Optimizing bioremediation techniques for soil decontamination in a linguistic intuitionistic fuzzy framework.

Bioremediation techniques, which harness the metabolic activities of microorganisms, offer sustainable and environmentally friendly approaches to contaminated soil remediation. These methods involve the introduction of specialized microbial consortiums to facilitate the degradation of pollutants, contribute to soil restoration, and mitigate environmental hazards. When selecting the most effective bioremediation technique for soil decontamination, precise and dependable decision-making methods are critical. This research endeavors to tackle the aforementioned concern by utilizing the tool of aggregation operators in the framework of the Linguistic Intuitionistic Fuzzy (LIF) environment. Linguistic Intuitionistic Fuzzy Sets (LIFSs) provide a robust framework for representing and managing uncertainties associated with linguistic expressions and intuitionistic assessments. Aggregation operators enrich the decision-making process by efficiently handling the intrinsic uncertainties, preferences, and priorities of MADM problems; as a consequence, the decisions produced are more reliable and precise. In this research, we utilize this concept to devise innovative aggregation operators, namely the linguistic intuitionistic fuzzy Dombi weighted averaging operator (LIFDWA) and the linguistic intuitionistic fuzzy Dombi weighted geometric operator (LIFDWG). We also demonstrate the critical structural properties of these operators. Additionally, we formulate novel score and accuracy functions for multiple attribute decision-making (MADM) problems within LIF knowledge. Furthermore, we develop an algorithm to confront the complexities associated with ambiguous data in solving decision-making problems in the LIF Dombi aggregation environment. To underscore the efficacy and superiority of our proposed methodologies, we adeptly apply these techniques to address the MADM problem concerning the optimal selection of a bioremediation technique for soil decontamination. Moreover, we present a comparative evaluation to delineate the authenticity and practical applicability of the recently introduced approaches relative to previously formulated techniques.

Awareness of consanguineous marriage burden and willingness towards premarital genetic testing in Sudan: a national cross-sectional study.

Background: Despite the widespread practice of consanguinity in Sudan, there is a lack of exploration into the community's awareness of its health implications on offspring and their overall attitude towards consanguineous unions. Aim: This study aimed to evaluate the community's awareness of the possible health adversities of consanguinity on children and assess the effect of knowledge level on the prevailing attitude towards this practice in Sudan. Methods: From August to December 2018, data were collected from adults aged 18 years and above in five provinces of Sudan regardless of their marital status. The analysis involved both descriptive and multivariate statistical techniques. Results: This study revealed a consanguinity rate of 30.2%. Despite a high awareness level (73.7%) regarding the effects of consanguineous marriage on the health of the offspring, a moderately negative attitude towards this practice (63.9%) was observed. Conclusion: The discordance between the high consanguinity rate in the Sudanese population and the moderately negative attitude suggests a potential persistence of this practice in the future. Without the implementation of educational programs and the provision of genetic counselling services to consanguineous couples, the prevalence of consanguinity is likely to endure.

Modeling the Binding of Anticancer Peptides and Mcl-1.

Mcl-1 (myeloid cell leukemia 1), a member of the Bcl-2 family, is upregulated in various types of cancer. Peptides representing the BH3 (Bcl-2 homology 3) region of pro-apoptotic proteins have been demonstrated to bind the hydrophobic groove of anti-apoptotic Mcl-1, and this interaction is responsible for regulating apoptosis. Structural studies have shown that, while there is high overall structural conservation among the anti-apoptotic Bcl-2 (B-cell lymphoma 2) proteins, differences in the surface groove of these proteins facilitates binding specificity. This binding specificity is crucial for the mechanism of action of the Bcl-2 family in regulating apoptosis. Bim-based peptides bind specifically to the hydrophobic groove of Mcl-1, emphasizing the importance of these interactions in the regulation of cell death. Molecular docking was performed with BH3-like peptides derived from Bim to identify high affinity peptides that bind to Mcl-1 and to understand the molecular mechanism of their interactions. The interactions of three identified peptides, E2gY, E2gI, and XXA1_F3dI, were further evaluated using 250 ns molecular dynamics simulations. Conserved hydrophobic residues of the peptides play an important role in their binding and the structural stability of the complexes. Understanding the molecular basis of interaction of these peptides will assist in the development of more effective Mcl-1 specific inhibitors.

The impact of heavy metal concentrations on aquatic insect populations in the Asan Wetland of Dehradun, Uttarakhand.

This study, centered on the Asan Wetland in Uttarakhand, examines the ecological impact of heavy metals on aquatic insects biodiversity. It highlights the detrimental effects of metals like chromium, mercury, and lead, stemming from natural and anthropogenic sources, on aquatic insects diversity. Aquatic insects, particularly sensitive to water quality, are emphasized as key indicators of environmental health, illustrating the importance of understanding and managing the influences on wetland ecosystems. Wetland ecosystems are vulnerable to various environmental stressors, including pollution from heavy metals. These toxic substances can alter water quality parameters, disrupt nutrient cycling, and negatively impact the biodiversity and ecological balance of the system. This study aimed to evaluate the impact of several heavy metals (namely Cd, As, Cu, Fe, Pb, Ni, Zn, Al, Cr) on the distribution and biodiversity of various aquatic insect species, including Coeleoptera, Diptera, Ephemeroptera, Odonata, Plecoptera, and Trichoptera. The research utilized data collected between November 2021 and October 2022 from specifically chosen sites (S1, S2, S3) within the Asan Wetland in Dehradun, Uttarakhand. After collecting and identifying samples, various statistical (Sorenson, Shannon-Weiner diversity index, Margelef index) and multivariate tests (CCA, PCA, One-way Anova), have been applied to show the effects of these parameters. This study offers significant findings regarding the distribution patterns of heavy metals, the abundance of aquatic insects, and their interconnectedness within the ecosystem of the Asan Wetland. The abundance of aquatic insects, represented by 13 genera belonging to 6 orders, was assessed at three different sites (S1, S2, and S3) within the wetland. It was concluded that the heavy metals concentration and aquatic insects' density increases and decreases vice-versa in monsoon and winter seasons might be due to unfavourable factors. These findings contribute to the understanding of ecological dynamics and potential impacts of heavy metals on aquatic biota in wetland environments.

Dendritic fibromyxolipoma with intramuscular involvement: A case mimicking slow flow vascular malformation on imaging.

Dendritic fibromyxolipoma (DFML) is a benign, very rare, and slow-growing soft tissue tumor commonly involving the muscular fascia of the foot, calf, shoulders, back, or head and neck muscles. Many authors consider dendritic fibromyxolipoma a variant of spindle cell lipoma composed of a plexiform vascular pattern, dendritic cytoplasmic processes, and keloidal collagen. Only a few cases have been reported in the shoulder region, and the presented case represents the second case in English literature whose histopathology showed intramuscular involvement. Recognition of such an entity is essential because it is considered a scarce type of benign tumor that can be mistaken for other aggressive neoplasms of myxoid pathology. We present a case of a dendritic fibromyxolipoma around the right shoulder with intramuscular involvement to the superficial fibers of the right trapezius muscle.

The role of delay in vaccination rate on Covid-19.

The role of vaccination in tackling Covid-19 and the potential consequences of a time delay in vaccination rate are discussed. This study presents a mathematical model that incorporates the rate of vaccination and parameters related to the presence and absence of time delay in the context of Covid-19. We conducted a study on the global dynamics of a Covid-19 outbreak model, which incorporates a vaccinated population and a time delay parameter. Our findings demonstrate the global stability of these models. Our observation indicates that lower vaccination rates are associated with an increase in the overall number of infected individuals. The stability of the corresponding time delay model is determined by the value of the time delay parameter. If the time delay parameter is less than the critical value at which the Hopf bifurcation occurs, the model is stable. The results are supported by numerical illustrations that have epidemiological relevance.

Special Issue "Probiotics and Their Metabolism": Editorial.

As a general theory, the benefits of probiotics to human health and the prevention of disease are promoted by metabolites, which include antimicrobial compounds, short-chain fatty acids (SCFAs), organic acids, and bio-actives [...].

Anti-Quorum Sensing Activity of Probiotics: The Mechanism and Role in Food and Gut Health.

BACKGROUND: Quorum sensing (QS) is a cell-to-cell communication mechanism that occurs between inter- and intra-bacterial species and is regulated by signaling molecules called autoinducers (AIs). It has been suggested that probiotics can exert a QS inhibitory effect through their metabolites. PURPOSE: To provide an overview of (1) the anti-QS activity of probiotics and its mechanism against foodborne pathogenic and spoilage bacteria; (2) the potential role of the QS of probiotics in gut health; and (3) the impact of microencapsulation on QS. RESULTS: Lactobacillus species have been extensively studied for their anti-QS activity and have been found to effectively disrupt QS in vitro. However, their effectiveness in a food matrix is yet to be determined as they interfere with the AI receptor or its synthesis. QS plays an important role in both the biofilm formation of probiotics and pathogenic bacteria. Moreover, in vitro and animal studies have shown that QS molecules can modulate cytokine responses and gut dysbiosis and maintain intestinal barrier function. In this scenario, microencapsulation was found to enhance AI activity. However, its impact on the anti-QS activity of probiotics and its underlying mechanism remains unclear. CONCLUSIONS: Probiotics are potential candidates to block QS activity in foodborne pathogenic and food spoilage bacteria. Microencapsulation increases QS efficacy. However, more research is still needed for the identification of the QS inhibitory metabolites from probiotics and for the elucidation of the anti-QS mechanism of probiotics (microcapsules and free cells) in food and the human gut.

Pharmacist-directed Sputnik V (GAM-COVID-VAC) surveillance program: a prospective observational study in Southern India.

OBJECTIVES: The study underwent to evaluate the adverse events, the incidence of COVID-19 and the participant's attitude and perception towards the vaccine following Sputnik V administration through an active surveillance program. METHODS: The prospective observational study was conducted four months in the Sputnik V vaccination center that enrolled 700 participants. Sociodemographic details, medical histories, COVID-19 incidences and adverse events following immunization (AEFI) of each sample were collected through face-to-face interviews and a telephonic feedback system. A self-prepared and validated questionnaire addressed their acceptances and perceptions towards the vaccination drive. RESULTS: Our study reported 42.1% of AEFIs after the first dose and 9.1% after the second. Fever, pain at the injection site, body pain, headache and fatigue were predominant, while dizziness and diarrhoea were rare. However, AEFIs were not influenced by the presence of comorbidities (p > 0.05). On the other hand, there were limited post immunization (1.8%) COVID-19 patients and that too with minor severity (p < 0.01). Our participants were overall satisfied with the Sputnik V immunization. However, those presented with AEFIs on the consecutive three days depicted slightly declined gratification (p < 0.05). CONCLUSIONS: Our pharmacist-directed surveillance program on Sputnik V showed fewer events of AEFIs and negligible occurrence of COVID19 following immunization. Moreover, the population had appreciable attitude and positive perceptions towards Sputnik V vaccination.

Comparing the efficiency of N-doped TiO2 and commercial TiO2 as photo catalysts for amoxicillin and ciprofloxacin photo-degradation under solar irradiation.

Advanced oxidation processes (AOPs) have gained traction as alternative solutions for eliminating pollutants from pharmaceutical wastewater for reuse. In this research, the performance of two photo-catalysts (Commercial TiO2 and synthesis N-doped TiO2) were compared in terms of the degradation of amoxicillin and ciprofloxacin from an aqueous solution using a photo-catalytic batch system under solar irradiation. The influence of five operating factors is: pH (5-11), H2O2 concentrations (200-600) mg/L, catalyst concentrations (25-100 mg/L), Antibiotic concentration (25-100) mg/L and reaction time (30-120 min), on the oxidation of the listed above pollutants were investigated using the central composite design (CCD) of response surface methodology (RSM). The catalyst of N-doping TiO2 was synthesized by sol-gel method, using the urea (CH4N2O) as a nitrogen source. The resulting material was analyzed using Scanning Electron Microscopy (SEM), X-Ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Additionally, it can be observed from the analysis of the characteristics of N-doped TiO2 the homogenous dispersion of nitrogen molecules, small particle sizes, and energy-gap reduction, prompting a 6% increase in antibiotic degradation compared with Com. TiO2. In the RSM analysis, the ideal conditions were found to be a pH of 5, H2O2 conc. of 400 mg/L, catalyst conc. of 50 mg, and antibiotics conc. of 25 mg/L for an antibiotics reduction rate of 89.31% (AMOX/Com. TiO2/Solar), 90.2 (CFX/Com. TiO2/Solar), 95.8% (AMOX/N-TiO2/Solar) and 97.3% (CFX/N-TiO2/Solar). Experimental results were in good agreement with predictions because the predicted R2 matched well with the adjusted R2.

Sustainable Energy Consumption Model for Textile Industry Using Fully Intuitionistic Fuzzy Optimization Approach.

Consumption of renewable energy is on the rise because new technologies have made it cheaper and easier to meet the needs of a long-term energy source. In the present study, the idea of optimal usage of sustainable energy is discussed, taking into consideration the environmental and economic conditions that exist in Pakistan's textile manufacturing industry. By taking into account the regional potential for the application of renewable energy resources, solar energy generators are taken into consideration, and a fully intuitionistic fuzzy (FIF) textile energy model is constructed. Using the FIF model to determine the optimal distribution of solar energy units resulted in a tolerable number of unused energy units. These units may be returned to the central power supply station, which would save both money and energy.

Diabetic ketoacidosis: knowledge and practice among patients with diabetes attending three specialized diabetes clinics in Khartoum, Sudan.

Introduction: diabetic Ketoacidosis is the leading cause of mortality in children and adolescents with T1DM and accounts for about 50% of all deaths in patients younger than 24 years with diabetes. It affects 8 out of 1000 people with diabetes annually, with a worldwide mortality rate of 2-10%. The purpose of this study is to assess the knowledge and practice towards DKA among patients with diabetes attending three diabetes clinics in Khartoum. Methods: we conducted a cross-sectional institution-based study. It included all patients with diabetes attending three diabetes clinics in Khartoum state over the period July - September 2016. A self-administered questionnaire was used to assess and score knowledge and practice towards DKA among patients with diabetes. Data were analyzed using SPSS 23.0. Results: one hundred and ten patients participated in the study, of whom 86 had heard of DKA and were questioned further. Fifty-six point nine percent of participants had poor knowledge (0-8 out of 24) and low practice scores (0-2 out of 6). There was a strong association between knowledge scores and attended clinics. Conclusion: there was an evident lack of knowledge and poor practice towards DKA among patients with diabetes attending diabetes clinics in Khartoum, Sudan.

Detection of Cytomegalovirus Infection in Infants with Biliary Atresia: A Meta-analysis.

Objectives Biliary atresia (BA) is the most common indication of liver transplantation in children. Several reports attributed BA to both prenatal and perinatal etiologies, including a viral infection-induced autoimmune response that targets the bile ducts. Cytomegalovirus (CMV) remains the most common virus being linked to BA. This meta-analysis aimed to estimate to what extent CMV infection is detected in patients with BA. Methods This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The databases of MEDLINE, Embase, Scopus, WHO-Virtual Health Library (VHL), ScienceDirect, and Google Scholar were used for the systematic search. The risk of bias was assessed using the Newcastle-Ottawa scale. Random effects model was used to estimate the pooled prevalence estimate with the corresponding 95% confidence interval (CI) using Comprehensive Meta-Analysis Software version 3.3. Results A total of 19 studies that fulfilled the eligibility criteria were included in the meta-analysis. The total number of infants with BA was 630 patients, and the pooled overall prevalence of CMV infection among them was 25.4% (95% CI: 15.9%-38.0%). There was high heterogeneity among studies (I 2 = 85.1%, p < .001), and subgroup analyses showed significant regional differences (X 2 = 48.9, p <.001). Data on the prognosis of CMV-associated BA were scarce and obtainable from few studies that suggested an association between detection of CMV infection and poor prognosis of BA. Conclusions The limited available data demonstrates that the rate of detection of CMV infection is high in infants with BA. There is still a need for large studies with appropriate controls for obtaining more reliable results about the various aspects of the association between CMV infection and BA.

Draft Genome Sequence of a Novel Iflavirus from Leafhoppers (Exitianus capicola) in Iraq.

The draft genome sequence of a novel virus was determined from a leafhopper insect (Exitianus capicola) via transcriptomic sequencing and rapid amplification of cDNA ends. Results of the sequence alignment suggested that the new virus is a member of the genus Iflavirus, family Iflaviridae. Thus, it was proposed to be named Exitianus capicola iflavirus 2 (ECIV2). ECIV2 has a single positive-strand RNA genome of 7,821 nucleotides [excluding the poly(A) tail] containing a single open reading frame (ORF) with typical iflavirus conserved domains, including a picornavirus capsid protein-like domain, a cricket paralysis virus capsid-like domain, a helicase, a peptidase, and an RNA-dependent RNA polymerase domain.

Sildenafil citrate as an adjuvant to clomiphene citrate for ovulation induction in polycystic ovary syndrome: crossover randomized controlled trial.

Introduction: To evaluate sildenafil citrate as an adjuvant to clomiphene citrate (CC) for ovulation induction (OI) in women with polycystic ovary syndrome (PCOS). Material and methods: A total of 595 infertile PCOS women were randomly assigned into either clomiphene/sildenafil (C/S) group or CC group. Transvaginal (TVS)-Doppler studies were done for participants when the dominant follicle reach 16 mm, to measure the resistance index, pulsatility index, and maximum velocity of sub-endometrial, uterine, and ovarian vessels. Participants were examined using TVS on the 21st day of the cycle to detect ovulation or, after a positive pregnancy test, for documentation of pregnancy. Participants with negative pregnancy tests were given 2 months' rest without OI, followed by crossover of OI medication between the 2 studied groups. The crossover results were assessed by TVS, TVS-Doppler, and pregnancy test. Results: The endometrial thickness was significantly higher among the C/S than the CC group during the first 3 months (9.6 ±1.2 vs. 8.7 ±1.0 mm, respectively, p = 0.003) and after crossover of OI (9.1 ±1.3 vs. 8.2 ±1.0 mm, respectively, p = 0.007).The chemical and clinical pregnancy rates were significantly higher among the C/S compared to the CC group (39.8% and 36.6% vs. 25% and 18.98%, respectively) (p = 0.01 and 0.001, respectively) during the first 3 months and after crossover of OI (36.6% and 33.1% vs. 23.8% and 20.6%, respectively) (p = 0.02 and 0.01, respectively). Conclusions: SC as an adjuvant to CC for OI in PCOS women increases the chemical and clinical pregnancy rates. It also improves the endometrial thickness and ovulation rate through improved endometrial and ovarian Doppler indices.

Quality control and mycotoxin levels in food in the Palestinian market.

A total of 51 food samples (18 rice, 17 wheat flour, and 16 nuts) were randomly collected from different shops and analysed for the presence of total aflatoxins, ochratoxin A and fumonisins, using a lateral flow competitive immunochromatographic assay method. Mycological contamination (total aerobic and fungi count), colour index (L*a*b*) and moisture content were also evaluated. Sensory characteristics for mycotoxins contaminated and uncontaminated samples of rice and wheat flour were evaluated by 40 panellists. Forty-five per cent of all samples were positive for aflatoxins as the most occurred mycotoxins, with a range of 2-8.1 µg/kg. Fungal counts were not significantly different between contaminated and uncontaminated rice and wheat flour samples. In addition, panellists were able to discriminate between contaminated and uncontaminated rice samples by detection of mouldy flavour, spoilage symptoms, earthy flavour, and the degree of freshness.

Economic Order Quantity Model-Based Optimized Fuzzy Nonlinear Dynamic Mathematical Schemes.

Fuzzy mathematics-informed methods are beneficial in cases when observations display uncertainty and volatility since it is of vital importance to make predictions about the future considering the stages of interpreting, planning, and strategy building. It is possible to realize this aim through accurate, reliable, and realistic data and information analysis, emerging from past to present time. The principal expenditures are treated as fuzzy numbers in this article, which includes a blurry categorial prototype with pattern-diverse stipulation and collapse with salvation worth. Multiple parameters such as a shortage, ordering, and degrading cost are not fixed in nature due to uncertainty in the marketplace. Obtaining an accurate estimate of such expenditures is challenging. Accordingly, in this research, we develop an adaptive and integrative economic order quantity model with a fuzzy method and present an appropriate structure to manage such uncertain parameters, boosting the inventory system's exactness, and computing efficiency. The major goal of the study was to assess a set of changes to the company current inventory processes that allowed an achievement in its inventory costs optimization and system development in optimizing inventory costs for better control and monitoring. The approach of graded mean integration is used to determine the most efficient actual solution. The evidence-based model is illustrated with the help of appropriate numerical and sensitivity analysis through the related visual graphical depictions. The proposed method in our study aims at investigating the economic order quantity (EOQ), as the optimal order quantity, which is significant in inventory management to minimize the total costs related to ordering, receiving, and holding inventory in the dynamic domains with nonlinear features of the complex dynamic and nonlinear systems as well as structures.

Public Knowledge, Attitude, and Perception towards COVID-19 Vaccination in Saudi Arabia.

Coronavirus disease-19 (COVID-19) is a highly contagious infection that mainly affects the respiratory system of patients. To date, more than 10 million people have been affected by this virus, and Saudi Arabia has also reported over 210 million cases. At present, there is no established treatment for COVID-19. Vaccination is one of the ways to defeat the pandemic. Recent reports have indicated rare but serious adverse events after vaccination, causing an anxious response from the general public worldwide. Therefore, this study was aimed at evaluating the knowledge, attitude, and perception of the COVID-19 vaccine among the Saudi population. This study is a cross-sectional, web-based online survey conducted using a snowball sampling technique. A self-administered questionnaire prepared in Arabic and English was used to collect feedback from the general population on their knowledge, attitudes, and perceptions about the COVID-19 vaccine. Participants (n = 2022) from different regions of the country replied to the questions. The responses to the questions were recorded on a spreadsheet and analyzed using the SPSS software. Statistical analysis was performed using one-way ANOVA and non-parametric tests to draw conclusions about the results. Multivariate stepwise regression analysis was performed to determine the association between the knowledge, attitude, and perception scores and the demographic variables. p < 0.05 was used to indicate the significance of the data. The data from the study indicated that most of the participants were males (81%), between 18 and 59 years of age (85.9%), Saudi nationals (98.3%), and possessed graduation or above as a qualification (62.9%). The results suggest that a major portion of respondents have satisfactory knowledge (76%), a positive attitude (72.4%), and perception (71.3%) towards the use of COVID-19 vaccines. Their responses can be categorized as between 'good' and 'fair'. However, 30-40% of respondents lacked information about COVID-19 vaccination availability for under 18-year-olds as well as for pregnant women, in addition to the lack of knowledge about the serious unreported adverse reactions and long-term protection offered by the vaccine against coronavirus. The correlation analysis between the variables (p > 0.05) indicated that the response to the KAP domains has no direct relationship. The survey results suggest that most of the Saudi population has sound knowledge and a positive attitude and perception. Since the COVID-19 vaccines have been approved for use in pregnancy and above 12-year-old children by health authorities, the lack of information shown by a significant percentage of participants requires strategies to update this information. Awareness programs targeting all sections of the population must be continued to provide all the updates, including vaccinations for pregnant women and children.

Salvadora persica protects libido by reducing corticosterone and elevating the testosterone levels in chronic cigarette smoke exposure rats.

BACKGROUND & OBJECTIVES: Cigarette smoke is associated with several diseased states including defects in reproductive behavior. Salvadora persica (S. persica) known as the toothbrush plant is reported to possess several pharmacological properties including antidepressants and anxiolytics. The present research was done to determine the libido-protective effect of S. persica in chronic cigarette smoke-exposed rats. MATERIALS AND METHODS: The decoction of freshly dried roots of S. persica (50, 100, and 200 mg/kg, oral) was administered to the chronic-cigarette smoke-exposed adult rats. The parameters related to libido were recorded using a close-camera circuit (CCTV). Serum corticosterone and testosterone levels were estimated. Further, the phytochemical constituents were identified in the decoction. The data obtained were analyzed using one-way analysis of variance and significance was considered at p < 0.05. RESULTS: The observation from the study revealed that cigarette smoke exposure reduces the sexual activity parameters significantly (p < 0.01), besides elevated the serum corticosterone and suppressed the testosterone levels in rats. Administration of S. persica at 200 mg/kg improved significantly (p < 0.05) the parameters related to libido. The decoction also reversed the changes in the levels of tested hormones in serum. INTERPRETATION AND CONCLUSION: The findings indicate that a 200 mg/kg S. persica decoction can protect libido in chronic cigarette smoke-exposed rats. The activity may be due to the presence of several phytoconstituents such as alkaloid, flavonoids and phytosterols that might produce vasodilatory effect in sex organs and enhance the synthesis of endogenous testosterone to improve libido characteristics weakened by chronic cigarette smoke exposure.

Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251).

BACKGROUND: This is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations. METHODS: Safety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI2.5). Secondary endpoints included %predicted FEV1 and sweat chloride level. RESULTS: Class IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV1 increased by 6.46%, LCI2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del. CONCLUSIONS: Icenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations. ClinicalTrials.gov: NCT02190604.