Trial of an Inexpensive Training Simulation Model for Laparoscopic Appendicectomy.

Introduction Laparoscopic surgery is now the gold standard for many common procedures; however, there has been a lack of emphasis on laparoscopic training at the junior level. Simulation is an effective form of training in surgery, but surgical simulation models and courses can be expensive and inaccessible to medical students and foundation doctors. With procedures becoming more minimally invasive, it is key that we train laparoscopic skills at an earlier stage; and to do so, we need to remove the barriers of cost and accessibility. Our study aims to develop and assess the effectiveness of a simulated laparoscopic appendicectomy training model in developing laparoscopic knowledge, skills, and confidence in a cohort of foundation doctors. Methods A simulated mesoappendix model was fashioned from supermarket chicken wings with the bone removed, and it was put inside a laparoscopic box trainer with laparoscopic tools and equipment. This was trialed in a surgical-themed hub day for foundation doctors in the East of England Deanery, UK, and the simulated model was set up as a workshop following a teaching session detailing the steps of a laparoscopic appendicectomy. Participants completed questionnaires pre- and post-session to assess perceived skills, experience, and confidence in laparoscopic surgery, laparoscopic skills, and the usefulness of this training model. Results A total of 29 foundation doctors with limited formal surgical training completed the survey. The model is quick to prepare and assemble, costing around £0.30 ($0.40). Trainees found the model acceptable and helpful in developing their laparoscopic skills and knowledge of laparoscopic surgery. There was also an increase in self-perceived confidence in performing laparoscopic procedures under supervision. Discussion This modification to the model allows the dissection and division of a simulated mesoappendix using only laparoscopic scissors and forceps in a box trainer. This simulation model is a promising and inexpensive tool which can be used for early-stage laparoscopic training for medical students and junior doctors.

Results of shared learning of a new radiofrequency identification localization device-a UK iBRA-NET breast cancer localisation study.

INTRODUCTION: Localisation methods for surgical excision of impalpable breast lesions have advanced in recent years, with increasing utilization of new wire-free technologies. The Hologic LOCalizer™ radiofrequency identification (RFID) tag is one such device; however, as is the case when new technologies are first introduced, little is known about clinical experiences, potential complications, and learning used to overcome perioperative challenges when changing from guidewires to RFID tags. This study reports shared learning experiences of clinicians using the LOCalizer™ as part of the national iBRA-NET localisation study. METHODS: This mixed-methods study captured shared-learning themes relating to LOCalizer™ usage as part of a multicentre prospective registry study, which collected data on each LOCalizer™ placement. Prospective, anonymized clinical and demographic data were collected and managed using a Research Electronic Data Capture (REDCap) database. Shared learning was captured prospectively as part of the registry study between January 2021 and July 2022, combined with a virtual qualitative webinar-style focus group. Learning events were then coded, grouped by theme, and suggestions for practice were produced. RESULTS: Twenty-four UK breast units submitted data on 1188 patient records pertaining to RFID-guided localisation between January 2021 and July 2022, of which 59 (5.0%) included a shared-learning event. The virtual webinar was attended by 108 healthcare professionals, including oncoplastic breast surgeons and breast radiologists. Shared-learning themes were categorized into preoperative, intraoperative, and postoperative events. CONCLUSIONS: By sharing learning outcomes associated with localisation techniques in this paper, the aim is to shorten the learning curve and potential for adverse events for users new to the LOCalizer™ technique.

Treatment With LAU-7b Complements CFTR Modulator Therapy by Improving Lung Physiology and Normalizing Lipid Imbalance Associated With CF Lung Disease.

Cystic fibrosis (CF) is the most common autosomal recessive genetic disease in Caucasians, affecting more than 100,000 individuals worldwide. It is caused by pathogenic variants in the gene encoding CFTR, an anion channel at the plasma membrane of epithelial and other cells. Many CF pathogenic variants disrupt the biosynthesis and trafficking of CFTR or reduce its ion channel function. The most frequent mutation, loss of a phenylalanine at position 508 (F508del), leads to misfolding, retention in the endoplasmic reticulum, and premature degradation of the protein. The therapeutics available for treating CF lung disease include antibiotics, mucolytics, bronchodilators, physiotherapy, and most recently CFTR modulators. To date, no cure for this life shortening disease has been found. Treatment with the Triple combination drug therapy, TRIKAFTA®, is composed of three drugs: Elexacaftor (VX-445), Tezacaftor (VX-661) and Ivacaftor (VX-770). This therapy, benefits persons with CF, improving their weight, lung function, energy levels (as defined by reduced fatigue), and overall quality of life. We examined the effect of combining LAU-7b oral treatment and Triple therapy combination on lung function in a F508deltm1EUR mouse model that displays lung abnormalities relevant to human CF. We assessed lung function, lung histopathology, protein oxidation, lipid oxidation, and fatty acid and lipid profiles in F508deltm1EUR mice.

Lateral chest wall perforator flaps in partial breast reconstruction.

BACKGROUND: Breast conserving surgery (BCS) has been a standard procedure for the treatment of breast cancer instead of mastectomy whenever possible. Lateral chest wall perforator flaps are one of the volume replacement techniques that participate in increasing the rate of BCS especially in small- to moderate-sized breasts with good cosmetic outcome. In this study, we tried to evaluate the outcome of those flaps as an oncoplastic procedure instead of the conventional flaps. METHODS: This study included 26 patients who underwent partial mastectomy with immediate reconstruction using lateral chest wall perforator flaps in the period from October 2019 to November 2020. The operative time, techniques, and complications were recorded. The cosmetic outcome was assessed 3 months post-radiation therapy through a questionnaire and photographic assessment. RESULTS: Lateral intercostal artery perforator (LICAP), lateral thoracic artery perforator (LTAP) and combined flaps were performed in 24, 1, and 1 patients, respectively. The mean operative time was 129.6 ± 13.2 min. The flap length ranged from 10 to 20 cm and its width from 5 to 9 cm. Overall patients' satisfaction was observed to be 88.5% as either excellent or good and the photographic assessment was 96.2% as either excellent or good. CONCLUSIONS: Lateral chest wall perforator flaps are reliable and safe option for partial breast reconstruction with an acceptable aesthetic outcome. In the era of oncoplastic breast surgery, they deserve to gain attention especially with the advantages of some modifications added to the classic technique.

The impact of Oncotype DX testing on adjuvant chemotherapy decision making in 1-3 node positive breast cancer.

BACKGROUND: Oncotype DX testing has reduced the use of adjuvant chemotherapy in node-negative early breast cancer but less is known about its impact in node positive patients. AIM: This study aimed to investigate the impact of Oncotype DX gene assay testing on the decision to offer adjuvant chemotherapy in oestrogen positive, human epidermal growth factor receptor 2 negative, 1-3 lymph node positive patients. METHODS: Retrospective review of all node positive patients who underwent Oncotype DX testing at a single centre. Clinicopathological data, as well as estimated survival benefit data (from the PREDICT tool), was evaluated by a multidisciplinary group of surgeons and oncologists. Treatment decisions based on clinicopathological data were compared to recurrence scores (RS). A cut off RS > 30 was used to offer adjuvant chemotherapy. RESULTS: The 69 patients were identified, of which 9 (13%) had an RS > 30 and assigned a high-genomic risk of recurrence. The 32 patients (46.4%) were offered adjuvant chemotherapy. Overall based on the use of the RS, the decision to offer adjuvant chemotherapy changed in 36% of patients, and ultimately 24 patients (34.7%) would have been spared chemotherapy. CONCLUSION: Using clinicopathological data alone to make decisions regarding adjuvant chemotherapy in node positive breast cancer leads to overtreatment. Additional information on tumour biology as assessed by the Oncotype DX RS helps to select those patients who will benefit from adjuvant chemotherapy and spare patients from unnecessary chemotherapy.

Tumor Mutation Burden Prediction Model in Egyptian Breast Cancer patients based on Next Generation Sequencing.

OBJECTIVES: This study aimed to identify the tumor mutation burden (TMB) value in Egyptian breast cancer (BC) patients. Moreover, to find the best TMB prediction model based on the expression of estrogen (ER), progesterone (PR), human epidermal growth factor receptor 2 (HER-2), and proliferation index Ki-67. METHODS: The Ion AmpliSeq Comprehensive Cancer Panel was used to determine TMB value of 58 Egyptian BC tumor tissues. Different machine learning models were used to select the optimal classification model for prediction of TMB level according to patient's receptor status. RESULTS: The measured TMB value was between 0 and 8.12/Mb. Positive expression of ER and PR was significantly associated with TMB ≤ 1.25 [(OR =0.35, 95% CI: 0.04-2.98), (OR = 0.17, 95% CI= 0.02-0.44)] respectively. Ki-67 expression positive was significantly associated with TMB >1.25 than those who were Ki-67 expression negative (OR = 9.33, 95% CI= 2.07-42.18). However, no significant differences were observed between HER2 positive and HER2 negative groups. The optimized logistic regression model was TMB = -27.5 -1.82 ER - 0.73 PR + 0.826 HER2 + 2.08 Ki-67. CONCLUSION: Our findings revealed that TMB value can be predicted based on the expression level of ER, PR, HER-2, and Ki-67.

PPAR agonists as effective adjuvants for COVID-19 vaccines, by modifying immunogenetics: a review of literature.

BACKGROUND: Several coronavirus vaccine have been fast-tracked to halt the pandemic, the usage of immune adjuvants that can boost immunological memory has come up to the surface. This is particularly of importance in view of the rates of failure of seroconversion and re-infection after COVID-19 infection, which could make the vaccine role and response debatable. Peroxisome proliferator-activated receptors (PPARs) have an established immune-modulatory role, but their effects as adjuvants to vaccination have not been explored to date. It is increasingly recognized that PPAR agonists can upregulate the levels of anti-apoptotic factors such as MCL-1. Such effect can improve the results of vaccination by enhancing the longevity of long-lived plasma cells (LLPCs). The interaction between PPAR agonists and the immune system does not halt here, as T cell memory is also stimulated through enhanced T regulatory cells, antagonizing PD-L1 and switching the metabolism of T cells to fatty acid oxidation, which has a remarkable effect on the persistence of T memory cells. What is even of a more significant value is the effect of PPAR gamma on ensuring a profound secretion of antibodies upon re-exposure to the offending antigen through upregulating lipoxin B4, therefore potentially assisting the vaccine response and deterring re-infection. SHORT CONCLUSION: In view of the above, we suggest the use of PPAR as adjuvants to vaccines in general especially the emerging COVID-19 vaccine due to their role in enhancing immunologic memory through DNA-dependent mechanisms.

Inflammatory Breast Cancer in Men: A rare clinical case report and a literature review.

INTRODUCTION AND IMPORTANCE: The initial misdiagnosis and delayed treatment for inflammatory breast cancer in men is brought about by its rarity and lack of readily available guidelines on pathways. CASE PRESENTATION: A 78-year-old male presented to the breast clinic with an abscess and was later diagnosed with inflammatory breast cancer. He presented with an abscess and was initially treated with antibiotics. Imaging showed a large left breast mass consistent with inflammatory carcinoma with axillary lymph node involvement. Patient was started on Tamoxifen as a bridge for surgery with no response. He eventually had a mastectomy and axillary clearance with the histology confirming the diagnosis and tumour emboli in the lymphatic vessels. Chemotherapy, radiation and dual hormone therapy were included in the adjuvant treatment plan. Two episodes of neutropenic sepsis led to completing only five out of six planned chemotherapy cycles. CLINICAL DISCUSSION: A review of literature and the reported cases was done by the team to contribute to the little information published about the disease and its management. The presented to the breast clinic during the height of the SARS- CoV-2 pandemic. The global impact of SARS-CoV-19 made surgical teams find ways to lessen elective lists to give way for patients affected during the pandemic. CONCLUSION: Very few cases of inflammatory breast cancer have been reported in men. The diagnosis can be missed leading to delay in management. Management can be challenging and complex.

The implications of a pathological complete response of the primary tumour after neoadjuvant chemotherapy for breast cancer on axillary surgery.

BACKGROUND: Management of the node-positive axilla after neoadjuvant chemotherapy is controversial. The aim of this study is to predict the group of patients who may require a less invasive approach for axillary management. One possible group are patients with pathological complete response of the primary after chemotherapy. RESULTS: A unicentral retrospective cohort study including all breast cancer patients with axillary node metastases at presentation who received neoadjuvant chemotherapy resulting in pathological complete response. Pathological complete response in the axillary lymph nodes was recorded. A correlation between the response in the primary tumour and the lymph nodes was assessed. A subgroup analysis was conducted for different biological groups. Complete response was seen in the axillary nodes in 80.5% of patients. Patients with lobular cancer were less likely to show a similar response in the axilla as the primary tumour (p = 0.077). A higher incidence of axillary response was observed in HER2-positive tumours (p = 0.082). All patients with grade 3 tumours achieved complete response in the axilla (p = 0.094). Patients with negative or weak positive hormone receptor status had a significantly higher rate of complete response in the axilla compared to strongly positive hormone receptor status (OR, 7.8; 95% CI, 1.7-34.5; p = 0.007). CONCLUSION: A less invasive axillary surgery may be safely recommended in selected group of node-positive patients after neoadjuvant chemotherapy when the primary tumour shows complete response. This group may include HER2-positive, ER-negative and grade 3 tumours. Less response is expected in ER-positive and lobular carcinoma even with complete response in the primary.

Treatment of Allergic Asthma with Fenretinide Formulation (LAU-7b) Downregulates ORMDL Sphingolipid Biosynthesis Regulator 3 (Ormdl3) Expression and Normalizes Ceramide Imbalance.

Zona pellucida binding protein 2 (Zpbp2) and ORMDL sphingolipid biosynthesis regulator 3 (Ormdl3), mapped downstream of Zpbp2, were identified as two genes associated with airway hyper-responsiveness (AHR). Ormdl3 gene product has been shown to regulate the biosynthesis of ceramides. Allergic asthma was shown to be associated with an imbalance between very-long-chain ceramides (VLCCs) and long-chain ceramides (LCCs). We hypothesized that Fenretinide can prevent the allergic asthma-induced augmentation of Ormdl3 gene expression, normalize aberrant levels of VLCCs and LCCs, and treat allergic asthma symptoms. We induced allergic asthma by house dust mite (HDM) in A/J WT mice and Zpbp2 KO mice expressing lower levels of Ormdl3 mRNA than WT. We investigated the effect of a novel formulation of Fenretinide, LAU-7b, on the AHR, inflammatory cell infiltration, mucus production, IgE levels, and ceramide levels. Although lower Ormdl3 expression, which was observed in Zpbp2 KO mice, was associated with lower AHR, allergic Zpbp2 KO mice were not protected from inflammatory cell infiltration, mucus accumulation, or aberrant levels of VLCCs and LCCs induced by HDM. LAU-7b treatment protects both the Zpbp2 KO and WT mice. The treatment significantly lowers the gene expression of Ormdl3, normalizes the VLCCs and LCCs, and corrects all the other phenotypes associated with allergic asthma after HDM challenge, except the elevated levels of IgE. LAU-7b treatment prevents the augmentation of Ormdl3 expression and ceramide imbalance induced by HDM challenge and protects both WT and Zpbp2 KO mice against allergic asthma symptoms. SIGNIFICANCE STATEMENT: Compared with A/J WT mice, KO mice with Zpbp2 gene deletion have lower AHR and lower levels of Ormdl3 expression. The novel oral clinical formulation of Fenretinide (LAU-7b) effectively lowers the AHR and protects against inflammatory cell infiltration and mucus accumulation induced by house dust mite in both Zpbp2 KO and WT A/J mice. LAU-7b prevents Ormdl3 overexpression in WT allergic mice and corrects the aberrant levels of very-long-chain and long-chain ceramides in both WT and Zpbp2 KO allergic mice.

Age-Dependent Progression in Lung Pathophysiology can be Prevented by Restoring Fatty Acid and Ceramide Imbalance in Cystic Fibrosis.

PURPOSE: Cystic fibrosis (CF) is a progressive disease which causes a continuous decline in lung capacity with age. Our study aimed to investigate the age-dependent deterioration in lung function and the effects of treatment with Fenretinide formulation (LAU-7b) in Cftr knockout (KO) mice. METHODS: Non-invasive whole-body plethysmography (WBP) was done to measure the baseline lung functions of KO and wild-type (WT) mice at the ages of 2 and 4 months. Mice were then treated for 21 days with PBS or 10 mg/kg/day LAU-7b initiated at 4 and 7 months. Standard airway resistance measurements, haematoxylin and eosin staining, and analysis of lipids, and markers of oxidation were performed. RESULTS: The 4- and 7-month-old KO mice had significantly higher lung enhanced pause (Penh) and resistance values than age-matched WT mice and 2-month-old KO mice. Likewise, analysis of ceramides showed that PBS-treated mice had higher levels of long-chain ceramides (LCCs; C14-C18) and lower levels of very-long-chain ceramides (VLCCs; C24-C26) compared to LAU-7b-treated mice. Cftr KO mice displayed markedly greater inflammatory cell infiltration and epithelial hyperplasia at the ages of 2, 4, and 7 months compared to WT. LAU-7b treatment significantly diminished this cellular infiltration and epithelial hyperplasia compared to PBS-treated mice. CONCLUSION: Our results demonstrate a progressive age-dependent decline in lung function in Cftr KO mice. Treatment with LAU-7b corrects the lipid imbalance observed in the aging KO and WT mice and, more importantly, inhibits the age-dependent deterioration in lung physiology and histopathology.

Efficacy of Optimized Treatment Protocol Using LAU-7b Formulation against Ovalbumin (OVA) and House Dust Mite (HDM) -Induced Allergic Asthma in Atopic Hyperresponsive A/J Mice.

PURPOSE: To assess the efficacy of the novel clinical formulation of fenretinide (LAU-7b) for the treatment of allergic asthma. To study the association between LAU-7b treatment in allergic asthma and the modulation of very long chain ceramides (VLCC). METHODS: We used two allergens (OVA and HDM) to induce asthma in mouse models and we established a treatment protocol with LAU-7b. The severity of allergic asthma reaction was quantified by measuring the airway resistance, quantifying lung inflammatory cell infiltration (Haematoxylin and eosin stain) and mucus production (Periodic acid Schiff satin). IgE levels were measured by ELISA. Immunophenotyping of T cells was done using Fluorescence-activated cell sorting (FACS) analysis. The analysis of the specific species of lipids and markers of oxidation was performed using mass spectrometry. RESULTS: Our data demonstrate that 10 mg/kg of LAU-7b was able to protect OVA- and HDM-challenged mice against increase in airway hyperresponsiveness, influx of inflammatory cells into the airways, and mucus production without affecting IgE levels. Treatment with LAU-7b significantly increased percentage of regulatory T cells and CD4+ IL-10-producing T cells and significantly decreased percentage of CD4+ IL-4-producing T cells. Our data also demonstrate a strong association between the improvement in the lung physiology and histology parameters and the drug-induced normalization of the aberrant distribution of ceramides in allergic mice. CONCLUSION: 9 days of 10 mg/kg of LAU-7b daily treatment protects the mice against allergen-induced asthma and restores VLCC levels in the lungs and plasma.

Endocannabinoid system in irritable bowel syndrome and cannabis as a therapy.

Irritable bowel syndrome (IBS) global burden is underestimated despite its high prevalence. It's a gastrointestinal disease having obscure pathophysiology with multiple therapies yet unsatisfactory remedies. The Endocannabinoid system (ECS) of our body plays a key role in maintaining normal physiology of the gastrointestinal tract as well as involves abnormalities including functional diseases like IBS. This review highlights the importance of the Endocannabinoid system, its connections with the normal gastrointestinal functions and abnormalities like IBS. It also discusses the role of cannabis as medical therapy in IBS patients. A literature search for articles related to endocannabinoids in IBS and medical cannabis in PubMed and Google Scholar was conducted. The studies highlighted the significant participation of ECS in IBS. However, the breach in obtaining the promising therapeutic model for IBS needed further investigation in ECS and uncover other treatments for IBS. This review summarizes ECS, highlights the relationship of ECS with IBS and explores cannabis as a potential therapy to treat IBS.

Fenretinide favorably affects mucins (MUC5AC/MUC5B) and fatty acid imbalance in a manner mimicking CFTR-induced correction.

Cystic fibrosis (CF) is the most common genetic disease in Caucasians. CF is manifested by abnormal accumulation of mucus in the lungs, which serves as fertile ground for the growth of microorganisms leading to recurrent infections and ultimately, lung failure. Mucus in CF patients consists of DNA from dead neutrophils as well as mucins produced by goblet cells. MUC5AC mucin leads to pathological plugging of the airways whereas MUC5B has a protective role against bacterial infection. Therefore, decreasing the level of MUC5AC while maintaining MUC5B intact would in principle be a desirable mucoregulatory treatment outcome. Fenretinide prevented the lipopolysaccharide-induced increase of MUC5AC gene expression, without affecting the level of MUC5B, in a lung goblet cell line. Additionally, fenretinide treatment reversed the pro-inflammatory imbalance of fatty acids by increasing docosahexaenoic acid and decreasing the levels of arachidonic acid in a lung epithelial cell line and primary leukocytes derived from CF patients. Furthermore, for the first time we also demonstrate the effect of fenretinide on multiple unsaturated fatty acids, as well as differential effects on the levels of long- compared to very-long-chain saturated fatty acids which are important substrates of complex phospholipids. Finally, we demonstrate that pre-treating mice with fenretinide in a chronic model of P. aeruginosa lung infection efficiently decreases the accumulation of mucus. These findings suggest that fenretinide may offer a new approach to therapeutic modulation of pathological mucus production in CF.

Evaluation of YouTube as a reliable source for patient education on aortic valve stenosis.

BACKGROUND: Aortic stenosis (AS) is a prevalent disease in the elderly population and has been a public health concern for decades. YouTube is currently being used for obtaining healthcare related information. We evaluated the quality of information about AS on YouTube for patient education. METHODS: YouTube was queried for the search phrases "aortic valve stenosis", "aortic valve replacement", "transcatheter aortic valve replacement" and "TAVR". Videos were assessed for their reliability and content with two five-point scales. They were categorized into groups according to usefulness and uploader source. All videos were assessed for audience interaction. Videos were viewed and analyzed by 2 independent investigators. Conflicts were resolved by a third investigator. RESULTS: Search phrases yielded 69,300 videos, among which, 120 videos were evaluated and 85 videos were included in the final analysis. Of the 85 videos, only 45 videos (53%) were found to be useful while 40 videos (47%) were found to be non-useful. The majority (98%) of the useful videos were uploaded by professional sources. Overall, videos uploaded by non-professional sources had higher number of views (23,553 vs. 11,110, P≤0.001) despite of being less useful (14% vs. 67%, P<0.001) when compared to videos uploaded by professional sources. CONCLUSIONS: There is a potential to increase public awareness about aortic valve stenosis and the available treatment options by utilizing YouTube. Professional societies are encouraged to provide more useful material that can deliver comprehensive and reliable information in an entertaining and intuitive manner to the public.

ETS-related gene (ERG) expression as a predictor of oncological outcomes in patients with high-grade prostate cancer treated with primary androgen deprivation therapy: a cohort study.

OBJECTIVES: To determine whether ETS-related gene (ERG) expression can be used as a biomarker to predict biochemical recurrence and prostate cancer-specific death in patients with high Gleason grade prostate cancer treated with androgen deprivation therapy (ADT) as monotherapy. METHODS: A multicentre retrospective cohort study identifying 149 patients treated with primary ADT for metastatic or non-metastatic prostate cancer with Gleason score 8-10 between 1999 and 2006. Patients planned for adjuvant radiotherapy at diagnosis were excluded. Age at diagnosis, ethnicity, prostate-specific antigen and Charlson-comorbidity score were recorded. Prostatic tissue acquired at biopsy or transurethral resection surgery was assessed for immunohistochemical expression of ERG. Failure of ADT defined as prostate specific antigen nadir +2. Vital status and death certification data determined using the UK National Cancer Registry. Primary outcome measures were overall survival (OS) and prostate cancer specific survival (CSS). Secondary outcome was biochemical recurrence-free survival (BRFS). RESULTS: The median OS of our cohort was 60.2 months (CI 52.0 to 68.3). ERG expression observed in 51/149 cases (34%). Multivariate Cox proportional hazards analysis showed no significant association between ERG expression and OS (p=0.41), CSS (p=0.92) and BRFS (p=0.31). Cox regression analysis showed Gleason score (p=0.003) and metastatic status (p<1×10-5) to be the only significant predictors of prostate CSS. CONCLUSIONS: No significant association was found between ERG status and any of our outcome measures. Despite a limited sample size, our results suggest that ERG does not appear to be a useful biomarker in predicting response to ADT in patients with high risk prostate cancer.

Depletion of BAFF cytokine exacerbates infection in Pseudomonas aeruginosa infected mice.

BACKGROUND: Cystic fibrosis (CF) is a genetic disease characterized by chronic inflammation of the lungs that is ineffective at clearing pathogens. B-cell activating factor (BAFF), a cytokine involved in the development of B-cells, is known to be elevated in CF patients with subclinical infections. We postulate that the elevated BAFF levels in CF patients might be triggered by Pseudomonas aeruginosa infection and it might play a protective role in the regulation of lung responses to infection. METHODS: To address this hypothesis, we used a well characterized model of CFTR.KO mice infected with a clinical strain of P. aeruginosa (PA508). We quantified cell types with flow cytometry, concentration of cytokines by ELISA tests, bacterial load by colony counting and lung physiology by metacholine-induced lung resistance. RESULTS: Our data demonstrates that BAFF is not elevated in uninfected CF mice, and infection with Pseudomonas leads to significant induction of this regulatory cytokine. We also demonstrate that the maintenance of BAFF levels and its induction during the infection is important for clearance of Pseudomonas infection as its depletion during the course of infection leads to decrease in the resolution of infection both in WT and CFTR-KO mice. Interestingly, the depletion of BAFF not only results in a depletion of B cells numbers but also to a significant decrease in the number of regulatory T cells in the non-infected lungs. CONCLUSIONS: Overall, our data demonstrate for the first time that BAFF is an important regulatory molecule helping to maintain the immunological response to infection and clearance of lung infection.

Oncologic and Cosmetic Outcomes of Oncoplastic Breast Surgery in Locally Advanced Breast Cancer After Neoadjuvant Chemotherapy, Experience from a Developing Country.

Oncoplastic surgery (OPS) has emerged as a new approach for extending breast conserving surgery (BCS) possibilities, reducing both mastectomy and re-excision rates, while avoiding breast deformities. OPS is based upon the integration of plastic surgery techniques for immediate reshaping after wide excision for breast cancer. This is a prospective feasibility cohort study of oncoplastic breast surgery after neoadjuvant chemotherapy that was carried at the National Cancer Institute, Cairo University and included 70 patients. The primary outcome was the local recurrence rate. Secondary outcomes included survival and margins obtained as well as cosmetic outcomes. Survival analysis was performed. Oncoplastic breast surgery did not compromise oncologic safety in the patients included in the study. It even allowed wider margins of resection which could be associated with better oncologic outcomes. At the same time, it gave a better cosmetic outcome and therefore higher patient satisfaction. Oncoplastic breast surgery includes a wide spectrum of surgical techniques, ranging from the basic level I techniques in breast conserving surgery to the more complex procedures of level II which are broadly classified into volume replacement (therapeutic mammoplasty) and volume displacement procedures. We suggest that oncoplastic breast surgery techniques should be the standard of care in breast surgery. They are the basis for breast conserving surgery techniques in early breast cancer. In our experience, oncoplastic surgery is feasible in locally advanced tumours after downstaging with neoadjuvant chemotherapy without compromising the oncologic safety.

Difference in plaque characteristics of coronary culprit lesions in a cohort of Egyptian patients presented with acute coronary syndrome and stable coronary artery disease: An optical coherence tomography study.

AIMS: This study was designed to utilize frequency-domain optical coherence tomography (FD-OCT) for assessment of plaque characteristics and vulnerability in patients with acute coronary syndrome (ACS) compared to stable coronary artery disease (SCAD). METHODS AND RESULTS: We enrolled 48 patients; divided into an ACS-group (27 patients) and SCAD-group (21 patients) according to their clinical presentation. Hypertension and diabetes mellitus were more prevalent in SCAD group. Patients with ACS showed higher frequency of lipid-rich plaques (96.3% vs. 66.7%, P = .015), lower frequency of calcium plaques (7.4% vs. 57.1%, P < .001), and fibrous plaques (14.8% vs. 81%, P < .001) when compared with SCAD patients. The TCFA (defined as lipid-rich plaque with cap thickness <65 µm) identified more frequently (33.3% vs. 14.3%, P = .185), with a trend towards thinner median fibrous cap thickness (70 (50-180) µm vs. 100 (50-220) µm, P = .064) in ACS group. Rupture plaque (52% vs. 14.3%, P = .014), plaque erosion (18.5% vs. 0%, P = .059) and intracoronary thrombus (92.6% vs. 14.3%, P < .001) were observed more frequently in ACS group, while cholesterol crystals were identified frequently in patients with SCAD (0.0% vs. 33.3%, P = .002). CONCLUSION: The current FD-OCT study demonstrated the differences of plaque morphology and identified distinct lesion characteristics between patients with ACS and those with SCAD. These findings could explain the clinical presentation of patients in both groups.

Loss of the zona pellucida-binding protein 2 (Zpbp2) gene in mice impacts airway hypersensitivity and lung lipid metabolism in a sex-dependent fashion.

The human chromosomal region 17q12-q21 is one of the best replicated genome-wide association study loci for childhood asthma. The associated SNPs span a large genomic interval that includes several protein-coding genes. Here, we tested the hypothesis that the zona pellucida-binding protein 2 (ZPBP2) gene residing in this region contributes to asthma pathogenesis using a mouse model. We tested the lung phenotypes of knock-out (KO) mice that carry a deletion of the Zpbp2 gene. The deletion attenuated airway hypersensitivity (AHR) in female, but not male, mice in the absence of allergic sensitization. Analysis of the lipid profiles of their lungs showed that female, but not male, KO mice had significantly lower levels of sphingosine-1-phosphate (S1P), very long-chain ceramides (VLCCs), and higher levels of long-chain ceramides compared to wild-type controls. Furthermore, in females, lung resistance following methacholine challenge correlated with lung S1P levels (Pearson correlation coefficient 0.57) suggesting a link between reduced AHR in KO females, Zpbp2 deletion, and S1P level regulation. In livers, spleens and blood plasma, however, VLCC, S1P, and sphingosine levels were reduced in both KO females and males. We also find that the Zpbp2 deletion was associated with gain of methylation in the adjacent DNA regions. Thus, we demonstrate that the mouse ortholog of ZPBP2 has a role in controlling AHR in female mice. Our data also suggest that Zpbp2 may act through regulation of ceramide metabolism. These findings highlight the importance of phospholipid metabolism for sexual dimorphism in AHR.