The correlation between increasing Body Mass Index and the incidence of local recurrence and distant metastasis in breast cancer patients

OBJECTIVE: Patients with breast cancer (BC) who are obese or overweight at the time of diagnosis have a low survival rate and a high death rate. We aimed to investigate if having a higher body mass index (BMI) at diagnosis raised the risk of local recurrence (LR) and distant metastasis. PATIENTS AND METHODS: Patients were divided into three categories based on their BMI. The patient's BMI was determined by dividing his weight in kilograms by his height in square meters (kg/m2). The WHO defines normal weight as 18.5 ≤ BMI < 25 kg/m2, overweight as 25 ≤ BMI < 30 kg/m2, and obesity as BMI ≥ 30 kg/m2. RESULTS: The mean BMI was 30.27±6.06 kg/m2. Out of 250 patients, 60 (24.0%), 73 (29.2%) and 117 (46.8%) patients had normal, overweight and obese BMI respectively. No significant difference between BMI and estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) was found, but there was an association between tumor (T) stage and lymph vascular invasion (LVI) (p<0.05). Obese patients had poorer disease-free survival (DFS) and overall survival (OS) than normal and overweight categories (35.38 ±1.72 vs. 42.38 ± 2.79 and 37.82 ± 2.27 months) (39.65±1.65 vs.45.70 ± 2.53 and 44.31 ± 2.04 months) (p<0.001). LR occurs more prevalent in over-weight and obese patients than normal (p<0.03) but there is no significant difference for distant metastasis. CONCLUSIONS: There is a strong negative association between increased BMI and BC prognosis and patient survival; controlling of this phenomenon may improve the response to treatment and survival, therefore health awareness programs should be implemented

ACHILLES Reading Guide 3: Asset scale deterioration

The deterioration of earthworks reduces theirserviceable performance and increases thelikelihood of instability. This can havesignificant impacts on the safe and reliableoperation of the transportation networks thatthey support. These deterioration processesare weather-driven and may lead to failuremany years after construction even in theabsence of increased mechanical loads.Evidence also indicates that climate changewill increase rates of asset deterioration andreduce time to failure. This documentsummarises the key conclusions on assetdeterioration drawn from the ACHILLES bodyof work. A more detailed overview of theACHILLES concept can be found in ReadingGuide 1 [1], the project website (achilles-grant.org.uk), and the following papers: [2,3]

Prevent Cracking in Deposition of Carbon Steel on Inconel 625

Welding procedure of clad steel including deposition of carbon steel on nickel base alloy usually gives unaccepted mechanical properties. Cracks were formed along type II boundary in nickel base alloy pass and a martensitic layer was formed in carbon steel pass. In this paper, cracks along type II boundary were prevented by lowering the martensitic start temperature (TMs) of the martensitic layer. Decreasing of TMs was obtained by two methods: Dilution method and Grain refining method. Three levels of TMs (approximately 350, 200, and 50⁰C) are obtained. The results showed that: cracks along type II boundary were prevented at TMs lower than 200⁰C; however type II boundary itself was prevented at TMs lower than 50. Also post weld heat treatment was necessary to achieve accepted impact properties

CYP1B1 and myocilin gene mutations in Egyptian patients with primary congenital glaucoma

Purpose: Primary congenital glaucoma (PCG) accounts for 26–29% of childhood blindness in Egypt. The identification of disease causing mutations has not been extensively investigated. We aimed to examine the frequency of CYP1B1 and MYOC mutations in PCG Egyptian patients, and study a possible genotype/phenotype correlation.Methods: Ninety-eight patients with PCG diagnosed at the Ophthalmology department ofAlexandria Main University Hospital were enrolled. Demographic and phenotypic characteristics were recorded. Patients and 100 healthy subjects (control group) were screened for two mutations in CYP1B1 gene (G61E, R368H) and one mutation in MYOC gene (Gln48His) using polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP). Phenotypic characteristics pertaining to disease severity were compared.Results: Nineteen patients (19%) with PCG were found positive for one or more of the mutations screened for. Seven patients (7%) were homozygous for the G61E mutation. Ten patients (10%) were heterozygous; 6 for the G61E mutation, 2 for the R368H mutation and 2 for the Gln48His mutation. Two patients (2%) were double heterozygotes harboring a R368H as well as a Gln48His mutation. The most common mutation observed was the G61E in 13 patients; 7 homozygotes and 6 heterozygotes for the mutation. The control group were negative for all mutations screened for. No significant correlations between the mutations and phenotype severity were detected. A statistically significant positive correlation however was found between the different mutations andeach of the IOP and the cup/disk ratio.Conclusion: The current study further endorses the role of CYP1B1 mutations in the etiology of PCG among Egyptian patients and is the first study to report MYOC gene mutation in Egyptian patients with PCG

Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele

Glycoprotein (GP)96 is essential for maintaining intestinal epithelial architecture by supporting its self-renewal capacity

BACKGROUND & AIMS Glycoprotein (GP)96 is an endoplasmic reticulum (ER)-resident master chaperone for cell surface receptors including the Wnt co-receptors LRP5/6. Intestinal epithelial cells (IEC)-specific deletion of Gp96 is embryonically lethal. However, the role of GP96 in adult intestinal tissue and especially within the intestinal stem cell (ISC) niche has not been studied so far. Here, we investigated how GP96-loss interferes with intestinal homeostasis by compromising viability, proliferation and differentiation of IEC. METHODS Tamoxifen was used to induce Cre-mediated deletion of Gp96 in GP96-Villin$^{creERT2}$ mice and intestinal organoids. With H&E- and immunofluorescence staining we assessed alterations in intestinal morphology and the presence and localization of IEC-types. Real-time PCR and Western blot analysis were performed to explore the molecular mechanisms underlying the severe phenotype of Gp96 KO mice and organoids. RESULTS IEC-specific deletion of Gp96 in adult mice resulted in a rapid degeneration of the stem cell niche, followed by a complete eradication of the epithelial layer and death within few days. These effects were due to severe defects in ISC renewal and premature ISC differentiation, which resulted from defective Wnt and Notch signaling. Furthermore, depletion of GP96 led to massive induction of ER stress. While effects on ISC renewal and adequate differentiation were partly reversed upon activation of Wnt/Notch signaling, viability could not be restored, indicating that reduced viability was mediated by other mechanisms. CONCLUSIONS Our work demonstrates that GP96 plays a fundamental role in regulating ISC fate and epithelial regeneration and is therefore indispensable for maintaining intestinal epithelial homeostasis

Spermidine ameliorates colitis via induction of anti-inflammatory macrophages and prevention of intestinal dysbiosis

BACKGROUND AND AIMS: Exacerbated immune activation, intestinal dysbiosis, and a disrupted intestinal barrier are common features among inflammatory bowel disease (IBD) patients. The polyamine spermidine, which is naturally present in all living organisms, is an integral component of the human diet, and exerts beneficial effects in human diseases. Here, we investigated whether spermidine treatment ameliorates intestinal inflammation and offers therapeutic potential for IBD treatment. METHODS: We assessed the effect of oral spermidine administration on colitis severity in the T cell transfer colitis model in Rag2 -/- mice by analysis of endoscopy, histology, and molecular inflammation markers. The effects on the intestinal microbiome were determined by 16S sequencing of mouse feces. The impact on intestinal barrier integrity was evaluated in co-cultures of patient-derived macrophages with intestinal epithelial cells. RESULTS: Spermidine administration protected mice from intestinal inflammation in a dose-dependent manner. While T helper cell subsets remained unaffected, spermidine promoted anti-inflammatory macrophages and prevented the microbiome shift from Firmicutes and Bacteroides to Proteobacteria, maintaining a healthy gut microbiome. Consistent with spermidine as a potent activator of the anti-inflammatory molecule protein tyrosine phosphatase non-receptor type 2 (PTPN2), its colitis-protective effect was dependent on PTPN2 in intestinal epithelial cells and in myeloid cells. The loss of PTPN2 in epithelial and myeloid cells, but not in T cells, abrogated the barrier-protective, anti-inflammatory effect of spermidine and prevented the anti-inflammatory polarization of macrophages. CONCLUSION: Spermidine reduces intestinal inflammation by promoting anti-inflammatory macrophages, maintaining a healthy microbiome, and preserving epithelial barrier integrity in a PTPN2-dependent manner

Sikh and Muslim perspectives on kidney transplantation: phase 1 of the DiGiT project – a qualitative descriptive study

Objectives Kidney transplantation offers patients better quality of life and survival compared with dialysis. The risk of end stage renal disease is higher among ethnic minorities and they experience longer wait times on transplant lists. This inequality stems from a high need for kidney transplantation combined with a low rate of deceased donation among ethnic minority groups. This study aimed to explore the perspectives around living donor kidney transplantation of members of the Sikh and Muslim communities with an aim to develop a digital intervention to overcome any barriers. Design A qualitative descriptive study using in person focus groups. Setting University Teaching Hospital and Transplant Centre. Participants Convenience sampling of participants from the transplant population. Three focus groups were held with 20 participants, all were of South Asian ethnicity belonging to the Sikh and Muslim communities. Methods Interviews were digitally audio-recorded and transcribed verbatim; transcripts were analysed thematically. Results Four themes were identified: (a) religious issues; (b) lack of knowledge within the community; (c) time; (d) cultural identification with transplantation. Conclusions Not only is the information given and when it is delivered important, but also the person giving the information is crucial to enhance consideration of live donor kidney transplantation. Information should be in a first language where possible and overtly align to religious considerations. A more integrated approach to transplantation counselling should be adopted which includes healthcare professionals and credible members of the target cultural group

Assessment of Sperm Morphometry in Evaluating Male Infertility

Background: Infertility is a complex issue affecting 15% of couples of reproductive age, with men accounting for 40%-50% of infertility cases. Semen analysis comprises various descriptive measures of sperm and seminal fluid to determine semen quality. Transforming qualitative descriptions of sperm deformities and shape changes into quantitative terms can aid in identifying sub-visual abnormalities. This study aimed to evaluate sperm morphometry parameters in both infertile and fertile men. Methods and Results: The study enrolled a total of 101 participants, divided into three groups: Group A included 38 subfertile patients with varicocele, Group B included 33 patients with idiopathic infertility (23 with asthenozoospermia and 10 with oligozoospermia), and Group C (the control group) included 30 healthy fertile men. The mean age of patients was 31.6±5.81, 31.3±6.0, and 29.47±4.27 years in Groups A, B, and C, respectively. Scrotal duplex examinations were performed to identify the presence of varicocele. Semen samples were collected following WHO Manual (2010). Semen dynamic and morphological analyses were conducted using CASA (Computer-Assisted Semen Analysis, MIRALAB, ISO9001, ISO13485). We found that sperm concentration, total sperm count, sperm progressive motility, and sperm progressive+non-progressive motility were significantly lower in Group A and Group B than in Group C (P=0.000 in all cases); however, there were no differences between Group A and Group B regarding these parameters (Table 5). The sperm morphology index was significantly lower in Group A than in Group C (P=0.0024); no differences were found between Group B and Group C and Group B and Group A. The mean value of the sperm deformity index was significantly lower in Group A than in Group C P=0.004). Conclusion: Our study highlights the significant association between sperm morphology and male infertility in varicocele and idiopathic subfertile males