Potential for Maternally Administered Vaccine for Infant Group B Streptococcus.

BACKGROUND: Natural history studies have correlated serotype-specific anti-capsular polysaccharide (CPS) IgG in newborns with a reduced risk of group B streptococcal disease. A hexavalent CPS-cross-reactive material 197 glycoconjugate vaccine (GBS6) is being developed as a maternal vaccine to prevent invasive group B streptococcus in young infants. METHODS: In an ongoing phase 2, placebo-controlled trial involving pregnant women, we assessed the safety and immunogenicity of a single dose of various GBS6 formulations and analyzed maternally transferred anti-CPS antibodies. In a parallel seroepidemiologic study that was conducted in the same population, we assessed serotype-specific anti-CPS IgG concentrations that were associated with a reduced risk of invasive disease among newborns through 89 days of age to define putative protective thresholds. RESULTS: Naturally acquired anti-CPS IgG concentrations were associated with a reduced risk of disease among infants in the seroepidemiologic study. IgG thresholds that were determined to be associated with 75 to 95% reductions in the risk of disease were 0.184 to 0.827 µg per milliliter. No GBS6-associated safety signals were observed among the mothers or infants. The incidence of adverse events and of serious adverse events were similar across the trial groups for both mothers and infants; more local reactions were observed in the groups that received GBS6 containing aluminum phosphate. Among the infants, the most common serious adverse events were minor congenital anomalies (umbilical hernia and congenital dermal melanocytosis). GBS6 induced maternal antibody responses to all serotypes, with maternal-to-infant antibody ratios of approximately 0.4 to 1.3, depending on the dose. The percentage of infants with anti-CPS IgG concentrations above 0.184 µg per milliliter varied according to serotype and formulation, with 57 to 97% of the infants having a seroresponse to the most immunogenic formulation. CONCLUSIONS: GBS6 elicited anti-CPS antibodies against group B streptococcus in pregnant women that were transferred to infants at levels associated with a reduced risk of invasive group B streptococcal disease. (Funded by Pfizer and the Bill and Melinda Gates Foundation; C1091002 ClinicalTrials.gov number, NCT03765073.).

Zirconium-based hydrophobic-MOFs as innovative electrode modifiers for flibanserin determination: Exploring the electrooxidation mechanism using a comprehensive spectroelectrochemical study.

Three different types of Zr-based MOFs derived from benzene dicarboxylic acid (BDC) and naphthalene dicarboxylic acid as organic linkers (ZrBDC, 2,6-ZrNDC, and 1,4-ZrNDC) were synthesized. They were characterized using X-ray diffraction analysis (XRD), X-ray photoelectron spectroscopy (XPS), Fourier-transform IR spectroscopy (FT-IR), and Transmission electron microscopy (TEM). Their hydrophilic/hydrophobic nature was investigated via contact angle measurements; ZrBDC MOF was hydrophilic and the other two (ZrNDC) MOFs were hydrophobic. The three MOFs were combined with MWCNTs as electrode modifiers for the determination of a hydrophobic analyte, flibanserin (FLB), as a proof-of-concept analyte. Under the optimized experimental conditions, a significant enhancement in the oxidation peak current of FLB was observed when utilizing 2,6-ZrNDC and 1,4-ZrNDC, being the highest when using 1,4-ZrNDC. Furthermore, a thorough investigation of the complex oxidation pathway of FLB was performed by carrying out simultaneous spectroelectrochemical measurements. Based on the obtained results, it was verified that the piperazine moiety of FLB is the primary site for electrochemical oxidation. The fabricated sensor based on 1,4-ZrNDC/MW/CPE showed an oxidation peak of FLB at 0.8 V vs Ag/AgCl. Moreover, it showed excellent linearity for the determination of FLB in the range 0.05 to 0.80 µmol L-1 with a correlation coefficient (r) = 0.9973 and limit of detection of 3.0 nmol L-1. The applicability of the developed approach was demonstrated by determination of FLB in pharmaceutical tablets and human urine samples with acceptable repeatability (% RSD values were below 1.9% and 2.1%, respectively) and reasonable recovery values (ranged between 97 and 103% for pharmaceutical tablets and between 96 and 102% for human urine samples). The outcomes of the suggested methodology can be utilized for the determination of other hydrophobic compounds of pharmaceutical or biological interest with the aim of achieving low detection limits of these compounds in various matrices.

Evaluation of masticatory performance and patient satisfaction for conventional and 3D-printed implant overdentures: a randomized crossover study.

BACKGROUND: This crossover clinical study aimed to evaluate and compare masticatory performance and patient satisfaction for patients rehabilitated with conventional heat-cured acrylic resin and 3D-printed mandibular implant overdentures retained with bar attachment. MATERIALS AND METHODS: Sixteen completely edentulous healthy participants received new conventional dentures. In the mandible, four interforaminal implants were inserted. Following the stage of osseointegration, the bar was constructed in a trapezoidal configuration. Each patient randomly received the following overdentures using a crossover design: (1) conventional heat-cured acrylic resin overdenture and (2) 3D-printed overdenture (developed by scanning of mandibular conventional overdenture). The masticatory performance was assessed by conducting a two-colour mixing ability test at 5, 10, 20, 30, and 50 masticatory cycles. Moreover, the McGill Denture Satisfaction Questionnaire (MDSQ) was employed to assess patient satisfaction. Evaluation was performed after 3 months of using each overdenture. Paired sample t tests were used to compare the masticatory performance and MDSQ scores of patients for both prostheses. RESULTS: No significant difference in masticatory performance was reported between the two types of overdentures. Regarding patient satisfaction, only the esthetic aspect was significantly better for conventionally processed overdentures than for printed overdentures. Insignificant differences were observed regarding other MDSQ items between the two overdentures. CONCLUSION: Within this clinical study, 3D-printed implant overdentures showed promising results in terms of chewing efficiency and patient satisfaction compared to conventionally fabricated implant overdentures. TRIAL REGISTRATION: Retrospectively registered at www. CLINICALTRIALS: gov : NCT06148727.(28/11/2023).

Evaluating systematic targeted universal testing for tuberculosis in primary care clinics of South Africa: A cluster-randomized trial (The TUTT Trial).

BACKGROUND: The World Health Organization (WHO) recommends systematic symptom screening for tuberculosis (TB). However, TB prevalence surveys suggest that this strategy does not identify millions of TB patients, globally. Undiagnosed or delayed diagnosis of TB contribute to TB transmission and exacerbate morbidity and mortality. We conducted a cluster-randomized trial of large urban and rural primary healthcare clinics in 3 provinces of South Africa to evaluate whether a novel intervention of targeted universal testing for TB (TUTT) in high-risk groups diagnosed more patients with TB per month compared to current standard of care (SoC) symptom-directed TB testing. METHODS AND FINDINGS: Sixty-two clinics were randomized; with initiation of the intervention clinics over 6 months from March 2019. The study was prematurely stopped in March 2020 due to clinics restricting access to patients, and then a week later due to the Coronavirus Disease 2019 (COVID-19) national lockdown; by then, we had accrued a similar number of TB diagnoses to that of the power estimates and permanently stopped the trial. In intervention clinics, attendees living with HIV, those self-reporting a recent close contact with TB, or a prior episode of TB were all offered a sputum test for TB, irrespective of whether they reported symptoms of TB. We analyzed data abstracted from the national public sector laboratory database using Poisson regression models and compared the mean number of TB patients diagnosed per clinic per month between the study arms. Intervention clinics diagnosed 6,777 patients with TB, 20.7 patients with TB per clinic month (95% CI 16.7, 24.8) versus 6,750, 18.8 patients with TB per clinic month (95% CI 15.3, 22.2) in control clinics during study months. A direct comparison, adjusting for province and clinic TB case volume strata, did not show a significant difference in the number of TB cases between the 2 arms, incidence rate ratio (IRR) 1.14 (95% CI 0.94, 1.38, p = 0.46). However, prespecified difference-in-differences analyses showed that while the rate of TB diagnoses in control clinics decreased over time, intervention clinics had a 17% relative increase in TB patients diagnosed per month compared to the prior year, interaction IRR 1.17 (95% CI 1.14, 1.19, p < 0.001). Trial limitations were the premature stop due to COVID-19 lockdowns and the absence of between-arm comparisons of initiation and outcomes of TB treatment in those diagnosed with TB. CONCLUSIONS: Our trial suggests that the implementation of TUTT in these 3 groups at extreme risk of TB identified more TB patients than SoC and could assist in reducing undiagnosed TB patients in settings of high TB prevalence. TRIAL REGISTRATION: South African National Clinical Trials Registry DOH-27-092021-4901.

Psychological legacies of intergenerational trauma under South African apartheid: Prenatal stress predicts greater vulnerability to the psychological impacts of future stress exposure during late adolescence and early adulthood in Soweto, South Africa.

BACKGROUND: South Africa's rates of psychiatric morbidity are among the highest in sub-Saharan Africa and are foregrounded by the country's long history of political violence during apartheid. Growing evidence suggests that in utero stress exposure is a potent developmental risk factor for future mental illness risk, yet the extent to which the psychiatric effects of prenatal stress impact the next generation are unknown. We evaluate the intergenerational effects of prenatal stress experienced during apartheid on psychiatric morbidity among children at ages 17-18 and also assess the moderating effects of maternal age, social support, and past household adversity. METHODS: Participants come from Birth-to-Twenty, a longitudinal birth cohort study in Soweto-Johannesburg, South Africa's largest peri-urban township which was the epicentre of violent repression and resistance during the final years of the apartheid regime. Pregnant women were prospectively enrolled in 1990 and completed questionnaires assessing social experiences, and their children's psychiatric morbidity were assessed at ages 17-18. RESULTS: Full data were available from 304 mother-child pairs in 2007-8. Maternal prenatal stress in 1990 was not directly associated greater psychiatric morbidity during at ages 17-18. Maternal age and past household adversity moderated the intergenerational mental health effects of prenatal stress such that children born to younger mothers and late adolescent/young adult children experiencing greater household adversity exhibited worse psychiatric morbidity at ages 17-18. Social support did not buffer against the long-term psychiatric impacts of prenatal stress. CONCLUSIONS: Greater prenatal stress from apartheid predicted adverse psychiatric outcomes among children born to younger mothers and adolescents/young adults who experienced greater concurrent stress. Our findings suggest that prenatal stress may affect adolescent mental health, have stress-sensitising effects, and represent possible intergenerational effects of trauma experienced under apartheid in this sample.

In vitro assessment of PEG-6000 coated-ZnO nanoparticles: modulating action to the resisted antibiotic activity against APEC.

BACKGROUND: Avian pathogenic Escherichia coli (APEC) are considered a growing health problem to both poultry and the public, particularly due to its multi-drug resistance. Zinc oxide nanoparticles (ZnO-NPs) are a promising multi-benefit candidate. This study focused on boosting the antimicrobial effect of the chemically synthesized ZnO-NPs using Polyethylene glycol-6000 (PEG-6000) and evaluating their potential to recover the sensitivity of Florfenicol and Streptomycin-resistant APEC to these drugs in a concentration range of 0.1-0.4 mg/mL. Four samples of ZnO-NPs were formulated and tested microbiologically. RESULTS: The physicochemical characterization showed well-crystallized spherical in situ synthesized ZnO-NPs using PEG-6000 (surfactant) and ethanol (co-surfactant) of ∼19-67 nm particle size after coating with PEG-6000 molecules. These ZnO-NPs demonstrated a strong concentration-dependent antibacterial effect against multidrug-resistant APEC strains, with a minimum inhibitory concentration of 0.1 mg/mL, Combining PEG-6000 coated in situ synthesized ZnO-NPs and Florfenicol induced 60% high sensitivity (30 mm inhibitory-zone), 30% intermediate sensitivity, and 10% resistance against APEC strains. The combination with Streptomycin revealed 50% high sensitivity, 30% intermediate sensitivity, and 20% resistance with a 20 mm maximum zone of inhibition using agar well diffusion test. CONCLUSION: In situ preparation of ZnO-NPs using PEG-6000 and ethanol followed by coating with PEG-6000 enhanced its antibacterial activity in minimum inhibitory concentration and regained the efficacy of Florfenicol and Streptomycin against APEC, referring to a non-antibiotic antimicrobial alternative and an effective combination regimen against multidrug-resistant APEC E. coli in veterinary medicine.

Valuation of environmental influence of recently invented high-performance liquid chromatographic method for hypoglycemic mixtures of gliflozins and metformin in the presence of melamine impurities: Application of molecular modeling simulation approach.

Molecular modeling is the science of representing molecular structures numerically and simulating their behavior with the equations of quantum and classical physics. Coupling molecular modeling and simulation with chromatographic resolution for pharmaceutical products constitutes a new technique in pharmaceutical analysis. An innovative high-performance liquid chromatographic (HPLC) methodology was developed for the quantification of metformin hydrochloride (MET), empagliflozin (EMP), and canagliflozin (CAN) in bulk, laboratory-developed combinations, pharmaceutical tablets, and in the presence of melamine. Chromatographic separation was accomplished using a Symmetry column with 0.03 M potassium dihydrogen phosphate buffer and 0.02 M heptane sulphonic acid: acetonitrile as the mobile phase. Molecular modeling using molecular operating environment software was applied to properly select the stationary phase suitable for the developed HPLC method. Additionally, molecular modeling estimates and validates binding between the studied analytes and the stationary phase to clarify and explain the chromatographic separation and elution order. In accordance with the International Conference of Harmonization recommendations, the method was validated in terms of linearity, accuracy, precision, and selectivity. The linearity ranges (µg/ml) were 200-1500 (MET), 2-15 (EMP), and 20-150 (CAN) and the limit of detection values were in the ranges of 0.17-54.58 µg/ml. Analysis of pharmaceutical tablets using the suggested approach yielded satisfactory outcomes. As a result, it might be used in quality control laboratories to analyze the aforementioned medications.

Infection, nutritional status, and body composition: Associations at birth and 6 months postnatally in Soweto, South Africa.

INTRODUCTION: The impact of infection on infant nutritional status, body size, and growth is well documented. However, research into the impact of infection on infant body composition is limited. Greater understanding is, therefore, needed on the effects of infection in early life. METHODS: Associations between a composite morbidity index consisting of the sum of the cumulative tallies for a range of symptoms representing infection and morbidity in the infants and nutritional status (height-for-age (HAZ), and weight-for-height (WHZ)), and body composition (fat-free mass (FFM), fat mass (FM), fat-free mass index (FFMI), and fat mass index (FMI)) at 6 months of age were investigated using hierarchical regression analysis. RESULTS: The sample comprised data between birth and 6 months postnatally, of 156 infants who were a priori born healthy in Soweto, South Africa. Morbidity, over the cumulative period of birth to 6 months, was associated with lower FMI (ß = -1.77) and lower FM (ß = -0.61), and conversely with higher FFM (ß = 0.94), in infants at 6 months. No associations were found between the morbidity index and FFMI, HAZ, and WHZ. Increased birthweight was associated with a higher FFM (ß = 0.66), HAZ (ß = 1.14), and WHZ (ß = 0.87). Finally, safely managed sanitation facilities, representative of reduced environmental exposure to fecal-oral transmission pathways were associated with a higher HAZ (ß = 1.21). DISCUSSION: Reduction in FMI and FM and exposure to inflammatory cytokines associated with mounting an immune response could alter phenotypic trajectories during to this period of plasticity. From a public health perspective, these results imply that it is important to intensify efforts to prevent infection in infants in the first 6 months postnatally, and that these efforts should concentrate on access to safely managed sanitation facilities.

Identification of Germline Non-coding Deletions in XIAP Gene Causing XIAP Deficiency Reveals a Key Promoter Sequence.

PURPOSE: X-linked inhibitor of apoptosis protein (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome of type 2 (XLP-2), is a rare immunodeficiency characterized by recurrent hemophagocytic lymphohistiocytosis, splenomegaly, and inflammatory bowel disease. Variants in XIAP including missense, non-sense, frameshift, and deletions of coding exons have been reported to cause XIAP deficiency. We studied three young boys with immunodeficiency displaying XLP-2-like clinical features. No genetic variation in the coding exons of XIAP was identified by whole-exome sequencing (WES), although the patients exhibited a complete loss of XIAP expression. METHODS: Targeted next-generation sequencing (NGS) of the entire locus of XIAP was performed on DNA samples from the three patients. Molecular investigations were assessed by gene reporter expression assays in HEK cells and CRISPR-Cas9 genome editing in primary T cells. RESULTS: NGS of XIAP identified three distinct non-coding deletions in the patients that were predicted to be driven by repetitive DNA sequences. These deletions share a common region of 839 bp that encompassed the first non-coding exon of XIAP and contained regulatory elements and marks specific of an active promoter. Moreover, we showed that among the 839 bp, the exon was transcriptionally active. Finally, deletion of the exon by CRISPR-Cas9 in primary cells reduced XIAP protein expression. CONCLUSIONS: These results identify a key promoter sequence contained in the first non-coding exon of XIAP. Importantly, this study highlights that sequencing of the non-coding exons that are not currently captured by WES should be considered in the genetic diagnosis when no variation is found in coding exons.

A ß-Cyclodextrin-Albumin Conjugate for Enhancing Therapeutic Efficacy of Cytotoxic Drugs.

Enhancing the selectivity of anticancer drugs currently used in the clinic is of great interest in order to propose more efficient chemotherapies with fewer side effects for patients. In this context, we developed a ß-cyclodextrin trimer that binds to circulating albumin to form the corresponding bioconjugate in the bloodstream. This latter can then entrap doxorubicin following its i.v. administration via the formation of a host-guest inclusion complex and deliver the drug in tumors. In this study, we demonstrate that the ß-cyclodextrin trimer improves the therapeutic efficacy of doxorubicin for the treatment of a subcutaneous murine Lewis lung carcinoma (LLC) implanted in C57BL/6 mice. This outcome is associated with an increased deposition of doxorubicin in malignant tissues when used in combination with the ß-cyclodextrin trimer compared to the administration of the drug alone.

Absent X-linked inhibitor of apoptosis protein expression in T cell blasts and causal mutations including non-coding deletion.

BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is one of inborn errors of immunity characterized by recurrent hemophagocytic lymphohistiocytosis and refractory inflammatory bowel disease (IBD), mimicking Crohn's disease. The aim of this study is to make an accurate diagnosis of XIAP deficiency based on genetic and XIAP expression studies and to investigate endoscopic findings shared by patients with this disease. METHODS: Four male patients with recurrent hemophagocytic lymphohistiocytosis and long-term refractory IBD were studied for the diagnosis of XIAP deficiency. Endoscopic findings of the four patients were also studied in parallel. RESULTS: These four patients were diagnosed with XIAP deficiency based on the absent XIAP expression in cultured T-cell blasts. Sequence analysis of the responsible gene, XIAP, demonstrated two novel nonsense mutations of p.Gln114X and p.Glu25X, and a previously reported nonsense mutation of p.Arg381X. Although no mutations in the coding region were detected in the fourth patient, further studies demonstrated a novel 2,199 bp deletion encompassing non-coding exon 1, presumably affecting transcription and stability of XIAP mRNA. All of the patients eventually underwent hematopoietic stem cell transplantation, leading to a complete or partial remission of IBD. These four patients shared an endoscopic finding of multiple wide and longitudinal ulcers with straight and non-raised edge in the colon. CONCLUSIONS: X-linked inhibitor of apoptosis protein expression in T-cell blasts could facilitate the diagnosis of this disease, especially with causal mutations in non-coding regions.

Variation Range of Different Inductor Topologies with Shields for RF and Inductive Sensing Applications.

In this study, different planar inductor topologies were studied to evaluate their characteristic parameters' variation range upon approaching Fe- and Cu-based shield plates. The use of such materials can differently alter the electrical properties of planar inductors such as the inductance, resonant frequency, resistance, and quality factor, which could be useful in multiple devices, particularly in inductive sensing and radio-frequency (or RF) applications. To reach an optimal design, five different square topologies, including spiral, tapered, non-spiral, meander, and fractal, were built on a printed circuit board (PCB) and assessed experimentally. At the working frequency of 1 MHz, the results showed a decrease in the inductance value when approaching a Cu-based plate and an increase with Fe-based plates. The higher variation range was noticeable for double-layer topologies, which was about 60% with the Cu-based plate. Beyond an intrinsic deflection frequency, the inductance value began to decrease when approaching the ferromagnetic plate because of the ferromagnetic resonance (FMR). It has been shown that the FMR frequency depends on the inductor topology and is larger for the double-layer spiral one. The Q-factor was decreasing for all topologies but was much faster when using ferromagnetic plates because of the FMR, which intensely increases the track resistance. The resonant frequency was increasing for all double-layer topologies and decreasing for single-layer ones, which was mainly due to the percentage change in the stray capacitance compared to the inductance variation. The concept of varying inductors by metal shielding plates has great potential in a wide range of nondestructive sensing and RF applications.

Development of Novel Isatin-Tethered Quinolines as Anti-Tubercular Agents against Multi and Extensively Drug-Resistant Mycobacterium tuberculosis.

We describe the design and synthesis of two isatin-tethered quinolines series (Q6a-h and Q8a-h), in connection with our research interest in developing novel isatin-bearing anti-tubercular candidates. In a previous study, a series of small molecules bearing a quinoline-3-carbohydrazone moiety was developed as anti-tubercular agents, and compound IV disclosed the highest potency with MIC value equal to 6.24 µg/mL. In the current work, we adopted the bioisosteric replacement approach to replace the 3,4,5-trimethoxy-benzylidene moiety in the lead compound IV with the isatin motif, a privileged scaffold in the TB drug discovery, to furnish the first series of target molecules Q6a-h. Thereafter, the isatin motif was N-substituted with either a methyl or benzyl group to furnish the second series Q8a-h. All of the designed quinoilne-isatin conjugates Q6a-h and Q8a-h were synthesized and then biologically assessed for anti-tubercular actions towards drug-susceptible, MDR, and XDR strains. Superiorly, the N-benzyl-bearing compound Q8b possessed the best activities against the examined M. tuberculosis strains with MICs equal 0.06, 0.24, and 1.95 µg/mL, respectively.

Assessment of Performance, Microbial Community, Bacterial Food Quality, and Gene Expression of Whiteleg Shrimp (Litopenaeus vannamei) Reared under Different Density Biofloc Systems.

Biofloc shrimp culture, as a way of improving shrimp production, gains worldwide consideration. However, the effects of the biofloc system on shrimp culture at high densities could be a challenge. Here, this study is aimed at identifying a better stocking density of whiteleg shrimp (Litopenaeus vannamei) between two intensive biofloc systems of 100 and 300 org./m2. Achieving that was done by comparing growth performance, water quality, feed utilization, microbial loads from water and shrimps, and gene expression of growth, stress, and immune-related genes. Shrimp postlarvae with a mean weight of 35.4 ± 3.7 mg were reared in six indoor cement tanks (36 m3 total capacity each) at two stocking densities (3 replicates each) for a rearing period of 135 days. Better final weight, weight gain, average daily weight gain, specific growth rate, biomass increase percentage, and survival rate were associated with lower density (100/m2), whereas high-density showed significantly higher total biomass. Better feed utilization was found in the lower density treatment. Lower density treatment enhanced water quality parameters, including higher dissolved oxygen and lower nitrogenous wastes. Heterotrophic bacterial count in water samples was recorded as 5.28 ± 0.15 and 5.11 ± 0.28 log CFU/ml from the high- and low-density systems, respectively, with no significant difference. Beneficial bacteria such as Bacillus spp. were identified in water samples from both systems, still, the Vibrio-like count was developed in the higher density system. Regarding shrimp food bacterial quality, the total bacterial count in the shrimp was recorded as 5.09 ± 0.1 log CFU/g in the 300 org./m2 treatment compared to 4.75 ± 0.24 log CFU/g in the lower density. Escherichia coli was isolated from the shrimps in a lower density group while Aeromonas hydrophila and Citrobacter freundii were associated with shrimps from a higher density system. Immune-related genes including prophenoloxidase, superoxide dismutase (SOD), and lysozyme (LYZ) expressions were all significantly higher expressed in the shrimp from the lower density treatment. Toll receptor (LvToll), penaiedin4 (PEN4), and stress-related gene (HSP 70) showed a decreased gene expression in the shrimp raised in the lower density. Significant upregulation of growth-related gene (Ras-related protein-RAP) expression was associated with the lower stocking density system. In conclusion, the current study found that applying high stocking density (300 org./m2) contributes negatively to performance, water quality, microbial community, bacterial food quality, and gene expression of immune, stress, and growth-related genes when compared with the lower stocking density system (100 org./m2) under biofloc system.

Modification of Parks Classification of Cryptoglandular Anal Fistula.

BACKGROUND: The Parks classification has been used for the classification of anal fistula for several years, but it does not allow for risk factors for failure after surgery. OBJECTIVE: This study aimed to describe a modification of the Parks classification of anal fistula and examine its predictive validity in the assessment of the outcome of anal fistula in terms of failure of healing and fecal incontinence. DESIGN: This is a retrospective review of a prospective database. SETTING: This study was conducted in the Colorectal Surgery Unit, Mansoura University Hospitals. PATIENTS: Adult patients with anal fistula who underwent surgery were included. INTERVENTIONS: Five risk factors for failure after fistula surgery were identified from the literature and were examined by multivariate analysis of our patients. Four risk factors proved to be significant independent predictors of failure: secondary extensions, horseshoe fistula, previous fistula surgery, and anterior anal fistula in women. We modified the Parks classification by dividing the transsphincteric type into high and low and by grouping supra- and extrasphincteric anal fistulas into 1 group. The first 3 stages were subdivided according to the absence or presence of predictors of failure. MAIN OUTCOME MEASURES: The primary outcome measured was the validity of the modified Parks classification with regard to the rates of failure and fecal incontinence after surgical treatment of each stage of anal fistula. RESULTS: A total of 665 patients with cryptoglandular anal fistula were included. Failure rates increased from 2.3% (95% CI, 0.9%-4.7%), to 17.4% (95% CI, 10.8%-25.9%), 19.5% (95% CI, 15%-24.6%), and 30.7% (95% CI, 9.1%-61.4%) across the 4 stages. The area under the receiver operating characteristic curve was 0.90 (95% CI, 0.85-0.94) indicating the strong discriminative ability of the final multivariable predictive model. The increase in failure and incontinence rates across the fistula stages was significant. LIMITATIONS: This is a retrospective, single-center study. CONCLUSION: Inclusion of predictors of poor outcome into the modified classification helped differentiate simple and complex fistulas within each stage and between the different stages, which can help in assessment and decision making for anal fistula. See Video Abstract at http://links.lww.com/DCR/B441. MODIFICACIN DE LA CLASIFICACIN DE PARKS DE LA FSTULA ANAL CRIPTOGLANDULAR: ANTECEDENTES:La clasificación de Parks se ha utilizado para la clasificación de la fístula anal durante varios años, sin embargo, no tuvo en cuenta los factores de riesgo de fracaso después de la cirugía.OBJETIVO:Describir una modificación de la clasificación de Parks de fístula anal y examinar su validez predictiva en la evaluación de los resultados de la fístula anal en términos de fracaso de la cicatrización e incontinencia fecal.DISEÑO:Revisión retrospectiva de la base de datos prospectiva.AJUSTE:Unidad de Cirugía Colorrectal, Hospital Universitario de Mansoura.PACIENTES:Pacientes adultos con fístula anal intervenidos quirúgicamente.INTERVENCIONES:Se identificaron cinco factores de riesgo de fracaso después de la cirugía de fístula de la literatura y se examinaron mediante análisis multivariante de nuestros pacientes. Cuatro factores de riesgo demostraron ser importantes predictores independientes de fracaso: extensiones secundarias, fístula en herradura, cirugía de fístula previa y fístula anal anterior en mujeres. Modificamos la clasificación de Parks dividiendo el tipo transesfinteriano en alto y bajo y agrupando la fístula anal supraesfinteriana y extraesfinteriana en un grupo. Las tres primeras etapas se subdividieron según la ausencia o presencia de predictores de fracaso.PRINCIPALES MEDIDAS DE RESULTADO:Validez de la clasificación de Parks modificada con respecto a las tasas de fracaso e incontinencia fecal después del tratamiento quirúrgico de cada etapa de la fístula anal.RESULTADOS:Se incluyeron 665 pacientes con fístula anal criptoglandular. Las tasas de fracaso aumentaron del 2,3% (IC del 95%: 0,9-4,7%), al 17,4% (IC del 95%: 10,8 al 25,9%), 19,5% (IC del 95%: 15-24,6%) y 30,7% (95% IC: 9,1- 61,4%) en las cuatro etapas. El área bajo la curva característica operativa del receptor fue 0,90 (IC del 95%: 0,85-0,94), lo que indica una fuerte capacidad discriminativa del modelo predictivo multivariable final. El aumento en las tasas de fracaso e incontinencia en las etapas de la fístula fue significativo.LIMITACIONES:Estudio retrospectivo, unicéntrico.CONCLUSIÓN:La inclusión de predictores de mal resultado en la clasificación modificada ayudó a diferenciar las fístulas simples y complejas dentro de cada etapa y entre las diferentes etapas, lo que puede ayudar en la evaluación y toma de decisiones para la fístula anal. Consulte Video Resumen en http://links.lww.com/DCR/B441.

Determinants of energy intake in Central African populations experiencing nutrition transition.

Central Africa is experiencing rapid urbanisation, and this situation comes along with changes in food habits and an increased prevalence of obesity and associated health risks. Factors influencing dietary intake among the diverse African populations are not well understood. Our objective was to characterise the dietary intake and their determinants in the two main ethnic groups experiencing nutrition transition in Cameroon, the Bamiléké and the Béti. We sampled Bamiléké (381) and Béti (347) adults living in both rural and urban, collected socio-demographic variables, assessed dietary patterns by using a food portion photographs book to administrate a FFQ and a 24-h dietary recall technique and derived their BMI from measured weight and height. The dietary patterns of Bamiléké people were composed of more energy-dense foods than the Béti people, regardless of the living area. The energy intake (13·8 (sd 4·6)-15·4 (sd 4·8) MJ v. 9·7 (sd 3·5)-11·2 (sd 3·9 MJ) and the obesity (15-29 % v. 5-8 %) were therefore higher in Bamiléké than in Béti, respectively. Multivariable linear regression analyses showed strong associations of both ethnicities (4·02 MJ; P < 0·001), living area (0·21 MJ; P < 0·001) and education (0·59 MJ; P < 0·048) with energy intake, independently of each other and other socio-demographic factors. The ethnicity factor has been characterised as the more important determinant of diet. Our findings provide new insights and perspectives highlighting the importance of anthropological factors when building prevention campaigns against obesity in Central Africa.

Synthesis, molecular modeling, selective aldose reductase inhibition and hypoglycemic activity of novel meglitinides.

In the present study, a novel generation of selective aldose reductase ALR2 inhibitors with significant hypoglycemic activities was designed and modulated based on rhodanine scaffold joined to an acetamide linker in between two lipophilic moieties. The synthesis of the novel compounds was accomplished throughout simple chemical pathways. Molecular docking was performed on B-cell membrane protein SUR1, aldehyde reductase ALR1 and aldose reductase ALR2 active sites. Compounds 10B, 11B, 12B, 15C, 16C, 26F and 27F displayed the highest hypoglycemic activities with 80.7, 85.2, 87, 82.3, 83.5, 81.4 and 85.3% reduction in blood glucose levels, respectively. They were more potent than the standard hypoglycemic agent repaglinide with 65.4% reduction in blood glucose level. Compounds 12B and 15C with IC50 0.29 and 0.35 µM were more potent than the standard ALR2 inhibitor epalrestat with IC50 0.40 µM. They were selective towards ALR2 over ALR1 134 and 116 folds, respectively. Molecular docking studies matched with the in-vitro and in-vivo results to elucidate the dual activities of both compounds 12B and 15C as potent antagonists for ALR2 over ALR1 and good agonists for the SUR1 protein.

Molecular hybridization design and synthesis of novel spirooxindole-based MDM2 inhibitors endowed with BCL2 signaling attenuation; a step towards the next generation p53 activators.

Despite the achieved progress in developing efficient MDM2-p53 protein-protein interaction inhibitors (MDM2 inhibitors), the acquired resistance of tumor cells to such p53 activators posed an argument about the druggability of the pathway. Combination studies disclosed that concomitant inhibition of MDM2 and BCL2 functions can sensitize the tumor cells and synergistically induce apoptosis. Herein, we employed a rapid combinatorial approach to generate a novel series of hybrid spirooxindole-based MDM2 inhibitors (5a-s) endowed with BCL2 signaling attenuation. The adducts were designed to mimic the thematic features of the chemically stable potent spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-ones MDM2 inhibitors while installing a pyrrole ring on the core via a carbonyl spacer inspired by the natural product marinopyrrole A that efficiently inhibits BCL2 family functions by various mechanisms. NCI 60 cell-line panel screening revealed their promising broad-spectrum antiproliferative activities. The NCI-selected derivatives were screened for cytotoxic activities against normal fibroblasts, MDA-MB 231, HepG-2, and Caco-2 cells via MTT assay, subjected to mechanistic apoptosis studies for assessment of p53, BCL2, p21, and caspase 3/7 status, then evaluated for potential MDM2 inhibition utilizing MST assay. The most balanced potent and safe derivatives; 5i and 5q were more active than 5-fluorouracil, exhibited low µmrange MDM2 binding (KD=1.32and 1.72 µm, respectively), induced apoptosis-dependent anticancer activities up to 50%, activated p53 by 47-63%, downregulated the BCL2 gene to 59.8%, and reduced its protein level (13.75%) in the treated cancer cells. Further downstream p53 signaling studies revealed > 2 folds p21 upregulation and > 3 folds caspase 3/7 activation. Docking simulations displayed that the active MDM2 inhibitors resided well into the p53 binding sites of MDM2, and shared key interactions with the co-crystalized inhibitor posed by the indolinone scaffold (5i, 5p, and 5q), the halogen substituents (5r), or the installed spiro ring (5s). Finally, in silico ADMET profiling predicted acceptable drug-like properties with full accordance to Lipinski's, Veber's, and Muegge's bioavailability parameters for 5i and a single violation for 5q.

Horizontal versus vertical plication of the rectovaginal septum in transperineal repair of anterior rectocele: a pilot randomized clinical trial.

AIM: Anterior rectocele is usually an asymptomatic condition in many women, yet it can be associated with obstructed defaecation syndrome (ODS). Transperineal repair of rectocele (TPR) has been followed by variable rates of improvement in ODS. The present pilot randomized clinical trial aimed to evaluate the outcome of TPR with vertical plication (VP) of the rectovaginal septum compared to horizontal plication (HP). METHODS: Adult women with anterior rectocele were recruited to the study and were randomly allocated to one of two equal groups. The first group underwent TPR with VP of the rectovaginal septum and the second group underwent TPR with HP. The main outcome measures were improvement in ODS, recurrence of rectocele, complications and dyspareunia. RESULTS: The trial included 40 female patients with anterior rectocele. There was no significant difference between the two groups regarding the postoperative Wexner score. Complete cure and significant improvement in ODS symptoms were comparable after the two techniques. The reduction in rectocele size after HP was significantly greater than after VP (1.7 vs. 2.6, P < 0.0001). Significant improvement in dyspareunia was recorded after HP (P = 0.001) but not after VP (P = 0.1). There was no significant difference between the two groups with regard to operating time, complications and recurrence. CONCLUSION: VP and HP of the rectovaginal septum in TPR were associated with a comparable improvement in ODS symptoms and similar complication rates. HP was followed by a greater reduction in the rectocele size and greater improvement in dyspareunia than VP.

Factors influencing treatment outcomes of tuberculosis patients attending health facilities in Galkayo Puntland, Somalia.

AIM: This study evaluated the underlying factors associated with poor tuberculosis (TB) treatment outcomes among patients attending health care facilities in Galkayo, Puntland, Somalia. METHODS: An institution-based cross-sectional study was conducted between 2016 and 2017 in three selected TB clinics. Data were collected from 400 TB patients, through medical record review and structured questionnaire. Multivariate logistic regression analyses were performed. RESULTS: Of the 400 TB respondents, 57.3% were new cases, 12.3% had smear-negative TB and 12.5% had extrapulmonary TB. The median age was (35.66 ± 13.16) with majority being male (65.5%). Overall, 85% of patients were successfully treated, 9.7% failed and 5.3% defaulted. Multivariate analysis revealed that patient's body weight (odds ratio [OR]: 1.078); diabetes (OR: 8.022); family size (OR: 3.851); patients' delay in diagnosis (OR: 11.946); frequency of receiving anti-TB medication (OR: 9.068); smoker (OR: 5.723); category of patients (retreatment versus new, OR: 5.504; retreatment versus transfer in, OR: 4.957); health facilities (OR: 6.716) and treatment duration (OR: 132.091) were independent factors associated with poor TB outcomes. CONCLUSIONS: Our findings highlight the need to improve TB services for vulnerable groups. They also emphasize the need for health system strengthening, public awareness and risk of treatment interruption. This may reduce both patients' delay in seeking care and TB treatment failure in Galkayo district.