Search Results (11)

The aim of this article is to investigate the relations between the exponent of the convergence of sequences and other characteristics defined for monotone sequences of positive numbers. Another main goal is to characterize such monotone sequences $\left(a_n\right)$ of positive numbers that, for each $n\ge 2$, satisfy the equality $a_n=K(a_{n-1},a_{n+1})$, where the function $K:{\mathbb{R}}^{+}\times {\mathbb{R}}^{+}\to {\mathbb{R}}^{+}$ is the mean, i.e., each value of $K(x,y)$ lies between $min\{x,y\}$ and $max\{x,y\}$. Well-known examples of such sequences are, for example, arithmetic (geometric) progression, because starting from the second term, each of its terms is equal to the arithmetic (geometric) mean of its neighboring terms. Furthermore, this accomplishment generalized and extended previous results, where the properties of the logarithmic sequence $\left(a_n\right)$ are referred to, i.e., in such a sequence that every $n\ge 2$ satisfies $a_n=L(a_{n-1},a_{n+1})$, where $L(x,y)$ is the logarithmic mean of positive numbers $x,y$ defined as follows: $L(x,y):=\left\{\begin{array}{ccc}{\displaystyle \frac{y-x}{lny-lnx}}\hfill & \mathrm{if}\hfill & x\ne y,\hfill \\ x\hfill & \mathrm{if}\hfill & x=y.\hfill \end{array}\right.$ Full article

Background/Objectives: Dermatophytosis due to Trichophyton (T.) indotineae has spread worldwide, and the acquisition of new drug resistances is making this threat challenging to face. We report four cases of dermatophytosis caused by T. indotineae and perform a systematic review of case reports to explore the most relevant clinical and demographic features and the treatment patterns of this infection. Methods: A literature search, using the PubMed database and following PRISMA guidelines, was performed up to the 6th of December 2024. Articles were included if written in English and presented in the form of case reports/series involving human subjects, with detailed information and T. indotineae infection confirmed by internal transcribed spacer sequencing. Results: Initially, 255 records were identified, and 30 articles were finally selected, including 64 patients, mainly from the Asian continent. Most patients were healthy and/or immunocompetent (65.52%), and the mean disease duration suggested long-lasting lesions. At least two different body sites were generally involved, with a predilection for lower body areas (groins included), as also observed in our patients (all from South Asia). Review results indicated itraconazole as the most commonly prescribed final medication. Treatment with itraconazole led to complete remission in three of our patients (one patient was lost to follow-up). Conclusions: T. indotineae infection should be suspected in case of extensive and/or recalcitrant dermatophytosis, especially in patients with a travel history to Asian countries. Further research is needed to develop rapid, inexpensive, and accurate techniques for the identification of T. indotineae and drug-resistant strains and to define the optimal preventive and treatment strategies. Full article

Background: Vericiguat was developed to treat patients with heart failure (HF). Currently, limited data are available to characterize vericiguat-treated patients in real-world clinical settings. Methods: This retrospective cohort study was done using a Japanese hospital administrative database to describe the use of vericiguat in patients with HF in real-world settings. Adult patients diagnosed with HF prescribed vericiguat between 1 July 2021 and 30 September 2022 were included. Patient characteristics at the initiation of vericiguat treatment, patterns of HF medication use, and vericiguat dose titrations were assessed within the first 90 days of treatment. Results: The study included 829 patients who were initiated on vericiguat therapy. The mean age was 75.5 years and 69.0% were male. Hypertension, coronary artery disease, and diabetes mellitus were present in 91.7, 71.3, and 60.1% of patients, respectively. Most patients had previously received HF medications, with high percentages using angiotensin-receptor blocker neprilysin inhibitors (ARNI; 43.9%) and sodium-glucose cotransporter-2 inhibitors (54.4%). During the first 90 days of vericiguat treatment, 65.8% of the patients were uptitrated from their starting dose, and 32.3% had reached the maximal daily dose. The median time to reach the maximal daily dose was 34 days. The multivariable model identified that initiating vericiguat treatment in an outpatient setting and using ARNI before initiating vericiguat treatment were factors significantly associated with reaching the maximal daily dose of vericiguat at any given time, whereas older age, chronic kidney disease, hyperkalemia, and anemia were not associated. Conclusions: These findings provide early insights into the use of vericiguat, which aid in optimizing the combinations and/or sequences of HF treatment incorporating vericiguat therapy. Full article

The purpose of this study was to compare the retention rate of Adeno-associated viral vector (AAV) gene therapy agents within different subretinal injection systems. The retention of AAV serotype 2-based voretigene neparvovec (VN) and a clinical-grade AAV serotype 8 vector within four different subretinal cannulas from two different manufacturers was quantified. A standardized qPCR using the universal inverted terminal repeats as a target sequence was developed. The instruments compared were the PolyTip^® cannula 25 g/38 g by MedOne Surgical, Inc., Sarasota, FL, USA, and three different subretinal injection needles by DORC, Zuidland, The Netherlands (1270.EXT Extendible 41G subretinal injection needle (23G), DORC 1270.06 23G Dual bore injection cannula, DORC 27G Subretinal injection cannula). The retention rate of VN and within the DORC products (10–28%) was comparable to the retention rate (32%) found for the PolyTip^® cannula that is mentioned in the FDA-approved prescribing information for VN. For the AAV8 vector, the PolyTip^® cannula showed a retention rate of 14%, and a similar retention rate of 3–16% was found for the DORC products (test–retest variability: mean 4.5%, range 2.5–20.2%). As all the instruments tested showed comparable retention rates, they seem to be equally compatible with AAV2- and AAV8-based gene therapy agents. Full article

Polymorphism in cytochrome P450 (CYP) 2C9 enzyme is known to cause significant inter-individual differences in drug response and occurrence of adverse drug reactions. Different alleles of the CYP2C9 gene have been identified, but the notable alleles responsible for reduced enzyme activity are CYP2C9*2 and CYP2C9*3. No pharmacogenetic data are available on CYP2C9*2 and CYP2C9*3 alleles in the Pakistani population. In Pakistan, pharmacogenetics, which examines the relationship between genetic factors and drug response, are in the early stages of development. We, for the first time, investigated the association between the CYP2C9 variant alleles CYP2C9*2 and CYP2C9*3 and the incidence of hypoglycaemia in patients with Type 2 diabetes mellitus (T2DM) receiving sulphonylurea medications. A total of n = 400 individuals of Pashtun ethnicity were recruited from 10 different districts of Khyber Pakhtunkhwa, Pakistan to participate in the study. The study participants were divided into two distinct groups: the case group (n = 200) and the control group (n = 200). The case group consisted of individuals with T2DM who were receiving sulphonylurea medications and experienced hypoglycaemia with it, whereas the control group included individuals with T2DM who were receiving sulphonylurea medication but did not experience sulphonylurea-induced hypoglycaemia (SIH). Blood samples were obtained from study participants following informed consent. DNA was isolated from whole blood samples using a Wiz-Prep DNA extraction kit. Following DNA isolation, CYP2C9 alleles were genotyped using MassARRAY sequencing platform at the Centre of Genomics at the Rehman Medical Institute (RMI). The frequency of CYP2C9*2 (low-activity allele) was more frequent in the diabetic patients with SIH compared to the control group (17.5% vs. 6.0%, p = 0.021). The frequency of its corresponding genotype CYP2C9*1/*2 was higher in cases compared to the control group (10% vs. 6% with p = 0.036); the same was true for genotype CYP2C9*2/*2 (7% vs. 3.5% with p = 0.028). Logistic regression analysis evidenced potential association of CYP2C9*2 allele and its genotypes with SIH. When adjusted for confounding factors such as age, weight, sex, mean daily dose of sulphonylurea, and triglyceride level, the association between the CYP2C9*2 allele and hypoglycaemia remained consistent. Confounding factors played no role in SIH (insignificant p-value) because both groups (cases and controls) were closely matched in term of age, weight, sex, mean daily dose of sulphonylurea, and triglyceride levels. Our study suggests that genetic information about a patient’s CYP2C9 gene/enzyme can potentially assist physicians in prescribing the most suitable and safest drug, based on their genetic make-up. Full article

Nowadays, in view of the growing traffic volume, an appropriate aircraft sequencing in the arrival sector is needed to maintain safety levels and improve the performance of the runway system and flight times. This paper presents a digital assistant supporting the air traffic controller in aircraft sequencing by providing suggestions for next waypoints, speed adjustments and altitude holdings. On the one hand, the suggested paths are such to preserve safety by ensuring the prescribed minimum separation, while also promoting environmental benefits through continuous descent operations (CDO). On the other hand, the suggestions aim to reduce landing times, improving the runway throughput. The proposed tool exploits multipath planning, for which a global optimization technique is used in conjunction with the dynamic time warping distance metric and a reinforcement learning approach to resolve conflicts through speed modulation and/or altitude holding. The performances of the assistant are assessed by means of a multi-agent simulator tailoring its reasoning on the procedures of Olbia airport (Italy). The analysis of a stream of many random aircraft has revealed its effectiveness in terms of arrival time reduction against a standard first-come-first-served strategy, usually adopted by controllers, and strong conflict reduction while considering a CDO-like adherence. Additionally, the man/machine interaction is investigated through an analysis of the overall latency from the suggestions provided by the digital assistant up to the actual aircraft maneuvers. Full article

Glaucoma is the leading cause of irreversible blindness, affecting 76 million globally. It is characterized by irreversible damage to the optic nerve. Pharmacotherapy manages intraocular pressure (IOP) and slows disease progression. However, non-adherence to glaucoma medications remains problematic, with 41–71% of patients being non-adherent to their prescribed medication. Despite substantial investment in research, clinical effort, and patient education protocols, non-adherence remains high. Therefore, we aimed to determine if there is a substantive genetic component behind patients’ glaucoma medication non-adherence. We assessed glaucoma medication non-adherence with prescription refill data from the Marshfield Clinic Healthcare System’s pharmacy dispensing database. Two standard measures were calculated: the medication possession ratio (MPR) and the proportion of days covered (PDC). Non-adherence on each metric was defined as less than 80% medication coverage over 12 months. Genotyping was done using the Illumina HumanCoreExome BeadChip in addition to exome sequencing on the 230 patients (1) to calculate the heritability of glaucoma medication non-adherence and (2) to identify SNPs and/or coding variants in genes associated with medication non-adherence. Ingenuity pathway analysis (IPA) was utilized to derive biological meaning from any significant genes in aggregate. Over 12 months, 59% of patients were found to be non-adherent as measured by the MPR80, and 67% were non-adherent as measured by the PDC80. Genome-wide complex trait analysis (GCTA) suggested that 57% (MPR80) and 48% (PDC80) of glaucoma medication non-adherence could be attributed to a genetic component. Missense mutations in TTC28, KIAA1731, ADAMTS5, OR2W3, OR10A6, SAXO2, KCTD18, CHCHD6, and UPK1A were all found to be significantly associated with glaucoma medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10⁻³) (PDC80). While missense mutations in TINAG, CHCHD6, GSTZ1, and SEMA4G were found to be significantly associated with medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10⁻³) (MPR80). The same coding SNP in CHCHD6 which functions in Alzheimer’s disease pathophysiology was significant by both measures and increased risk for glaucoma medication non-adherence by three-fold (95% CI, 1.62–5.8). Although our study was underpowered for genome-wide significance, SNP rs6474264 within ZMAT4 (p = 5.54 × 10^–6) was found to be nominally significant, with a decreased risk for glaucoma medication non-adherence (OR, 0.22; 95% CI, 0.11–0.42)). IPA demonstrated significant overlap, utilizing, both standard measures including opioid signaling, drug metabolism, and synaptogenesis signaling. CREB signaling in neurons (which is associated with enhancing the baseline firing rate for the formation of long-term potentiation in nerve fibers) was shown to have protective associations. Our results suggest a substantial heritable genetic component to glaucoma medication non-adherence (47–58%). This finding is in line with genetic studies of other conditions with a psychiatric component (e.g., post-traumatic stress disorder (PTSD) or alcohol dependence). Our findings suggest both risk and protective statistically significant genes/pathways underlying glaucoma medication non-adherence for the first time. Further studies investigating more diverse populations with larger sample sizes are needed to validate these findings. Full article

To ensure optimal prescribing practices in the dolutegravir-era in Cameroon, we compared first-line virological response (VR) under tenofovir + lamivudine + dolutegravir (TLD) according to prior exposure to tenofovir + lamivudine + efavirenz (TLE). A facility-based survey was conducted among patients initiating antiretroviral therapy (ART) with TLD (I-TLD) versus those transitioning from TLE to TLD (T-TLD). HIV viral load was performed and unsuppressed participants (VL > 1000 copies/mL) had genotyping performed by Sanger sequencing. Of the 12,093 patients followed, 310 (mean-age: 41 ± 11 years; 52.26% female) complied with study criteria (171 I-TLD vs. 139 T-TLD). The median ART-duration was 14 (12–17) months among I-TLDs versus 28 (24.5–31) months among T-TLDs (15 (11–19) on TLE and 14 (9–15) on TLD), and 83.15% (148/178) were at WHO clinical stages I/II. The viral suppression rate (<1000 copies/mL) was 96.45%, with 97.08% among I-TLDs versus 95.68% among T-TLDs (p = 0.55). VR was similar in I-TLD versus T-TLD at <400 copies/mL (94.15% versus 94.42%) and age, gender, residence, ART-duration, and WHO stages were not associated with VR (p > 0.05). Genotyping was successful for 72.7% (8/11), with no major mutations to integrase inhibitors found. VR is optimal under first-line TLD after 14 months, even among TLE-exposed, thus confirming the effectiveness of transitioning from TLE to TLD in similar settings, supported by strong pharmacological potency and genetic barrier of dolutegravir. Full article

This retrospective chart review study explored the etiology, use, and yield of the etiological investigations of 651 children and adolescents diagnosed with borderline intellectual functioning (BIF). Neurological, neurodevelopmental, or neuropsychiatric comorbidities were frequent, and in 23%, the BIF diagnosis evolved into an intellectual disability (ID) by the time of discharge. A primary etiological cause was found in 37.6%, the most prevalent causes being pre- or perinatal conditions, genetic syndromes/chromosomal abnormalities, fetal exposure to maternal substance use, cerebral dysgenesis, and neurological diseases. In total, 79.1% of patients went through one or more investigations during their follow-up. The best etiologic yield leading to a diagnosis in this study population was with exome sequencing, a specific gene panel, microarrays, electroneuromyography, and brain magnetic resonance imaging (MRI). Etiological investigations were performed more frequently among those children receiving an ID diagnosis. Yet, there was no statistically significant difference in the proportion of abnormal findings between the BIF and ID groups. This may mean that the current strategy for determining the need for etiological investigations or current means to gain an etiology is still indecisive. Considering that BIF is defined to include individuals performing between normal cognitive functioning and mild ID, this implies that the prevalence would be anywhere between 7 and 14%. Thus, it could be argued whether in-depth etiological investigations may be justified in cases other than ID in this age group of children over five. With these children and adolescents, the clinicians have to discern between those with a normal variation and those having major difficulties in adaptive behavior affecting everyday life in order to specify and prescribe the rehabilitation or other measures needed. We advocate for a targeted etiological search after careful history-taking and neurological examination. National guidelines that take into account the severity of developmental delay are warranted. Full article

Polyampholytes (PA) are a special class of polymers comprising both positive and negative monomers along their sequence. Most proteins have positive and negative residues and are PAs. Proteins have a well-defined sequence while synthetic PAs have a random charge sequence. We investigated the translocation behavior of random polyampholyte chains through a pore under the action of an electric field by means of Monte Carlo simulations. The simulations incorporated a realistic translocation potential profile along an extended asymmetric pore and translocation was studied for both directions of engagement. The study was conducted from the perspective of statistics for disordered systems. The translocation behavior (translocation vs. rejection) was recorded for all $2^{20}$ sequences comprised of N = 20 charged monomers. The results were compared with those for ${10}^7$ random sequences of N = 40 to better demonstrate asymptotic laws. At early times, rejection was mainly controlled by the charge sequence of the head part, but late translocation/rejection was governed by the escape from a trapped state over an antagonistic barrier built up along the sequence. The probability distribution of translocation times from all successful attempts revealed a power-law tail. At finite times, there was a population of trapped sequences that relaxed very slowly (logarithmically) with time. If a subensemble of sequences with prescribed net charge was considered the power-law decay was steeper for a more favorable net charge. Our findings were rationalized by theoretical arguments developed for long chains. We also provided operational criteria for the translocation behavior of a sequence, explaining the selection by the translocation process. From the perspective of protein translocation, our findings can help rationalize the behavior of intrinsically disordered proteins (IDPs), which can be modeled as polyampholytes. Most IDP sequences have a strong net charge favoring translocation. Even for sequences with those large net charges, the translocation times remained very dispersed and the translocation was highly sequence-selective. Full article

The abandonment of the economic activities of agriculture, livestock, and forestry since the second half of the 20th century, in conjunction with the exodus of inhabitants from rural areas, has resulted in an increase in the forest mass as well as an expansion of forest areas. This, in turn, has led to a greater risk of forest fires and an increase in the intensity and severity of these fires. Moreover, these forest masses represent a fire hazard to adjacent urban areas, which is a problem illustrated here by the village of Capafonts, whose former agricultural terraces have been invaded by shrubs, and which in the event of fire runs the risk of aiding the propagation of the flames from the forest to the village’s homes. One of the tools available to reduce the amount of fuel in zones adjoining inhabited areas is prescribed burns. The local authorities have also promoted measures to convert these terraces into pasture; in this way, the grazing of livestock (in this particular instance, goats) aims to keep fuel levels low and thus reduce the risk of fire. The use of prescribed fires is controversial, as they are believed to be highly aggressive for the soil, and little is known about their long-term effects. The alternation of the two strategies is more acceptable—that is, the use of prescribed burning followed by the grazing of livestock. Yet, similarly little is known about the effects of this management sequence on the soil. As such, this study seeks to examine the impact of the management of the abandoned terraces of Capafonts by means of two prescribed fires (2000 and 2002), which were designed specifically to prevent forest fires from reaching the village. Following these two prescribed burns, a herd of goats began to graze these terraces in 2005. Here, we report the results of soil analyses conducted during this period of years up to and including 2017. A plot comprising 30 sampling points was established on one of the terraces and used to monitor its main soil quality properties. The data were subject to statistical tests to determine whether the recorded changes were significant. The results show modifications to the concentration of soil elements, and since the first prescribed burn, these changes have all been statistically significant. We compare our results with those reported in other studies that evaluate optimum soil concentrations for the adequate growth of grazing to feed goats, and conclude that the soil conditions on the terrace after 17 years are optimum for livestock use. Full article