Bayesian bi-level variable selection for genome-wide survival study

Mild cognitive impairment (MCI) is a clinical syndrome characterized by the onset and evolution of cognitive impairments, often considered a transitional stage to Alzheimer’s disease (AD). The genetic traits of MCI patients who experience a rapid progression to AD can enhance early diagnosis capabilities and facilitate drug discovery for AD. While a genome-wide association study (GWAS) is a standard tool for identifying single nucleotide polymorphisms (SNPs) related to a disease, it fails to detect SNPs with small effect sizes due to stringent control for multiple testing. Additionally, the method does not consider the group structures of SNPs, such as genes or linkage disequilibrium blocks, which can provide valuable insights into the genetic architecture. To address the limitations, we propose a Bayesian bi-level variable selection method that detects SNPs associated with time of conversion from MCI to AD. Our approach integrates group inclusion indicators into an accelerated failure time model to identify important SNP groups. Additionally, we employ data augmentation techniques to impute censored time values using a predictive posterior. We adapt Dirichlet-Laplace shrinkage priors to incorporate the group structure for SNP-level variable selection. In the simulation study, our method outperformed other competing methods regarding variable selection. The analysis of Alzheimer’s Disease Neuroimaging Initiative (ADNI) data revealed several genes directly or indirectly related to AD, whereas a classical GWAS did not identify any significant SNPs.

Changing the name of diabetes insipidus: a position statement of the working group to consider renaming diabetes insipidus

"What's in a name? That which we call a rose / By any other name would smell as sweet" (Juliet, from Romeo and Juliet by William Shakespeare). Shakespeare's implication is that a name is nothing but a word and it therefore represents a convention with no intrinsic meaning. Whilst this may be relevant to romantic literature, disease names do have real meanings, and consequences, in medicine. Hence, there must be a very good rational for changing the name of a disease that has a centuries-old historical context. A working group of representatives from national and international endocrinology and endocrine pediatric societies now proposes changing the name of "diabetes insipidus" to "Arginine Vasopressin Deficiency (AVP-D)" for central etiologies, and "Arginine Vasopressin Resistance (AVP-R)" for nephrogenic etiologies This editorial provides both the historical context and the rational for this proposed name change.

The emerging role and targetability of the TCA cycle in cancer metabolism

The tricarboxylic acid (TCA) cycle is a central route for oxidative phosphorylation in cells, and fulfills their bioenergetic, biosynthetic, and redox balance requirements. Despite early dogma that cancer cells bypass the TCA cycle and primarily utilize aerobic glycolysis, emerging evidence demonstrates that certain cancer cells, especially those with deregulated oncogene and tumor suppressor expression, rely heavily on the TCA cycle for energy production and macromolecule synthesis. As the field progresses, the importance of aberrant TCA cycle function in tumorigenesis and the potentials of applying small molecule inhibitors to perturb the enhanced cycle function for cancer treatment start to evolve. In this review, we summarize current knowledge about the fuels feeding the cycle, effects of oncogenes and tumor suppressors on fuel and cycle usage, common genetic alterations and deregulation of cycle enzymes, and potential therapeutic opportunities for targeting the TCA cycle in cancer cells. With the application of advanced technology and in vivo model organism studies, it is our hope that studies of this previously overlooked biochemical hub will provide fresh insights into cancer metabolism and tumorigenesis, subsequently revealing vulnerabilities for therapeutic interventions in various cancer types.

Actividad comparativa in vitro de doripenem y otros carbapenemicos frente a pseudomonas aeruginosa aisladas en el laboratorio de microbiología del hospital Vargas de Caracas / Comparative in vitro activity of dorypenem and other carbapenems in pseudomonas aeruginosa isolates on Vargas Caracas Hospital´s Microbiology

Los ensayos de cuantificación de ARN plasmáticos de VIH-1 son importantes para el control de pacientes infectados, así como el monitoreo de la respuesta a la terapia antirretroviral. Por lo tanto, los ensayos comerciales empleados para este propósito deben presentar buena correlación entre si, para dar lugar al manejo terapéutico apropiado. El objetivo del estudio consistió en correlacionar los resultados obtenidos mediante el ensayo de amplificación de señal (bDNA) y PCR en tiempo real (RT-PCR), ambas casas comerciales aprobadas por la FDA y con diferente diana de detección del VIH-1. La validación se realizó con 180 muestras clínicas de pacientes referidos al INHRR. Los resultados fueron comparados con la subpoblación de linfocitos TCD4+ determinados mediante citometría de flujo. El análisis estadístico se realizó empleando el coeficiente de regresión lineal de Pearson (R2) y el valor de contraste de hipótesis con una significancia del 95 %, usando el programa SPSS Statistics v10.0. Se observó una buena correlación entre los ensayos (R2=0.961, p<0.05), siendo la RTPCR más sensible. Las diferencias cuantitativas de carga viral entre las técnicas ensayadas fue menor de 0.5 log10 copias/ml para el 89% de las muestras, y >1 log10 copias/ml solo en dos pacientes, no indicando necesariamente cambio terapéutico. Adicionalmente, se encontró una correlación inversa entre los linfocitos TCD4+ y carga viral del VIH-1 medida por bDNA (R2= 0.20, p<0.05) y RT-PCR (R2= 0.15, p<0.05). Los ensayos evaluados mostraron que ambas técnicas puedes ser empleadas indistintamente para el control de los pacientes VIH positivo.

The assay for quantification of plasma HIV-1 RNA are important for the control of patients infected, as well as the monitoring of the response to antiretroviral therapy. Therefore, the commercial assays used for this purpose must submit good correlation between to give place to the appropriate therapeutic management. In this study, we correlate the results obtained through the testing of signal amplification (bDNA) and real-time PCR (RT-PCR), two comercial technical approved by the FDA and with different targets of detection HIV-1. The validation was carried out with 180 clinical samples of patients referred to the INHRR. The results were compared with the subpopulation of lymphocytes TCD4+ determined by flow cytometry. The statistical analysis was performed using the program SPSS Statistics v10. It was observed good correlation between the tests studied (R2=0.961, p<0.05), with RT-PCR more sensitive. The quantitative differences in viral load between the techniques tested was less than 0.5 log10 copies/ml for the 89% of the samples, and >1 log10 copies/ml in only two patients. Additionally, it was found an inverse correlation between lymphocytes TCD4+ and viral load of HIV-1, measured by bDNA (R2= 0.20, p<0.05) and RT-PCR (R2= 0.15, p<0.05). Therefore, these assays can be employed for the patient control HIV.

Susceptibilidad a ceftarolina en staphylococcus aureus meticilino resistente / Susceptibility ceftaroline in methicillin-resistant staphylococcus aureus

Ceftarolina es un antibiótico de última generación del subgrupo de las cefalosporinas. Es el primer beta-lactámico comercializado que presenta actividad frente a Staphylococcus aureus resistente a la meticilina (SARM). El objetivo del presente estudio fue describir el patrón de susceptibilidad a ceftarolina en SARM aislados en el Laboratorio de Microbiología del Hospital Vargas de Caracas. Material y métodos: El aislamiento e identificación de las cepas se realizo por pruebas bioquímicas convencionales y las pruebas de susceptibilidad por el método de Difusión en Disco según CLSI 2015. Resultados: Se analizaron un total de 100 cepas SARM, de las cuales el 100% resultó sensible para ceftarolina (≥ 24 mm), con un rango de 26-35 mm, no detectándose ninguna cepa intermedia ni resistente. Conclusión: Ceftarolina muestra una excelente actividad in vitro frente a SARM, por lo que podría presentarse como una alternativa prometedora en el tratamiento de infecciones causadas por este microorganismo.

Ceftaroline is an antibiotic of last generation cephalosporins subgroup. Is the first marketed beta-lactam having activity against Methicillin-resistant S. aureus (MRSA). The aim of this study was to describe the pattern of susceptibility to ceftaroline in MRSA isolated in the Microbiology Laboratory of Hospital Vargas of Caracas. Methods: Isolation and identification of the strains was performed by conventional biochemical tests and susceptibility testing by disk diffusion method according to CLSI 2015. Results: A total of 100 MRSA strains were analyzed, of which 100% he was sensitive to ceftaroline (≥ 24 mm), with a range of 26-35 mm, not detected any intermediate or resistant strain. Conclusion: Ceftaroline shows excellent in vitro activity against MRSA, so it could be presented as a promising alternative in the treatment of infections caused by this organism.

Review of giant cell arteritis

Giant-cell arteritis [GCA] is a systemic autoimmune disease affecting primarily the elderly. Giant cell arteritis can cause sudden and potentially bilateral sequential vision loss in the elderly. Therefore, it is considered a medical emergency in ophthalmology and a significant cause of morbidity in an increasingly aging population. Ophthalmologists need to be able to recognize the classic symptoms and signs of this disease, and then be able to work-up and treat these patients in an efficient manner. An in-depth review of GCA from the literature as well as personal clinical experience follows

Pulmonary hypertension in Saudi Arabia: a single center experience

Several international studies have described the epidemiology of pulmonary hypertension [PH]. However, information about the incidence and prevalence of PH in Saudi Arabia is unknown. To report cases of PH and compare the demographic and clinical characteristics of PH due to various causes in a Saudi population. Newly diagnosed cases of PH [defined as mean pulmonary artery pressure > 25 mmHg at right heart cauterization [RHC]] were prospectively collected at a single tertiary care hospital from January 2009 and June 2012. Detailed demographic and clinical data were collected at the time of diagnosis, along with hemodynamic parameters. Of the total 264 patients who underwent RHC, 112 were identified as having PH. The mean age at diagnosis was 55.8 +/- 15.8 years, and there was a female preponderance of 72.3%. About 88 [78.6%] of the PH patients were native Saudis and 24 [21.4%] had other origins. Twelve PH patients [10.7%] were classified in group 1 [pulmonary arterial hypertension], 7 [6.2%] in group 2 [PH due to left heart disease], 73 [65.2%] in group 3 [PH due to lung disease], 4 [3.6%] in group 4 [chronic thromboembolic PH], and 16 [14.3%] in group 5 [PH due to multifactorial mechanisms]. PH associated with diastolic dysfunction was noted in 28.6% of group 2 patients, 31.5% of group 3 patients, and 25% of group 5 patients. These results offer the first report of incident cases of PH across five groups in Saudi Arabia

Mendelian breeding units versus standard sampling strategies: Mitochondrial DNA variation in southwest Sardinia

We report a sampling strategy based on Mendelian Breeding Units (MBUs), representing an interbreeding group of individuals sharing a common gene pool. The identification of MBUs is crucial for case-control experimental design in association studies. The aim of this work was to evaluate the possible existence of bias in terms of genetic variability and haplogroup frequencies in the MBU sample, due to severe sample selection. In order to reach this goal, the MBU sampling strategy was compared to a standard selection of individuals according to their surname and place of birth. We analysed mitochondrial DNA variation (first hypervariable segment and coding region) in unrelated healthy subjects from two different areas of Sardinia: the area around the town of Cabras and the western Campidano area. No statistically significant differences were observed when the two sampling methods were compared, indicating that the stringent sample selection needed to establish a MBU does not alter original genetic variability and haplogroup distribution. Therefore, the MBU sampling strategy can be considered a useful tool in association studies of complex traits.

Effect of Dietary Fat Supplementation during Late Pregnancy and First Six Months of Lactation on Maternal and Infant Vitamin A Status in Rural Bangladesh.

Dietary fat intake is extremely low in most communities with vitamin A deficiency. However, its role in vitamin A status of pregnant and lactating women is poorly understood. The aim of the study was to examine the effect of supplementing women with fat from mid-/late pregnancy until six months postpartum on their vitamin A status and that of their infants. Women recruited at 5-7 months of gestation were supplemented daily with 20 mL of soybean-oil (n=248) until six months postpartum or received no supplement (n=251). Dietary fat intake was assessed by 24-hour dietary recall at enrollment and at 1, 3 and 6 months postpartum. Concentrations of maternal plasma retinol, β-carotene, and lutein were measured at enrollment and at 1, 3 and 6 months postpartum, and those of infants at six months postpartum. Concentration of breastmilk retinol was measured at 1, 3 and 6 months postpartum. The change in concentration of plasma retinol at three months postpartum compared to pregnancy was significantly higher in the supplemented compared to the control women (+0.04 vs -0.07 μmol/L respectively; p<0.05). Concentrations of plasma β-carotene and lutein declined in both the groups during the postpartum period but the decline was significantly less in the supplemented than in the control women at one month (β-carotene -0.07 vs -0.13 μmol/L, p<0.05); lutein -0.26 vs -0.49 μmol/L, p<0.05) and three months (β-carotene -0.04 vs -0.08 μmol/L, p<0.05; lutein -0.31 vs -0.47 μmol/L, p<0.05). Concentration of breastmilk retinol was also significantly greater in the supplemented group at three months postpartum than in the controls (0.68±0.35 vs 0.55±0.34 μmol/L respectively, p<0.03). Concentrations of infants’ plasma retinol, β-carotene, and lutein, measured at six months of age, did not differ between the groups. Fat supplementation during pregnancy and lactation in women with a very low intake of dietary fat has beneficial effects on maternal postpartum vitamin A status.

Docetaxel and irinotecan as first-line chemotherapy in patients with advanced non-small-cell lung cancer: a pilot study

The aim of this study is to evaluate the activity and toxicity of the combination docetaxel and irinotecan as first-line therapy for advanced non-small-cell lung cancer [NSCLC]. Twenty-two chemotherapy-naive patients with stage IIIB with pleural effusion or stage IV NSCLC received irinotecan 50 mg/m[2] on days 1, 8, and 15, and docetaxel 50 mg/m[2] on day 2, every 28 days until disease progression. Median follow-up was 10 months [range: 2-28 months]. The overall response rate was 36.4% [8/22 patients; 95% confidence interval: 16.8-56.0], with no complete responses. Median time to disease progression was 5 months [range: 1-24 months] and median overall survival was 10 months [range: 2-28]. Grade 3-4 diarrhea was observed in 2 patients [9.1%]. Grade 3-4 neutropenia occurred in 2 patients [9.1%]: 1 episode of febrile neutropenia in one patient, and 1 death due to neutropenic sepsis in another patient. One patient received transfusion for grade 4 anemia. Irinotecan showed a moderate response rate and overall survival of clinical interest. Diarrhea was the main toxicity. This regimen may be suitable for patients unable to tolerate cisplatin-based therapy, for elderly and/or for patients with poor performance status, and should be investigated in a larger trial

Inherited neurodevelopmental brain diseases: applications of homozygosity mapping to identify new genetic causes of disease

The last two decades have seen major advancements in our understanding of some of the most common neurodevelopmental disorders in the field of child neurology. However, in the majority of individual patients, it is still not possible to arrive at a molecular diagnosis, due in part to lack of knowledge of molecular causes of these tremendously complex conditions. Common genetic disorders of brain development include septo-optic dysplasia, schizencephaly, holoprosencephaly, lissencephaly and hindbrain malformations. For each of these disorders, a critical step in brain development is disrupted. Specific genetic diagnosis is now possible in some patients with most of these conditions. For the remaining patients, it is possible to apply gene-mapping strategies using newly developed high-density genomic arrays to clone novel genes. This is especially important in countries like Iran where large family size and marriage between relatives makes these strategies tremendously powerful

Evidence-based dentistry: Reality and dilemmas

The concept of evidence-based practice [EBP] relies on rendering treatment, the effectiveness is solidly demonstrated by rigorous research, not just empirical experience. The aim of this paper is to review the foudation of EBP and the reality of its application. Evidence is commonly ordered up in a "hierarchy" from expert opinion to case report, case series, case-control study, cohort study, randomized controlled trial, and systematic review/meta-analysis. We stratify this hierarchy into 3 categories ascending from perspective, to investigation then synthesis. Depending on the type and feasibility of research, the higher levels of evidence do not negate the value of lower strata. The application of evidence is illustrated in two representative areas of dentistry: timing of early orthodontic treatment and immediate loading of osseointegrated implants. The clinician faces dilemmas in the need to ground treatment into unquestionable basis and the difficulty of relating this basis to the individual treatment. Reasons for this dichotomy include the scale of variation around mean results delivered by the most sophisticated research and the potential for new more encompassing research to deviate from prior findings. While research sets central tendencies, individual variation favors interpretation of the evidence. In the face of viewpoints on EBP ranging from support to rejection, the clinician should not indict a needed process, but rather use judgment to apply the average response shown in investigations to the individual circumstances of patients

Influence of biological and physicochemical characteristics of larval habitats on the body size of Anopheles gambiae mosquitoes (Diptera: Culicidae) along the Kenyan coast.

BACKGROUND & OBJECTIVES: The number and productivity of larval habitats ultimately determine the density of adult mosquitoes. The biological and physicochemical conditions at the larval habitat affect larval development hence affecting the adult body size. The influence of biological and physicochemical characteristics on the body size of Anopheles gambiae was assessed in Jaribuni village, Kilifi district along the Kenyan Coast. METHODS: Ten cages measuring 1 x 1 x 1 m (1 m3) with a netting material were placed in 10 different aquatic habitats, which were positive for anopheline mosquito larvae. Emergent mosquitoes were collected daily by aspiration and the wing lengths were determined by microscopy. In the habitats, physicochemical parameters were assessed: pH, surface debris, algae and emergent plants, turbidity, substrate, nitrate, ammonia, phosphate and chlorophyll a content. RESULTS: A total of 685 anopheline and culicine mosquitoes were collected from the emergent cages. Only female mosquitoes were considered in this study. Among the Anopheles spp, 202 were An. gambiae s.s., eight An. arabiensis, two An. funestus, whereas the Culex spp was composed of 214 Cx. quinquefasciatus, 10 Cx. tigripes, eight Cx. annulioris and one Cx. cumminsii. The mean wing length of the female An. gambiae s.s. mosquitoes was 3.02 mm (n=157), while that of An. arabiensis was 3.09 mm (n=9). There were no associations between the wing lengths and the environmental and chemical parameters, except for a positive correlation between wing length of An. gambiae and chlorophyll a content (r = 0.622). The day on which the mosquitoes emerged was not significant for the anopheline (p = 0.324) or culicine mosquitoes (p = 0.374), because the mosquito emerged from the cages on a daily basis. INTERPRETATION & CONCLUSION: In conclusion, there was variability in production of emergent mosquitoes from different habitats, which means that there should be targeted control on these habitats based on productivity.

Spatial distribution and habitat characterisation of Anopheles larvae along the Kenyan coast.

BACKGROUND & OBJECTIVES: A study was conducted to characterise larval habitats and to determine spatial heterogeneity of the Anopheles mosquito larvae. The study was conducted from May to June 1999 in nine villages along the Kenyan coast. METHODS: Aquatic habitats were sampled by use of standard dipping technique. The habitats were characterised based on size, pH, distance to the nearest house, coverage of canopy, surface debris, algae and emergent plants, turbidity, substrate, and habitat type. RESULTS: A total of 110 aquatic habitats like stream pools (n=10); puddles (n=65); tire tracks (n=5); ponds (n=5) and swamps (n=25) were sampled in nine villages located in three districts of the Kenyan coast. A total of 7,263 Anopheles mosquito larvae were collected, 63.9% were early instars and 36.1% were late instars. Morphological identification of the III and IV instar larvae by use of microscopy yielded 90.66% (n=2377) Anopheles gambiae Complex, 0.88% (n=23) An. funestus, An. coustani 7.63% (n=200), An. rivulorum 0.42% (n=11), An. pharoensis 0.19% (n=5), An. swahilicus 0.08% (n=2), An. wilsoni 0.04% (n=1) and 0.11% (n=3) were unidentified. A subset of the An. gambiae Complex larvae identified morphologically, was further analysed using rDNA-PCR technique resulting in 68.22% (n=1290) An. gambiae s.s., 7.93% (n=150) An. arabiensis and 23.85% (n=451) An. merus. Multiple logistic regression model showed that emergent plants (p = 0.019), and floating debris (p = 0.038) were the best predictors of An. gambiae larval abundance in these habitats. Interpretation & conclusion: Habitat type, floating debris and emergent plants were found to be the key factors determining the presence of Anopheles larvae in the habitats. For effective larval control, the type of habitat should be considered and most productive habitat type be given a priority in the mosquito abatement programme.

Individual appraisal of facial soft and hard tissues with the mesh diagram

The lateral cephalometric mesh diagram analysis presents advantages not readily available in conventional cephalometric methods. The face is oriented on the patient's natural head position, which provides comparability between cephalometric findings and the clinical facial examination. The patient's profile is not directly compared with the population norm but with an "individualized norm" derived from the application of the population norm to a grid scaled on the patient's facial shape namely, the upper face height [N-ANS] and facial depth [N-S]. Each landmark is assessed by its proportionate location in the mesh diagram grids. Thus, facial form is evaluated in one single display easily interpretable without computation of linear and angular measurements. These principles are illustrated for diagnosis of malocclusions and treatment with a combination of orthodontics and orthognathic surgery. The discrepancies between hard and soft tissues are readily ascertained and measured through the mesh display, and allow the formulation of conclusions on treatment and outcome. The mesh diagram is a flexible cephalometric analysis that should be incorporated in the routine dentofacial diagnosis and treatment planning

Sequencing cleft lip and palate treatment

Comprehensive treatment of cleft lip/palate involves a team approach [surgeon, orthodontist, prosthodontist, speech therapist, etc.] for long-term multidisciplinary planning, to achieve proper function and esthetics of facial structures, as well as optimal hearing and intelligible speech. Our aim is to review evidence-based treatment timing in relation to key growth events. Sequence: Within the first year of life, lip adhesion and/or closure are performed; soft palate closure is indicated with or without hard palate surgery, which is not delayed beyond the age of 2 years. Feeding appliances may be given to non-thriving infants. Before school begins [age 3-5 years], the lip and columella are lengthened and the alar base is repaired if indicated. In early to mid-childhood [6-12 years], orthodontics is initiated before secondary alveolar bone grafting [ABG]: expansion appliances are used to correct posterior/anterior crossbites; maxillary segments and teeth adjacent to the cleft are aligned. The optimal time for ABG is before the dental emergence age of 10 years, as research indicates the prevalence of ectopic tooth eruption if bone is provided later. A pharyngeal flap may be needed at the same time. In the adolescent years, final revisions of the lip and soft palate, and rhinoplasty, are performed. Orthodontic treatment is completed alone or with adjunctive orthognathic surgery. Permanent cosmetic and functional dental restorations are done last. Maxillofacial orthopedic treatment of cleft lip/palate is enhanced by proper sequencing, coordinated and implemented by a team of specialists from birth to adulthood

Effect of compromised nasal breathing on craniofacial development

The impact of nasal respiration impairment on craniofacial growth and development has been evaluated intensively in human and animal studies. The aims of this paper are to critically review: 1- the causes and diagnostic methods of nasal obstruction, specifically septal deviation, turbinate dysfunction, lymphoid tissue hypertrophy, and soft tissue alteration. 2- the growth pattern of the adenoids in relation to age and their size change in response to environmental factors. 3- the role of mouth breathing in the development of characteristic malocclusions and associated patterns of facial growth ["adenoid fades"], with a focus on available and needed research. 4- the ongoing debate about removal of lymphoid tissues to avoid facial dysmorphology, and the corollary issue of optimal timing of adenoidectomy and/or tonsillectomy that would prevent the development of such dysmorphology. The importance of a multidisciplinary approach in diagnosing, referring and treating patients with airway impairment will be emphasized

Root resorption during orthodontic tooth movement: a literature review

External root resorption [ERR] of permanent teeth is an unpredictable consequence of orthodontic treatment, usually diagnosed on periapical radiographs. The etiological and biochemical mechanisms are still unclear. Theories include excessive force that leads to the development of an avascular area referred to as hyalinized, resulting, through a cascade of cellular events, in increased cementoclast-osteoclast activity. Yet, risk .factors are incriminated that may be classified in two major categories: constitutional factors [gender, chronologic and dental ages, genetics, individual susceptibility, systemic factors, tooth structure, alveoloar hone density, specific tooth vulnerability to root resorption]; physiologic and environmental factors [nutrition, habits, occlusal trauma, endodontic treatment, trauma prior to orthodontic treatment, mechanical pressure such as types of orthodontic movement, appliances, and forces, duration of orthodontic treatment, repeated orthodontic treatment]. When resorption is detected, treatment objectives should be modified to maintain appropriate crown-to-root ratio and periodontal health, while light forces are used and root length monitored