Aim: Efavirenz is still widely used as the preferred first-line antiretroviral agent in the middle- and low- income countries, including Malaysia. The efavirenz population pharmacokinetic profile among HIV-positive smokers is still unknown. We aimed to assess the association of smoking with efavirenz and the differences in HIV clinical outcomes. Methods: A total of 154 stable HIV-positive patients on efavirenz in northern Malaysia were recruited with a sparse sampling for this multicentre prospective cohort study. The association between smoking and efavirenz pharmacokinetic parameters was determined using the non-linear mixed-effect model (NONMEM). A mixture model of clearance was adopted to describe the metaboliser status because genetic data is unavailable. The effect of smoking on HIV clinical markers (CD4, CD4 / CD8 ratio and viral blips) for at least two years after the antiretroviral initiation was also investigated. Results: Our data were best fitted with a one-compartment mixture model with first-order absorption without lag time. Smoking significantly associated with higher clearance (CL/F) (β = 1.39; 95% confidence interval (CI): 1.07 to 1.91), while weight affected both CL/F and volume (V/F). From the mixture model, 20% of patients were in the slow clearance group, which mimic the genotype distribution of slow metaboliser. An efavirenz dose reduction is not recommended for smokers ≥60kg with normal metabolism rate. Smoking significantly associated with slower normalisation of CD4 and CD4 / CD8 ratio. Conclusion: HIV-positive smokers presented with significantly higher efavirenz clearance and unfavourable clinical outcomes. Close monitoring of adherence and clinical response among smokers is warranted.

Sea Lettuce (Ulva spp.; Ulvophyceae, Ulvales, Ulvaceae) is an important ecological and economical entity, with a worldwide distribution and is a well-known source of near-shore blooms blighting many coastlines. Species of Ulva are frequently misidentified in public repositories, including herbaria and gene banks, making species identification based on traditional barcoding hazardous. We investigated the species distribution of 295 individual distromatic foliose strains from the North East Atlantic by traditional barcoding or next generation sequencing. We found seven distinct species, and compared our results with all worldwide Ulva spp sequences present in the NCBI database for the three barcodes rbcL, tufA and the ITS1. Our results demonstrate a large degree of species misidentification in the NCBI database. We estimate that 21% of the entries pertaining to foliose species are misannotated. In the extreme case of U. lactuca, 65% of the entries are erroneously labelled specimens of another Ulva species, typically U. fenestrata. In addition, 30% of U. rigida entries are misannotated, U. rigida being relatively rare and often misannotated U. laetevirens. Furthermore, U. armoricana and U. scandinavica present as being synonymous to U. laetevirens. An analysis of the global distribution of registered samples from foliose species also indicates possible geographical isolation for some species, and the absence of U. lactuca from Northern Europe. Altogether, exhaustive taxonomic clarification by aggregation of a library of barcode sequences highlights misannotations, and delivers an improved representation of Ulva species diversity and distribution. This approach could be easily adapted to other taxa.

Nutcracker syndrome (NCS) is known as a status of compression of the left renal vein (LRV) between the abdominal aorta and superior mesenteric artery (SMA). We here report a case of NCS in Marfan patients with type B aortic dissection who presented with sudden gross hematuria. Computed tomography revealed the compression of the LRV sandwiched between the SMA and the dilated dissecting abdominal aorta. The compression was released after surgical intervention and the hematuria was promptly recovered. This report highlights that NCS should be considered as a differential diagnosis of unexplained hematuria in patients with the chronic dissecting aorta.

All organisms are susceptible to the environment and changing environmental conditions can infer structural modifications in predator-prey communities. A change in the environment can influence, for example, the mortality rate of both the prey and the predator, or determine how long the interaction between both partners is. This may have a substantial impact on ecological, but also evolutionary dynamics. Experimental studies, in which microbial populations are maintained by a repeated dilution into fresh conditions after a certain period of time, are able to dissipate underlying mechanisms in a controlled way. By design, dilution rate (modifying mortality) and transfer interval (determining the time of interaction) are crucial factors, but they often receive little attention in experimental design. We study data from a live predator-prey (bacteria and ciliates) system used to gain insight into eco-evolutionary principles and apply a mathematical model to predict how various dilution rates and transfer intervals would affect such an experiment. We find the ecological dynamics to be surprisingly robust for both factors. However, the evolutionary rates are expected to be affected. Our work predicts that the evolution of the anti-predator defence in the bacteria, and the evolution of the predation efficiency in the ciliates, both decrease with higher dilution rate, but increase with longer transfer intervals. Our results provide testable hypotheses for future studies of predator-prey systems and we hope this work will help improving our understanding how ecological and evolutionary processes together shape composition of microbial communities.

Reconciling niche-based process and neutral dynamics in a portion of an infinite system, the regional species pool may be already not free parameter, and the divergent ecological-evolutionary mechanisms may operate consistently. The individual-based model was implemented in the two-dimensional grid with periodic boundary condition. The model was explored using a fixed speciation rate, and a range of system sizes, dispersal rates, environmental structures and initial conditions of regional species pool. The model communities in the center of system had a fixed population size, and approximated from an area encompassing independent biogeographic units to an area packed in a biogeographic unit with open boundary conditions, and presented the three environmental structures; four humps, linear and random. Across scenarios, the number of guilds in system achieved first to a stationary state; then, the species richness converged eventually to a dynamical equilibrium through speciation-extinction balance. In simulations, the per capita ecological difference among species only contributed to the probabilities of immigration success, so the weighted lottery process was more efficient and immediate at higher dispersal rates. The increase of functional redundancy in model communities suggested that the relative role of neutral dynamics increased in an area encompassing independent biogeographic units. The variation partitioning based on canonical analysis inferred that not only the neutral dynamics among the species of single guild, but also the competition-colonization trade-off among the species of more than two guilds with similar environmental optimum and different levels of specialization operated in the spatial structures found within and among patchy habitats. Ecologist to disentangle the influence of alternative processes must shift focus from the contribution of local competitions and regional dispersals to detecting the spatio-temporal-environmental scales on which the per capita ecological difference and equivalence among species are emerged through divergent ecological-evolutionary mechanisms.

The antidepressant vortioxetine is primarily metabolised by the polymorphic enzyme CYP2D6. The objective of this study was to investigate the effect of CYP2D6 genotype on exposure and therapeutic failure of vortioxetine. The analysis included data from CYP2D6-genotyped patients (N=458) on vortioxetine treatment from a Norwegian therapeutic drug monitoring database. Compared with CYP2D6 normal metabolizers (NMs; N=242), vortioxetine exposure was 3.0-fold (p<0.001) increased in poor metabolizers (PMs; N=35), 1.5-fold (p<0.001) increased in intermediate metabolizers (IMs; N=173), and not significantly changed (p=0.21) in ultra-rapid metabolizers (UMs; N=8). Compared with NMs, treatment switch from vortioxetine to alternative antidepressants was 8.0-fold (95%CI: 2.0-32.3, p=0.001) more frequent among PMs and 12.7-fold (95%CI: 1.1-94.9, p=0.02) more frequent among the CYP2D6 UMs. In conclusion, CYP2D6 genotype was associated with significant changes in vortioxetine exposure and may also be associated with risk of therapeutic failure.

Differential diagnostic challenges during the Covid-19 pandemic for pediatricians in an Eastern European country where newborn screening of cystic fibrosis is not availableSzofia Hajósi-Kalcakosz MD1, Borbála Zsigmond MD1, Andrea Párniczky MD, PhD2, Réka Bodnár MD, PhD21Heim Pál Children’s Hospital, Department of Infectious Diseases, Budapest, Hungary2Heim Pál Children’s Hospital, Cystic Fibrosis Outpatient Care Unit, Budapest, HungaryCorresponding author e-mail address: rekabodnar@ymail.compostal address: Heim Pál Children’s Hospital, 1089, Üllői Street 86., Budapest, HungaryKeywords: Covid-19, cystic fibrosis, newborn screeningTo the editor,we are writing this letter to emphasize the need of new born screening of cystic fibrosis in Hungary.A cluster of cases of pneumonia were reported in Wuhan, China in December 2019. In January 2020 the genetic sequence of the novel corona virus was detected and in March the World Health Organization (WHO) characterized Covid-19 as a pandemic. Heim Pál Children’s Hospital was assigned to hospitalize suspected or verified SARS-CoV-2 infected children in Central Hungary on 21st March.A two-year-old girl was admitted to our hospital with a suspected diagnosis of SARS-CoV-2 pneumonia in March 2020. She presented in infancy with chronic cough, frequent respiratory illnesses, and failure to thrive (BMI 3rd percentile, Z score = -1,99).In March 2020 she was admitted to the local hospital, in Eastern Hungary with fever, difficulty of breathing and one week history of coughing. Due to her respiratory symptoms a SARS-CoV-2 PCR test was carried out on the 7th day of her illness. The result of the PCR test was unclear therefore she was transferred to our hospital. On arrival tachypnea, wheezing, lung crackles, hepatomegaly, clubbing of the fingers were found during the physical examination. It was also noticed that her weight was under the 3rd percentile. Her saturation was 95% on 3 l/min oxygen flow via the nebulizing mask. Laboratory evaluation showed high white blood cell count with neutrophilia. Shortly after admission her work of breathing significantly increased, therefore high flow nasal cannula (HFNC) oxygen therapy was implemented. Despite the frequent use of bronchodilators and steroids wheezing did not improve. On the 10th day of her illness nasopharyngeal swab for SARS-CoV-2 was reported to be positive by our hospital.The result was a surprise as the case did not fulfill the environmental criteria of Covid-19 infection. First of all, the girl came from the rural part of Eastern Hungary where the number of confirmed Covid-19 cases was extremely low, and second of all, no one in the family was confirmed to be positive either. In addition to that, the severity of symptoms and her past medical history brought up the possibility of an undiagnosed underlying chronic condition. At that time, no false positive SARS-CoV-2 PCR result was reported in the literature, therefore we repeated the tests. Further testing, real time PCR nasopharyngeal swab tests and serology tests were all found to be negative therefore we excluded the diagnosis of Covid-19. According to our recent knowledge, above 34 replication cycles no positive viral culture is obtained. (1) Our explanation for the initial positive test could have come from the fact that our laboratory repeated the PCR replication above 34 cycles and nonspecific signals were misinterpreted positive.On day 10 after admission, she was transferred to the Pediatric Intensive Care unit for invasive ventilation due to further respiratory distress on HFNC. All together, she required 10 days of mechanical ventilation. Due to the worsening clinical picture, high resolution computed tomography (HRCT) was performed, which revealed bronchial wall thickening, mucus plugging and bronchiectasis consistent with CF (Figure). Pseudomonas aeruginosa and methicillin-sensitive Staphylococcus aureus (MSSA) was isolated from sputum, therefore piperacillin-tazobactam (100 mg/kg/piperacillin four times a day) and aminoglycoside (20 mg/kg/day once a day) were applied. After extubation, she needed further 10 days of non-invasive ventilation before she was finally stepped down to the General Pediatric ward.Later on sweat chloride test (112 mmol/l) confirmed the diagnosis of cystic fibrosis (CF), and a genetic test revealed a F508 del and G542X mutation. The patient was started on regular pancreatic enzyme replacement therapy, fat-soluble vitamins and nebulised colistimethate sodium. She was also assessed by multidisciplinary CF team and was started on regular physiotherapy. The CF-specific therapy led to a better physical condition, but the consequences of the delayed diagnosis and treatment are unknown at this stage.The Covid-19 pandemic in Hungary was started in the beginning of March. Children are mostly reported to have milder symptoms or are asymptomatic. The cause of the milder form of the disease is hypothesized due to the high exposure of other viruses and the low expression of ACE2 receptors. (2)In 2018 in Hungary, there was a total of 523 patients with CF (age at diagnosis 2.65 years) out of 9.7 million inhabitants. Unfortunately the number of phenotyping, the average FEV1% and the BMI z-score lag far behind the European average and the age of time at lung transplantation is lower.In Europe there are many different CF NBS protocols. All current protocols rely on immunoreactive tripsinogen (IRT) at birth, intermediate tiers consists of CFTR mutation analysis or an IRT resampling, and as a last step a sweat chloride test is made to distinguish between NBS false and true positive cases. (3) In Hungary national NBS program is not available yet. However, the protocol of the NBS is elaborated for years. (4) This case underlines the need of a national NBS program of CF in Hungary.Early diagnosis and CF specific therapy from the early stage may protect lungs from serious damages and disease progression. It is well known that countries where NBS was introduced, the median age at the diagnosis decreased; for example in England from 2,4 years to 3 weeks of age. Mak et al. compared different provinces in Canada at the same time where NBS was already introduced and where it was not applied yet. (5) With the introduction of NBS, CF was diagnosed earlier, pancreatic insufficiency was less common, mean z-scores for weight-for-age and height-for-age was higher. The frequency of hospital admission was reduced and there was a lower prevalence of colonization with Pseudomonas aeruginosa and Staphylococcus aureus. Lung infections were treated earlier so they did not cause irreversible lung damage.Our experience suggests that the lack of national NBS program of CF leads to delayed diagnosis in Hungary. Introducing NBS of CF may decrease the age at the time of diagnosis that could lead to a better quality of life and clinical state of the patients. In the meantime, clinicians in Hungary should always consider CF as part of their differential diagnosis at cases with recurrent respiratory infections and failure to thrive.

The White Sands pupfish (Cyprinodon tularosa), endemic to New Mexico in Southwestern North America, is of conservation concern due in part to invasive species, chemical pollution, and groundwater withdrawal. Herein, we developed a high quality draft reference genome and use it to provide biological insights into the evolution and conservation of C. tularosa. Specifically, we localized microsatellite markers previously used to demarcate Evolutionary Significant Units, evaluated the possibility of introgression into the C. tularosa genome, and compared genomic diversity among related species. The de novo assembly of PacBio Sequel II error-corrected reads resulted in a 1.08Gb draft genome with a contig N50 of 1.4Mb and 25,260 annotated protein coding genes, including 95% of the expected Actinopterigii conserved orthologs. Many of the previously described C. tularosa microsatellite markers fell within or near genes and exhibited a pattern of increased heterozygosity near genic areas compared to those in intergenic regions. Genetic distances between C. tularosa and the widespread invasive species C. variegatus, which diverged ~1.6-4.7 MYA, were 0.027 (nuclear) and 0.022 (mitochondrial). Nuclear alignments revealed putative tracts of introgression that merit further investigation. Genome-wide heterozygosity was markedly lower in C. tularosa compared to estimates from related species, likely because of smaller long-term effective population sizes constrained by their isolated and limited habitat. These population inferences, generated from our new genome assembly, provide insights into the long term and contemporary White Sands pupfish populations that are integral to future management efforts.

Objective: To study the differences in sexual dysfunction (SD) and time to pregnancy (TTP) between infertile couples pursuing timed intercourse (TI- around the time of ovulation) and regular intercourse (RI- at least twice a week). Design: Prospective cohort study Setting: Infertility clinics of Kolkata over three years Population or Sample: Infertile couples pursuing TI (n=283) or RI (n=88), having no preexisting sexual or psychiatric illness, and no medical contraindications to frequent intercourse. Methods: At the first visit, SD of both the partners was assessed using the Arizona Sexual Experiences Scale (ASEX) and the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V). The couples for whom natural conception was possible were followed up to determine TTP using Kaplan Meier Analysis. Main Outcome Measure: Differences in SD and differences in TTP. Results: TI significantly increased the risk of SD than RI for both males (Odds ratio [OR] 15.24, 95% confidence interval [CI] 7.96-29.15) and females (OR 5.52, 95% CI 2.38- 12.78). This difference persisted even after adjusting for age, medical disorders, obesity, smoking, cause of infertility, and previous assisted reproductive techniques. TI carried a higher risk of developing ED, premature ejaculation, male hypoactive sexual dysfunction, female sexual interest-arousal disorder, and female orgasmic disorder. IIEF-5 score was significantly better in the RI group than in the TI. The TTP for natural conception was similar between them (Log-rank p= 0.1365). Conclusions: TI increased the risk of sexual dysfunction without accelerating the time to achieve pregnancy, compared with RI.

Surface cracks have been recognized as major causes for fracture failures of ductile pipes. This paper intends to derive a normalized fully plastic J-integral solution to mixed-mode fracture caused by inclined surface cracks in pressurized ductile pipes. A combined J-integral and finite element method is developed to evaluate the J-integral for inclined surface cracks. A set of predictive formulas for normalized fully plastic J-integrals are developed. It is found in this paper that the normalized fully plastic J-integral increases with the decrease of crack inclination angle and aspect ratios, and the increase of strain hardening exponent. It is also found that the critical locations of crack propagation occur between the surface point and the deepest point of cracks when the inclination angle is relatively small. The paper concludes that the developed formulas can accurately predict the normalized fully plastic J-integrals along the front of inclined surface cracks. The results presented in the paper can enable researchers and practitioners to accurately predict the mixed-mode fracture failure of pressurized pipes subject to inclined surface cracks.

Let $\{L^{(\alpha)}_n\}_{n\geq 0}$, ($\alpha\neq-m, \ m\geq1$), be the monic orthogonal sequence of Laguerre polynomials. We give a new differential operator, denoted here $\mathscr{L}^{+}_{\alpha}$, raises the degree and also the parameter of $L^{(\alpha)}_n(x)$. More precisely, $\mathscr{L}^{+}_{\alpha}L^{(\alpha)}_n(x)=L^{(\alpha+1)}_{n+1}(x), \ n\geq0$. As an illustration, we give some properties related to this operator and some other operators in the literature, then we give some connection results between Laguerre polynomials via this new operator.

Deranged liver enzymes due to hyperthyroidism rather than intrinsic liver pathology are not uncommon. We present two cases that highlight the impact of hyperthyroidism on liver biochemistry tests and good response to treatment. A high index of suspicion is paramount in patients presenting with unexplained deranged liver enzymes or jaundice.

Retroperitoneal hemorrhage is a rare but severe vascular access-related complication of transfemoral transcatheter aortic valve implantation. The diagnosis is often delayed because of nonspecific clinical presentations. Although the best management protocol is still controversial, endovascular treatment or embolization should be chosen in uncontrollable ongoing bleeding.

In this paper, we introduce the notions of equiaffine arclength and curvature with fractional order for a plane curve and compare them with the standard ones. In terms of the equiaffine curvature with fractional order we obtain an equiaffine Frenet formula and then construct an analogue of the Fundamental Theorem. The plane curves of constant equiaffine curvature with fractional-order are classified. Several examples are also illustrated.

An obstetric ultrasound of a multi-gravid mother at 37-week of gestation showed a female fetus with alobar holoprosencephaly, polydactyly, short ribs, narrow chest and short upper and lower extremity bones, consistent with Holoprosencephaly-polydactyly syndrome and Asphyxiating thoracic dystrophy overlap. Apgar score was 0 in the first and fifth minutes.

This case report deals with a clinical case of a patient who underwent inpatient treatment of the underlying disease acute leukemia. In the selection of treatment for complications, medications of various groups were prescribed. This therapy led to the clinical death of the patient, caused by drug-induced QT/QTc prolongation.

Lung cancer is the leading cause of cancer-related death. NSCLC accounts for 80-90% of cases. In younger patients, adenocarcinoma is the most frequent histotype and 3-7% expresses the rearrange-ment of ALK oncogene, sensitive to TKIs. Crizotinib is the first ALK inhibitor approved by FDA. We present the case of a 17-year-old male with metastatic naïve ALK-positive adenocarcinoma, treated with crizotinib. He received crizotinib and obtained a prolonged response with PFS of 33 months. Crizotinib can be extremely effective in adolescent with naïve ALK-positive NSCLC but it hardly penetrates blood-brain barrier. Resistance mechanisms will be investigated for a better man-agement.

Background and Purpose: Identification of accurate targets is essential for a successful development of targeted therapy in cancer. Studies have shown that matrine has antitumor activity against many types of cancers. However, the direct target in cancer cells of its anticancer effect has not been identified. The purpose of this study was to find the molecular target of matrine to inhibit the proliferation of cancer cells and explore its mechanism of action. Experimental Approach: The effect of matrine on the proliferation of cancer cells were examined by MTT assay. Pull-down assay and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) were performed to explore the target of matrine. A series of in vitro and in vivo experiments were conducted to reveal the mechanisms by which matrine targeted Src to regulate the downstream signaling pathways of Src in cancer cells. Key Results: Herein we showed that matrine inhibited the proliferation of cancer in vitro and in vivo. Pull-down assay with matrine-amino coupling resins (MA beads) and LC-MS/MS identified Src as the target of matrine. Src kinase domain is required for its interaction with matrine and Ala392 in the kinase domain participated in matrine-Src interaction. Intriguingly, matrine was proven to inhibit Src kinase activity in a non-ATP-competitive manner by blocking the autophosphorylation of Tyr419. Matrine down-regulated the phosphorylation levels of MAPK/ERK, JAK2/STAT3 and PI3K/Akt signaling pathways. Conclusions and Implications: Collectively, matrine targeted Src, inhibited kinase activity and down-regulated its downstream MAPK/ERK, JAK2/STAT3 and PI3K/Akt phosphorylation signaling pathways to inhibit the proliferation of cancer cells.

Ouabain (OUA) is an inhibitor of Na+, K+ -ATPase that has been identified as an endogenous substance present in human plasma, and it has been shown to be associated with the response to acute stress in both animals and humans. Chronic stress is a major aggravating factor of psychiatric disorders, including depression and anxiety. The present work investigates the effects of OUA intermittent administration during chronic unpredictable stress (CUS) protocol in the rat’s central nervous system (CNS). Adult male Wistar rats were pretreated intraperitoneally with ouabain (1.8 μg/kg), followed by CUS protocol for 14 days. The levels of serum corticosterone, ACTH, and CRH serum were evaluated through ELISA and the expression of CRH, CRHR1, and CRHR2 genes in the hypothalamus and hippocampus of the animals through RT-PCR. Inflammatory parameters were also investigated, as well as the behavioral CUS effects on memory, that were assayed through the object recognition task, contextual fear conditioning, and memory extinction paradigms. The results suggest that intermittent OUA treatment reversed CUS-induced HPA axis hyperactivity through the reduction of (i) glucocorticoids levels, (ii) CRH-CRHR1 expression, and by decreasing neuroinflammation with the reduction of iNOS activity, without interfering with the expression of antioxidant enzymes. These changes in both the hypothalamus and hippocampus may reflect in the rapid extinction of aversive memory. The present data demonstrate, for the first time, the ability of OUA to modulate the HPA axis as well as the disappearance of aversive memory in rats.

Extreme precipitation can have profound consequences for communities, resulting in natural hazards such as rainfall-triggered landslides that cause casualties and extensive property damage. A key challenge to understanding and predicting rainfall-triggered landslides comes from observational uncertainties in the depth and intensity of precipitation preceding the event. Practitioners and researchers must select among a wide range of precipitation products, often with little guidance. Here we evaluate the degree of precipitation uncertainty across multiple precipitation products for a large set of landslide-triggering storm events and investigate the impact of these uncertainties on predicted landslide probability using published intensity-duration thresholds. The average intensity, peak intensity, duration, and NOAA-Atlas return periods are compared ahead of 228 reported landslides across the continental US and Canada. Precipitation data are taken from four products that cover disparate measurement methods: near real-time and post-processed satellite (IMERG), radar (MRMS), and gauge-based (NLDAS-2). Landslide-triggering precipitation was found to vary widely across precipitation products with the depth of individual storm events diverging by as much as 296 mm with an average range of 51 mm. Peak intensity measurements, which are typically influential in triggering landslides, were also highly variable with an average range of 7.8 mm/hr and as much as 57 mm/hr. The two products more reliant upon ground-based observations (MRMS and NLDAS-2) performed better at identifying landslides according to published intensity-duration storm thresholds, but all products exhibited hit-ratios of greater than 0.56. A greater proportion of landslides were predicted when including only manually-verified landslide locations. We recommend practitioners consider low-latency products like MRMS for investigating landslides, given their near-real time data availability and good performance in detecting landslides. Practitioners would be well-served considering more than one product as a way to confirm intense storm signals and minimize the influence of noise and false alarms.

Modelling results in the small (1.78 km2) experimental catchment Uhlířská located in the northern part of the Czech Republic at the average elevation of 822 m a.s.l. are presented. While the basic hydrological and meteorological monitoring has started already in 1982, investigation of the subsurface flow adjoined in 1995. A detailed survey of water and isotope (18O, 2H, 3H, 3H/3He) fluxes across the catchment storage compartments has been in operation since 2006. The combined vadose/saturated zones modeling with support of partial extrapolation of 18O content in precipitation yielded the following mean balance for the period 1961-2014: 456 out of 1220 mm annual precipitation depth are percolating through the soil matrix domain and 534 mm through the preferential domain in the hillslope soil profile. The saturated zone is recharged annually by 416 mm, consisting of the entire matrix flow and 12,5 % of the preferential flow from the permeable hillslopes covered by Cambisols and Podzols, as well as by the contribution of 22 mm from the less permeable riparian wetland Histosols. The aquifer geometry was determined by means of electrical resistivity tomography (ERT) including inverse modelling (RES2DINV). Water and isotope fluxes were computed using a sequence of models. They include S1D software for the vadose zone modeling including 18O transport and Modflow, Modpath and MT3DS determining residence time and flow trajectories in the saturated zone. Isotopes 3H and 3H/3He improved the model confidence. The water residence time on the hillslopes does not exceed 1 year, while the saturated zone indicates about 10 years, with a 20% portion of water older than 100 years in the deepest part of the aquifer. The combination of numerical modelling approaches with computation of water balance and isotope-supported calibration is considered innovative, particularly the 3H/3He method to determine water residence times of young groundwater in the saturated zone.

Germline mutations in the DNA mismatch repair (MMR) genes cause Lynch syndrome (LS). Insertions of retrotransposons in MMR genes have been reported as a rare cause of LS. Here, we present a novel SINE-VNTR-Alu (SVA) insertion in exon 12 of MSH2 in an individual with early-onset colorectal cancer and strong LS family history. RT-PCR analysis indicated a larger aberrant MSH2 transcript in one of the family members. MSK-IMPACT next-generation sequencing testing and long-range PCR revealed an insertion in MSH2 exon 12 at the c.1972 position in an antisense orientation. The insertion was further characterized as an SVA element approximately 3 kb in length, belonging to the SVA_F1 family of retrotransposons.

A document by Mehreen Zaigham. Click on the document to view its contents.

Objective To compare current surgical practice for women with AOC to ultra-radical surgery; to assess whether the new approach would be cost-effective under NICE guidelines of approximately £20,000/QALY. Design Cost-effectiveness analysis. Setting NHS, using data from a variety of sources. Population Patients with advanced ovarian cancer (FIGO stages IIIC-IV). Methods A decision analytic model (microsimulation model) was built to examine the Objective; deterministic and probabilistic sensitivity analyses were used to test the susceptibilities of the baseline model and its assumptions. Main Outcome Measures ICER (incremental cost-effectiveness ratio). Results The standard model yielded an ICER of £5325.06; this is in spite of an associated overall decrease in utility due to predicted increase in surgical mortality. The parameters with the most significant impact on the ICER are the cost of ultra-radical surgery, the utility associated with progression-free survival, and the probability of death from ultra-radical surgery. Conclusions Ultra-radical surgery is cost-effective under NICE willingness-to-pay thresholds of £20000; the costs of ultra-radical surgery are bound to decrease as centres specialise further, and its effectiveness is also likely due to increase with development of newer techniques and more surgical training.