. Furthermore, the redox status of treated A549 cells revealed a marked rise in GSH and GPx activity levels and a decline in 4-HNE levels, indicating low oxidative stress following CPO treatment of A549 cells. In conclusion, cell cycle arrest and apoptosis, which are unrelated to oxidative stress, were the mechanisms by which CPO reduced cancer lung cell growth. This finding might be a potential therapeutic target for the treatment of lung cancer. Hypothetical scheme of CPO anticancer effects (mechanism of signaling) in A549 cells; in vitro. CPO treatment increases expression of p21, p53 and DNA fragmentation. These events cause arrest of cell cycle which was associated with significant induction in apoptosis via increase expression of caspases (-3,-7,-9), and Bax and downregulation of Bcl-2.

Exploring Real World Outcomes with Nivolumab Plus Ipilimumab in Patients with Metastatic Extra-Pulmonary Neuroendocrine Carcinoma (EP-NEC).

Background: Dual utilization of the immune checkpoint inhibitors (ICPIs) nivolumab plus ipilimumab has demonstrated clinical promise in the treatment of patients with refractory high-grade neuroendocrine neo-plasms (NENs) in phase II clinical trials (DART SWOG 1609 and CA209), while single agent ICPIs have largely been ineffective for these types of tumors. While both trials demonstrated promising results in high grade NENs, there was no adequate description of the association between tumor differentiation (high-grade well-differentiated neuroendocrine tumor vs poorly-differentiated extra-pulmonary neuroendocrine carcinoma (EP-NEC) and ICPI outcomes in the DART SWOG 1609 trial. Our study reports on the effectiveness and toxicity profile of dual ICPIs in a real world second-line EP-NEC patient population. Methods: Data on metastatic EP-NEC patients, treated with either ICPIs (single and dual ICPIs) or chemo-therapy in the second-line setting, were retrieved from databases of three comprehensive cancer centers. Associations between treatment characteristics and outcomes, including progression-free survival (PFS) and overall survival (OS), were evaluated. Results: From 2007 to 2020, we identified 70 patients with metastatic EP-NEC (predominantly of gastro-enteropancreatic origin), of whom 42 patients (23 males, 19 females, median age 62 years old) were eligible for the final analysis. All patients were refractory to platinum etoposide doublet chemotherapy in the first-line setting. The median PFS for patients who received dual ICPIs (11 patients), single agent ICPI (8 patients), and cytotoxic chemotherapy (23 patients) was 258 days, 56.5 days, and 47 days, respectively (p = 0.0001). Median overall survival (OS) for those groups was not reached (NR), 18.7 months, and 10.5 months, respectively (p = 0.004). There were no significant differences in treatment outcomes in patients according to tumor mismatch repair (MMR) or tumor mutational burden (TMB) status. Grade 3-4 adverse events (AEs) were reported in 11.1% of the patients who received dual ICPIs; however, none of these AEs led to permanent treatment discontinuation. Conclusions: In the second-line setting, patients with EP-NECs treated with dual ICPIs (nivolumab plus ipilimumab) experienced improved PFS and OS compared to patients treated with single agent ICPI or cytotoxic chemotherapy. These results echo some of the current evidence for ICPIs in grade 3 NENs and need to be validated in future prospective studies.

Selective Separation and Preconcentration of Caffeine from Natural and Pharmaceutical Products using New Polyurethane Foams

Abstract Two polyurethane foam-based sorbents (PUF) were synthesized by imprinting and grafting techniques and examined for selective separation and preconcentration of caffeine (CAF) in some pharmaceutical products and in black tea. Molecularly imprinted PUF was synthesized based on hydrogen-bonding interactions between CAF and alizarin yellow G (AYG) and subsequent polymerization into PUF. The static experiments indicated optimum sorption conditions at pH=6.5 and 5.5 for imprinted PUF (AY-IPUF) and grafted PUF (AY-GPUF), respectively. In the online experiments, the suitable preconcentration time was found to be 40 and 20s for (AY-IPUF) and (AY-GPUF), respectively, at a flow rate of 1.75 mL.min-1. Desorption of CAF has been affected by passing 500 µL of 0.05, 0.01 mol.L−1 HCl eluent onto (AY-IPUF) and (AY-GPUF), respectively. The online methods have provided satisfactory enrichment factors of 8.4 and 10.5 for (AY-IPUF) and (AY-GPUF), respectively. The time consumed for preconcentartion, elution and determination steps was 1.48 and 1.05 min, thus, the throughput was 42 and 57 h-1, for (AY-IPUF) and (AY-GPUF), respectively. The developed sorbents were studied for the determination of CAF in pharmaceutical samples which will be helpful to minimize caffeinism. Finally, in silico bioactivity, ADMET and drug-likeness predictive computational studies of caffeine were also carried out

Bio-modulated mice epithelial endometrial organoids by low-level laser therapy serves as an invitro model for endometrial regeneration.

Endometrial regeneration is a dynamic process that is not well understood. The destruction of the endometrium with the formation of intrauterine adhesions is known as Asherman's syndrome. The lesions range from minor to severe adhesions and their impact on pregnancy is well documented. Operative hysteroscopy is the mainstay of diagnosis and treatment of intrauterine adhesions. Nevertheless, the recurrence rates remain high. It was recorded that low-level laser therapy in low doses has a stimulatory effect on different tissues while the high dose produces a suppressive effect. Organoid is a three-dimensional assembly that displays architectures and functionalities similar to in vivo organs that are being developed from human or animal stem cells or organ-specific progenitors through a self-organization process. Our prospective was to study the effect of Low-Level Laser Therapy (LLLT) on mouse epithelial endometrial organoids regarding cell proliferation and endometrial regeneration as a new modality of treatment. An in vitro clinical trial to generate mouse epithelial organoid model and testing LLLT using He:Ne 632.8 nm device on organoids proliferation, function, and their response to ovarian hormones was performed. Trying endometrial regeneration by culturing organoids with decellularized uterine matrix (DUM) and studying the LLLT effect on the regeneration process. LLLT produced a proliferative effect on the epithelial mouse organoids confirmed by Ki67 and PCNA IHC. The organoids could regenerate the epithelial layer of the endometrium in vitro on DUM and LLLT could help in this process. In conclusion, organoids whether control or bio-stimulated proved a new modality to regenerate the endometrium.

Adoption of single agent anticancer therapy for advanced hepatocellular carcinoma and impact of facility type, insurance status, and income on survival: Analysis of the national cancer database 2004-2014.

BACKGROUND: This study analyzes the pattern of use of single agent anticancer therapy (SAACT) in the treatment and survival of advanced hepatocellular carcinoma (aHCC) before and after sorafenib was FDA approved in 2007. METHODS: Adult patients diagnosed with HCC and treated with only ACT from 2004 - 2014 were identified in NCDB database. Patients were analyzed during three time frames: 2004-2006 (pre-sorafenib (PS)), 2007-2010 (early sorafenib (ES)) and 2011-2014 (late sorafenib (LS)). Cox proportional hazards models and Kaplan-Meier method were used for analyses. RESULTS: The NCDB contained 31,107 patients with HCC diagnosed from 2004-2014 and treated with ACT alone. Patients were generally men (78.0%), >50 years of age (92.5%). A significant increase in the rate of adaption of SAACT was observed over time: 6.2% PS, 15.2% ES, and 22.2% LS (p < 0.0001). During this later period, the highest proportion of SAACT is among academic and integrated network facilities (23.3%) as compared to community facilities (17.0%, p < 0.0001). The median overall survival of patients with aHCC treated only with SAACT improved significantly over time from 8.0 months (m) (95% CI: 7.4-8.8) to 10.7 m (10.4-11.2) to 15.6 m (15.2-16.0, p < 0.001). Multivariate analysis indicates worse outcomes for patients treated at community cancer programs (HR 1.28, (5% CI: 1.23-1.32), patients without insurance (HR 1.11, 1.06-1.16) and estimated household income of <$63,000 (HR 1.09, 1.05-1.13). CONCLUSION: aHCC patients treated only with ACT have experienced an overall improvement in survival, but significant differences exist between facility type, insurance status, and income.

A Survey of Blockchain Enabled Cyber-Physical Systems.

Cyber-physical systems (CPS) is a setup that controls and monitors the physical world around us. The advancement of these systems needs to incorporate an unequivocal spotlight on making these systems efficient. Blockchains and their inherent combination of consensus algorithms, distributed data storage, and secure protocols can be utilized to build robustness and reliability in these systems. Blockchain is the underlying technology behind bitcoins and it provides a decentralized framework to validate transactions and ensure that they cannot be modified. By distributing the role of information validation across the network peers, blockchain eliminates the risks associated with a centralized architecture. It is the most secure validation mechanism that is efficient and enables the provision of financial services, thereby giving users more freedom and power. This upcoming technology provides internet users with the capability to create value and authenticate digital information. It has the capability to revolutionize a diverse set of business applications, ranging from sharing economy to data management and prediction markets. In this paper, we present a holistic survey of various applications of CPS where blockchain has been utilized. Smart grids, health-care systems, and industrial production processes are some of the many applications that can benefit from the blockchain technology and will be discussed in the paper.

Has the time come to include low-level laser photobiomodulation as an adjuvant therapy in the treatment of impaired endometrial receptivity?

Low-level laser therapy (LLLT) has been used in photobiomodulation to promote healing, regenerate, and restore tissue function. Women with persistent thin endometrium were assumed to encounter diminished activity in the regenerative and functional capacity of their endometrium. The aim of this study was to examine the ability of LLLT in 635 nm wavelength to enhance the proliferation and gene expression of in vitro cultured endometrial cells. Single (SE) versus multiple exposures (ME) to LLLT were examined in the study groups and compared to controls. A fluence dose of 4.27 J/cm2 for 16 min was given once in the SE or divided in three equal sessions in days 2, 4, and 6 of the culture in ME. Cellular response was evaluated by measuring viable cell numbers and surface area. Pattern of MUC1, ITGA5, ITGB3, LIF, and PTEN gene expression was assessed using the qRT-PCR. Greater numbers of cells were found in both study groups (P < 0.001) as compared to controls. The surface area of cells at the end of culture phase was highly significant (P < 0.001) in ME when compared to SE and controls. A statistically significant difference was found in terms of gene expression in both irradiated groups (P < 0.001) as compared to controls, although greater difference in PTEN tumour suppressor gene (Phosphatase and tensin homolog) expression was toward ME. The introduction of LLLT to the armamentarium of infertility will serve as a new adjuvant therapy in this field. The current study proofed that LLLT was able to increase the proliferative and functional capacity of cultured endometrial cells.

Thymoquinone potentiates chemoprotective effect of Vitamin D3 against colon cancer: a pre-clinical finding.

Prevention of colon cancer among high-risk group has been long lasting research goal. Emerging data have evidenced the anticancer activities of Vitamin D3 (Vit.D) and Thymoquinone (TQ). The aim of the current study was to evaluate the synergistic potential of Thymoquinone and Vitamin D3 in the control of colon cancer progression using azoxymethane-induced rat model. Vit.D and TQ were given individually or in combination 4 week prior to induction and continued for a total of 20 week. At the end of the study, all animals were euthanized and their resected colons were examined macroscopically and microscopically for tumor growth. Colonic tissue preparations were used for measuring gene expression and/or protein levels of selected pro and anti-tumor biomarkers using quantitative RT-PCR, ELISA and immunohistochemistry. Compared with their individual supplementation, combined Vit.D/TQ showed prominent anti-tumor effect manifested by significant reduction (P < 0.05) of the numbers of grown tumors and large aberrant crypts foci. Mechanistically, gene expression and/or protein quantification studies revealed that combined Vit.D/TQ supplementation induced significant reduction (P < 0.01 and P < 0.05) of pro-cancerous molecules (Wnt, ß-catenin, NF-κB, COX-2, iNOS, VEGF and HSP-90) as well as significant increase (P < 0.01 and P < 0.05, respectively) of anti-tumorigenesis biomarkers (DKK-1, CDNK-1A, TGF-ß1, TGF-ß/RII and smad4) as compared to un-supplemented or individually supplemented groups, respectively. In conclusion, TQ augmented the chemopreventive effect of Vit.D during the initiation phase of colon cancer in rat model, with the potential to suppress progression of pre-neoplastic lesions in colon carcinogenesis.

Vitamin D3 enhances the tumouricidal effects of 5-Fluorouracil through multipathway mechanisms in azoxymethane rat model of colon cancer.

BACKGROUND: Vitamin D3 and its analogues have recently been shown to enhance the anti-tumour effects of 5- Fluorouracil (5-FU) both in vitro and in xenograft mouse model of colon cancer. This study measured the potential mechanism(s) by which vitamin D3 could synergise the tumouricidal activities of 5-FU in azoxymethane (AOM) rat model of colon cancer. METHODS: Seventy-five male Wistar rats were divided equally into 5 groups: Control, AOM, AOM-treated by 5-FU (5-FU), AOM-treated by vitamin D3 (VitD3), and AOM-treated by 5-FU + vitamin D3 (5-FU/D). The study duration was 15 weeks. AOM was injected subcutaneously for 2 weeks (15 mg/kg/week). 5-FU was injected intraperitoneally in the 9th and 10th weeks post AOM (8 total injections were given: 12 mg/kg/day for 4 successive days, then 6 mg/kg every other day for another 4 doses) and oral vitamin D3 (500 IU/rat/day; 3 days/week) was given from week 7 post AOM till the last week of the study. The colons were collected following euthanasia for gross and histopathological examination. The expression of ß-catenin, transforming growth factor-ß1 (TGF-ß1), TGF-ß type 2 receptor (TGF-ßR2), smad4, inducible nitric oxide synthase (iNOS), and heat shock protein-90 (HSP-90) proteins was measured by immunohistochemistry. In colonic tissue homogenates, quantitative RT-PCR was used to measure the mRNA expression of Wnt, ß-catenin, Dickkopf-1 (DKK-1) and cyclooxygenase-2 (COX-2) genes, while ELISA was used to measure the concentrations of TGF-ß1, HSP-90 and COX-2 proteins. RESULTS: Monotherapy with 5-FU or vitamin D3 significantly decreased the number of grown tumours induced by AOM (P < 0.05); however, their combination resulted in more significant tumouricidal effects (P < 0.05) compared with monotherapy groups. Mechanistically, vitamin D3/5-FU co-therapy significantly decreased the expression of Wnt, ß-catenin, iNOS, COX-2 and HSP-90 and significantly increased the expression of DKK-1, TGF-ß1, TGF-ßR2, smad4 (P < 0.05), in comparison with their corresponding monotherapy groups. CONCLUSIONS: Vitamin D3 and 5-FU synergise together and exhibit better anticancer effects by modulating Wnt/ß-catenin pathway, TGF-ß1 signals, iNOS, COX-2 and HSP-90. Further studies are required to illustrate the clinical value of vitamin D supplementation during the treatment of colon cancer with 5-FU in human patients.

Intense pulsed light versus benzoyl peroxide 5% gel in treatment of acne vulgaris.

Acne is a common disorder affecting the pilosebaceous unit. Despite many advances in the treatments of acne vulgaris the best option is still controversial as the pathogenesis of acne is rather complex, necessitating various combination therapies. The objective of this study is to compare the clinical efficacy of intense pulsed light therapy (IPL) versus benzoyl peroxide 5% for the treatment of inflammatory acne. Fifty patients of both sexes, (15 males and 35 females) aged (18-27 years), with mild-to-severe acne and Fitzpatrick skin phototype IV were enrolled in this study. The patients were equally divided into two groups. The first group was treated by benzoyl peroxide while the second group was treated by IPL. For both therapies, patients experienced a significant reduction in the mean of the inflammatory lesion counts over the treatment period. Comparing the effects of both therapies, BP produced better results than IPL. The difference in the results was statistically significant at the midpoint of the study. However, this difference was insignificant at the end of study. Treatment with both benzoyl peroxide and IPL resulted in considerable improvement of the acne after 5 weeks of treatment. Comparing the effects of both therapies, BP produced better results than IPL. The difference in the results was statistically significant at the midpoint of the study. However, this difference was insignificant at the end of study.