Summary Targeting epidermal growth factor receptor (EGFR) is an important treatment option for non-small cell lung cancer (NSCLC). These targeted therapies have been studied extensively in NSCLC in ...first line and subsequent lines, including maintenance in empiric fashion or in patients with tumors harboring the EGFR mutations. In this manuscript, we will review in details the evolutions of these targeted therapy in the management of NSCLC.
Genetic testing in pediatric cholestasis can be very informative but genetic causes have not been fully characterized.
Exome sequencing and positional mapping in seven families with cholestatic liver ...disease and negative clinical testing for known disease genes.
KIF12, which encodes a microtubule motor protein with a tentative role in cell polarity, was found to harbor three homozygous likely deleterious variants in three families with sclerosing cholangitis. KIF12 expression is dependent on HNF-1β, deficiency which is known to cause bile duct dysmorphogenesis associated with loss of KIF12 expression. In another extended family, we mapped an apparently novel syndrome of sclerosing cholangitis, short stature, hypothyroidism, and abnormal tongue pigmentation in two cousins to a homozygous variant in PPM1F (POPX2), a regulator of kinesin-mediated ciliary transport. In the fifth family, a syndrome of normal gamma glutamyltransferase (GGT) cholestasis and hearing loss was found to segregate with a homozygous truncating variant in USP53, which encodes an interactor with TJP2. In the sixth family, we mapped a novel syndrome of transient neonatal cholestasis, intellectual disability, and short stature to a homozygous variant in LSR, an important regulator of liver development. In the last family of three affected siblings, a novel syndrome of intractable itching, hypercholanemia, short stature, and intellectual disability was mapped to a single locus that contains a homozygous truncating variant in WDR83OS (C19orf56), known to interact with ATP13A2 and BSEP.
Our results expand the genetic heterogeneity of pediatric cholestatic liver disease and highlight the vulnerability of bile homeostasis to a wide range of molecular perturbations.
Retinal arterial macroaneurysms with supravalvular pulmonic stenosis (RAMSVPS), also known as Familial Retinal Arterial Macroaneurysms (FRAM) syndrome, is a very rare multisystem disorder. Here, we ...present a case series comprising ophthalmologic and systemic evaluation of patients homozygous for RAMSVPS syndrome causative IGFBP7 variant. New clinical details on 22 previously published and 8 previously unpublished patients are described. Age at first presentation ranged from 1 to 34 years. The classical feature of macroaneurysms and vascular beading involving the retinal arteries was universal. Follow up extending up to 14 years after initial diagnosis revealed recurrent episodes of bleeding and leakage from macroaneurysms in 55% and 59% of patients, respectively. The majority of patients who underwent echocardiography (18/23) showed evidence of heart involvement, most characteristically pulmonary (valvular or supravalvular) stenosis, often requiring surgical correction (12/18). Four patients died in the course of the study from complications of pulmonary stenosis, cerebral hemorrhage, and cardiac complications. Liver involvement (usually cirrhosis) was observed in eight patients. Cerebral vascular involvement was observed in one patient, and stroke was observed in two. We conclude that RAMSVPS is a recognizable syndrome characterized by a high burden of ocular and systemic morbidity, and risk of premature death. Recommendations are proposed for early detection and management of these complications.
Retinal arterial macroaneurysms with supravalvular pulmonic stenosis (RAMSVPS).
Objective: This study aimed to compare serum insulin-like growth factor (IGF)-1 levels on cycle day 2 among poor ovarian responders, age-matched normal responders, and high responders undergoing in ...vitro fertilization (IVF). The investigation sought to understand the potential correlation between IGF-1 levels and ovarian response, with a focus on advanced maternal age and poor ovarian response. Methods: Conducted at the High Institute of Infertility Diagnosis and Assisted Reproductive Technologies in Baghdad, this clinical experiment involved 30 infertile individuals. The primary outcome measures included Cycle Day 2 IGF-1 serum levels, anti-Müllerian hormone (AMH) levels, antral follicle count (AFC), and retrieved oocytes. Secondary outcomes comprised intrauterine pregnancy, live birth, unfavorable pregnancy outcomes, oocyte maturation, and fertilization. Participants were categorized based on antral follicle count: Group 1 (≤3 AFC) and Group 2 (4 to 10 AFC). Results: In participants with usual responses, 72.5% had 4-10 AFC, while poor responders had ≤3 AFC in 27.5% of cases. Poor responders exhibited higher mean ages, lower mean AMH, and higher mean IGF-1 levels. However, poor responders and normal responders showed similar mean FSH levels. Female age positively correlated with FSH and IGF-1, while negatively correlating with AMH. The study also indicated negative correlations between female AMH, FSH, and IGF-1, along with a positive correlation between IGF-1 and FSH. Conclusion: The findings suggest that FSH, AMH, and IGF-1 readings in fertility-assessed women can serve as indicators of ovarian age and reserve. The observed correlations with age imply a diminishing ovarian function. This study contributes valuable insights into the relationship between serum IGF-1 levels, ovarian response, and aging, particularly in the context of poor ovarian responders undergoing IVF.
Background:
There are only a few case reports and small case series on neonatal-onset Dubin–Johnson syndrome (DJS), particularly from Far-East Asia, Iranian and Moroccan Jews, and Europe.
Objectives:
...In this first study from the Arabs and the largest series reported to date, we characterized the clinical, laboratory, and molecular features and outcome of gene-confirmed neonatal-onset DJS.
Methods:
We reviewed our database of 533 cases of neonatal cholestasis that presented to our center during the period from 2008 to 2019. We identified neonates with a disease-causing mutation in
ABCC2
gene.
Results:
Twenty-eight neonates with DJS were diagnosed (5.3%). All of the 28 were full-term, well looking neonates without hepatosplenomegaly, with cholestasis, and normal liver synthetic function since the 1 week of life that resolved within 3–6 months of age, followed by a benign course punctuated by recurrent episodes of jaundice in 43% during a median follow up period of 9.25 (range 2.5–14 years). Alanine aminotransferase levels were within normal range in 26 patients (92%) and mildly elevated in two patients. ALT levels were significantly lower in neonates with DJS than in other cases with neonatal cholestasis from other causes (
p
< 0.001). The median urinary coproporphyrin I% was 88% (IQ1–IQ3 = 84.2–92.7%). We identified four homozygous variants in the
ABCC2
gene (from 22 unrelated families), one splicing variant (c.3258+1G>A; p.?), and three were missense variants; two of which were novel missense variants c.1594G>A (p.Glu532Lys) and c.2439G>C (p.Lys813Asn). The p.Gly758Val mutation has occurred in 23 patients (from 19 unrelated families).
Conclusions:
Our study suggests that normal ALT-cholestasis in a well-looking neonate should trigger evaluation for DJS. The p.Gly758Val variant in ABCC2 is the most predominant mutation among Arabs with “founder effects.” Identification of the predominant
ABCC2
variant in any population is likely to facilitate rapid molecular analysis by future targeting of that specific mutation.
Differing threshold levels of hepatitis B virus (HBV) DNA and alanine aminotransferase (ALT) are recommended by international guidelines for commencement of antiviral therapy. These guidelines ...advocate therapy for patients with significant fibrosis (METAVIR score ≥F2); we assessed the accuracy of these guideline-defined thresholds in identifying patients with ≥F2 fibrosis.
We applied the European (European Association for the Study of the Liver EASL 2012), Asian-Pacific (Asian-Pacific Association for the Study of the Liver APASL 2012), American (American Association for the Study of Liver Diseases AASLD 2009), and United States Panel Algorithm (USPA 2008) criteria to 366 consecutive hepatitis B e antigen-negative patients with liver biopsy samples: EASL, ALT >laboratory-defined upper limit of normal (ULN) and HBV DNA ≥2000 IU/mL (n = 171); APASL, ALT >2-fold laboratory-defined ULN and HBV DNA ≥2000 IU/mL (n = 87); AASLD, ALT >2-fold the updated ULN (0.5-fold ULN corresponding to ≤19 U/L for women and 0.75-fold the ULN corresponding to ≤30 U/L for men) and HBV DNA ≥20,000 IU/mL (n = 53); and USPA, ALT >updated ULN (>0.5-fold ULN for women and >0.75-fold ULN for men) and HBV DNA ≥2000 IU/mL (n = 173).
Overall, 113 patients (30.9%) had ≥F2 fibrosis, which was more frequent among patients who fulfilled any guideline criteria (45.7% vs 17.9% for those who did not fulfill any criteria, P < .0001). In applying the EASL, AASLD, APASL, and USPA criteria, sensitivity and specificity values for detection of ≥F2 fibrosis were 45.6%, 58.5%, 56.3%, and 45.7% (P = .145) and 82.1%, 73.8%, 77.1%, and 82.4% (P = .366), respectively. The EASL criteria (area under the receiver operating characteristic AUROC curve, 0.66; 95% confidence interval CI, 0.61-0.71) and USPA criteria (AUROC, 0.66; 95% CI, 0.58-0.73) performed better than APASL (AUROC, 0.64; 95% CI, 0.59-0.69; P = .421) and significantly better than the AASLD criteria (AUROC, 0.59; 95% CI, 0.54-0.64; P = .013).
In hepatitis B e antigen-negative patients with chronic hepatitis, the EASL, AASLD, APASL, and USPA criteria identify patients with ≥F2 fibrosis with low levels of accuracy. However, the EASL and USPA criteria are the most accurate for identification of these patients.
Abstract
The cover image is based on the Original Article
Phenotypic delineation of the retinal arterial macroaneurysms with supravalvular pulmonic stenosis syndrome
by Hisham Alkuraya et al.,
...https://doi.org/10.1111/cge.13676
.
image
Development and evaluation of buccal formulations is highly challenging and requires lengthy permeation studies. In vitro studies include preparation of freshly excised mucosa from sacrificed animals ...that should be immediately employed to test permeation. In addition, inconsistent permeability results arise due to variations in tissue preparation. A simple and rapid method for in vitro evaluation is required to overcome erratic results, save on animals, and accelerate the development process of buccal products. The current work investigated the use of model polymeric membranes; cellulose acetate and cellulose acetate-nitrate, as rapid-screening alternative to the natural mucosa. Permeability coefficient and steady-state flux for carvedilol, a model hydrophobic drug, were determined in natural and artificial membranes. The effect of chemical enhancers on permeability through polymeric membranes was measured and compared against that in porcine and rabbit mucosa. A strong and statistically significant correlation between artificial membranes and buccal mucosa for the delivery of carvedilol was established.
Background and aim: Histological changes in hepatitis C virus (HCV)‐infected patients with persistently normal alanine aminotransferase (PNALT) have not been evaluated for updated upper limits of ...normal (ULN; ≤19/30U/L for females/males). We assessed significant fibrosis (≥F2, METAVIR) in patients with PNALT and persistently elevated alanine aminotransferase (PEALT).
Patients and methods: Nine hundred and twenty consecutive, unselected HCV patients were stratified into four groups: Group I: (n=124) PNALT within the updated ULN 0.5 × ULN (corresponding to ≤19 U/L) for females; 0.75 × ULN (corresponding to ≤30 U/L) for males; Group II (n=173): PNALT≤1 × ULN but greater than Group I; Group III (n=313): PEALT 1–2 × ULN; and Group IV (n=310): PEALT>2 × ULN. PNALT was defined as ≥3 determinations within the normal range over ≥6 months.
Results: Advanced ≥F3 and ≥F2 fibrosis increased incrementally across Groups I; II; III; and IV: 24.2 and 45.2%; 25.4 and 56.1%; 36.1 and 64.2%; and 50 and 77.1% respectively (P<0.0001 for both). Multivariable logistic regression analysis identified age odds ratio (OR), 1.05; 95% confidence intervals (CI): 1.02–1.08; P<0.0001, alanine aminotransferase (ALT) groups (OR 1.38; 95% CI: 1.03–1.83; P=0.030), presence of moderate–severe steatosis (OR 2.70; 95% CI: 1.19–6.15; P=0.018) and ≥A2 necroinflammation (OR 17.9; 95% CI: 8.88–36.20; P<0.0001) as independent predictors of ≥F2 fibrosis. Updated ULN for ALT were better at excluding ≥F2 fibrosis compared with traditional ULN (90.6 vs. 74.2%, P=0.0041) but less specific (20.8 vs. 44%, P=0.0007) with similar positive/negative predictive values.
Conclusions: HCV patients with ‘updated’ normal ALT have the lowest prevalence of significant fibrosis, although utilizing these levels without resorting to biopsy would miss significant fibrosis in almost one‐half of such patients.
Customers are the core of any business. With the extreme competition between leading telecommunication companies, customer satisfaction is always considered a priority. High rates of customer ...satisfaction increase both customer retention and attraction rates. As a result, telecommunication companies are always seeking new methods and strategies to achieve these objectives. In a typical call center, large volume of calls is received from customers complaining on phishing or spam attacks on daily basis. However, it is not possible to manually identify the purpose of the call. Hence, there is need of an automatic system that will classify calls as complaints on spam or phish or for other purposes. In this work we expand on previous efforts to focus more on consumers of phone spam or phish and optimize call centers outcome. The study focuses on both mediums of communication, phone call or message. A historical sample of complaining customers database was taken and a proper technical approach was used to analyze the calls. The proposed methodology uses different machine learning algorithms to build a robust call classifier. The performance of the baseline classifier achieves an accuracy of 63.4\% that is based on CatBoost. The predictive model will be able to identify whether an individual is likely complaining or to complain on a spam or phish attack. Moreover, we will be able to identify phish or spam consumers demographics. The results show that people of age 45 are more likely to complain. On the other hand, males are less likely to complain. The system can also be used as a call routing mechanism to increase call centers quality by pairing the caller to the best suited agent. Finally, we point to directions for future work.
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