Analgesic efficacy of inter-semispinal fascial plane block in Patients undergoing Cervical Spine Surgery through Posterior Approach: a randomized controlled trial.

BACKGROUND: Posterior cervical spine surgery is commonly performed in elderly patients with significant comorbidities and is considered one of the most painful surgical procedures. Accordingly, perioperative pain management during posterior cervical spine surgery represents a unique challenge for anesthesiologists. Inter-semispinal plane block (ISPB) represents a promising analgesic technique for spine surgery through the blockade of the dorsal rami of the cervical spinal nerves. The present study aimed to investigate the analgesic effect of bilateral ISPB as an opioid-sparing nerve block technique for posterior cervical spine surgeries. METHODS: This prospective randomized controlled trial enrolled 52 patients planned for cervical spine surgery via the posterior approach. Patients were randomly assigned to one of two groups in a one-to-one ratio, with 26 patients allocated to the block group (ISPB) who received general anesthesia preceded by bilateral ISP using 20 mL 0.25% bupivacaine on each side and the remaining 26 patients allocated to the control group who received general anesthesia only. The primary outcome was total perioperative opioid consumption through two co-primary outcomes, i.e. total amount of fentanyl administered intraoperatively and total morphine consumption during the first 24 hours postoperatively. The secondary outcomes included intraoperative hemodynamic parameters, assessment of numerical rating scores (NRS) during the first 24 hours postoperatively, time to first rescue analgesia and opioid-related side effects. RESULTS: A significantly lower amount of intraoperative fentanyl was administered in the ISPB group (median, 175 µg; range, 110-220 µg] compared to the control group [median, 290 µg; range 110-350 µg). Patients in the ISPB group consumed significantly lower doses of morphine (median, 7 mg; range, 5-12 mg]) within the first 24 h postoperatively compared to the control group (median, 12 mg; range, 8-21 mg). In addition, NRS values were significantly lower in the ISPB group during the first 12 h postoperatively than in the control group. No significant differences in mean arterial pressure (MAP) or heart rate (HR) were observed between intraoperative time points in the ISPB group. However, a significant increase in MAP was observed during surgery in the control group (p < 0.001). The incidence of opioid side effects such as nausea, vomiting, and sedation was significantly greater in the control group compared to the ISPB group. CONCLUSIONS: Inter-semispinal plane block (ISPB) represents an effective analgesic technique and reduces opioid consumption in both intra- and postoperative settings. Moreover, the ISPB could significantly decrease opioid-associated side effects.

A Randomized Trial of Autologous Chondrocyte Implantation Versus Alternative Forms of Surgical Cartilage Management in Patients With a Failed Primary Treatment for Chondral or Osteochondral Defects in the Knee.

BACKGROUND: There are limited randomized controlled trials with long-term outcomes comparing autologous chondrocyte implantation (ACI) versus alternative forms of surgical cartilage management within the knee. PURPOSE: To determine at 5 years after surgery whether ACI was superior to alternative forms of cartilage management in patients after a failed previous treatment for chondral or osteochondral defects in the knee. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: In total, 390 participants were randomly assigned to receive either ACI or alternative management. Patients aged 18 to 55 years with one or two symptomatic cartilage defects who had failed 1 previous therapeutic surgical procedure in excess of 6 months prior were included. Dual primary outcome measures were used: (1) patient-completed Lysholm knee score and (2) time from surgery to cessation of treatment benefit. Secondary outcome measures included International Knee Documentation Committee and Cincinnati Knee Rating System scores, as well as number of serious adverse events. Analysis was performed on an intention-to-treat basis. RESULTS: Lysholm scores were improved by 1 year in both groups (15.4 points [95% CI, 11.9 to 18.8] and 15.2 points [95% CI, 11.6 to 18.9]) for ACI and alternative, with this improvement sustained over the duration of the trial. However, no evidence of a difference was found between the groups at 5 years (2.9 points; 95% CI, -1.8 to 7.5; P = .46). Approximately half of the participants (55%; 95% CI, 47% to 64% with ACI) were still experiencing benefit at 5 years, with time to cessation of treatment benefit similar in both groups (hazard ratio, 0.97; 95% CI, 0.72 to 1.32; P > .99). There was a differential effect on Lysholm scores in patients without previous marrow stimulation compared with those with marrow stimulation (P = .03; 6.4 points in favor of ACI; 95% CI, -0.4 to 13.1). More participants experienced a serious adverse event with ACI (P = .02). CONCLUSION: Over 5 years, there was no evidence of a difference in Lysholm scores between ACI and alternative management in patients who had previously failed treatment. Previous marrow stimulation had a detrimental effect on the outcome of ACI. REGISTRATION: International Standard Randomised Controlled Trial Number: 48911177.

Safety and Efficacy of Ultrasound-Guided Combined Segmental Thoracic Spinal Epidural Anesthesia in Abdominal Surgeries and Laparoscopic Procedures: A Prospective Randomized Clinical Study.

Background: Thoracic segmental spinal anesthesia (SA) may be a good alternative to general anesthesia (GA) for abdominal operations and laparoscopic procedures, especially in high-risk patients. Objectives: The aim of this study was to investigate the safety and efficacy of thoracic segmental SA vs GA during abdominal operations and laparoscopic procedures. Methods: This study was conducted at our university hospital and involved a total of 46 patients who underwent abdominal operations and laparoscopic procedures. The study period spanned from January 15, 2022, to October 15, 2022. Patients were divided into 2 groups: Group 1 (n = 23) received standard GA, and group 2 (n = 23) received thoracic segmental SA. A combination of 10 mg of hyperbaric bupivacaine 0.5% and 25 µg of fentanyl was injected through the spinal needle. The epidural catheter was then threaded through the Tuohy needle after withdrawal of the spinal needle to keep only 4 cm up in the epidural space. Demographic data, both intra and postoperative hemodynamic parameters, were monitored. Postoperatively, pain in both groups was treated with intravenous (IV) morphine by patient controlled analgesia (PCA), PCA settings were 1 mg morphine/mL, no background infusion, bolus dose 2 mL and lockout interval 15 min. Postoperative, both resting VAS and VAS during cough were measured for all patients at fixed intervals, and all patients were followed up for postoperative complications. Results: No significant variation was found in demographic data. Intra and postoperative mean arterial pressure (MAP) and heart rate (HR) measurements were higher in group 1 than in group 2 but without a statistically significant difference (P < 0.029). Early postoperative VAS values and discharge time from the postanesthesia care unit (PACU) were significantly reduced in group 2 than in group 1 (P < 0.001). The number of patients asked for analgesia and total opioid consumption were substantially reduced in group 2 than in group 1. Also, the time of the first analgesia request and patient satisfaction were substantially greater in group 2 than in group 1. Conclusions: Combined thoracic spinal/epidural block results in stable hemodynamics, longer postoperative analgesia with fewer side effects, and greater surgeon and patient satisfaction in patients undergoing abdominal operations and laparoscopic procedures.

Evaluation of the outcome of a proposed more physiological bypass surgery technique in morbid obesity: Long term 3 years follows up.

Background: Obesity is a chronic condition that affects millions globally; consequently, bariatric surgery is the key to this serious issue. Bariatric procedures are rapidly expanding in number and methods to address the recognized problems. So, it would make a sense for surgeons and patients if there is a more physiological bypass surgery technique in Morbid obesity. This study aims to evaluate the outcome proposed technique. Patients and methods: The present study is a retrospective analysis on 256 participants subjected to the proposed bypass procedure from December 1999 to January 2017, the participants were followed up for an interval of 3years. Results: The findings of the present study revealed a significant Excess Weight Loss (EWL). In addition, patients experienced decreased calcium, iron, vitamin B12, Hemoglobin, zinc, and Prothrombin Concentration. However, three to six months after surgery, they experienced a significant improvement until they reached normal levels without any supplement by the end of 12,18 months, with a three-year follow-up. Conclusion: This proposed Bypass Operation aims to adequate digestions as well as selective absorption without inducing any vital deficit. Most of study's population showed no elements inadequacies, although few percentages emerged during the interval of maximal weight reduction, and it were transient and minimal. No minerals or vitamins were needed.

Ultrasound-guided Retrolaminar Block Versus Thoracic Epidural Analgesia for Pain Control Following Laparoscopic Cholecystectomy.

BACKGROUND: Anesthesiologists are always looking for a regional analgesic technique which is easy, safe, has a low complication rate, and provides satisfactory analgesia. A retrolaminar block is a recent modified paravertebral technique for analgesia in  thoracoabdominal procedures with a local anesthetic injected at the retrolaminar site. It has the advantage of being safe and easy compared with traditional thoracic epidural analgesia but is still under investigation. OBJECTIVE: This study aimed to compare ultrasound-guided bilateral retrolaminar block with ultrasound-guided thoracic epidural analgesia for pain relief after laparoscopic cholecystectomy. STUDY DESIGN: A prospective randomized double-blinded clinical study. SETTING: Academic University Hospitals. METHODS: Fifty-two adult patients were randomly allocated into 2 equal groups at the end of the surgery: Group R (n = 26) received a bilateral ultrasound-guided retrolaminar block with 20 mL of 0.25% bupivacaine and 5 µg/mL adrenaline (1:200000) in each side. Group T (n = 26) received ultrasound-guided thoracic epidural analgesia with 20 mL of 0.25% bupivacaine and 5 µg/mL adrenaline (1:200000). RESULTS: The Numeric Rating Scale  scores both at rest and during cough were statistically significantly lower in Group R compared with Group T at 30 minutes and one hour postoperatively. The pain scores were statistically significantly lower for about 4 hours in Group R group compared with 6 hours in Group T. The time for the first call of nalbuphine was highly statistically significantly shorter in Group R group (233.04 ± 5.27 minutes) compared with Group T (353.77 ± 5.16 minutes) (mean difference -120.37, (95% CI,  -123.6 to -117.8) P < 0.001. The total amount of nalbuphine consumption in the first 12 hours was statistically significantly decreased in Group T (17.31 ± 5.52 mg) compared with Group R (27.69 ± 5.52 mg) (Mean difference 10.4, 95% CI  7.3-13.5), P < 0.001. The total number of patients who developed nausea and vomiting were statistically significantly greater in Group T (9 patients) compared with Group R group (3 patients), P = 0.04. Moreover, hypotension was statistically significantly more common among patients in Group T group (10 patients) compared with Group R (3 patients), P = 0.025. Both groups were comparable regarding patient satisfaction. LIMITATIONS: There is limited literature in the field of the present study and sensory dermatome assessment, but this does not affect the results as we used an ultrasound-guided technique. CONCLUSIONS: A single injection retrolaminar block provides adequate postoperative pain relief for about 4 hours compared with a single shot thoracic epidural that lasts about 6 hours. Patient satisfaction with both techniques was the same; about two-thirds of the patients were satisfied or very satisfied with either block.

Recurrent cutaneous basal cell carcinoma after surgical excision: A retrospective clinicopathological study.

Background: Recurrence of basal cell carcinoma (BCC) after complete surgical excision is rarely reported. Risk factors for this negative outcome are not well-studied. We present the clinical and histological features of recurrent BCCs in our institution. Methods: All patients between January 2016 to December 2020 whose primary BCCs were excised with free surgical margins according to the histopathology report, and represented later with local recurrence were included. The medical files were retrieved to record patient's age, sex, sun exposure, tumor site, size, clinical diagnosis, histopathology variant of primary lesion, least free margin distance of the original lesion, and recurrence time. Results: Eighteen patients (11 males and 7 females ranged between 50 and 75 years old) fulfilled the inclusion criteria; all of their lesions were located in head and neck regions. The mean recurrence time was 31.2 months (11-86) and the histological variant was the same of primary in 17/18 patients. Primary tumors showed nodular subtype in 77.8% of patients and 55.6% of the primary tumors were less than 15 mm in diameter. Sun exposure history was given by 77.8% of patients while the rest of patients had non-significant exposure. All recurrent excised lesions were of free margin less than 4 mm. Conclusion: We found that the primary tumors of all studied recurrent BCCs were excised with surgical margins less than 4 mm. We recommend follow up for all excised BCCs either those of low or high risk histological variants. Tumor size does not appear a considerable risk factor for local recurrence.

Incidence and Risk Factors of Thyroid Malignancy in Patients with Toxic Nodular Goiter.

Background: Although hyperfunctioning thyroid disorders were thought to be protective against malignancy, some recent studies reported a high incidence of incidentally discovered cancer in patients with hyperfunctioning benign thyroid disorders. We performed this study to estimate the incidence and predictors of malignant thyroid disease in patients with toxic nodular goiter (TNG). Patients and Methods. The data of 98 patients diagnosed with TNG were reviewed (including toxic multinodular goiter SMNG and single toxic nodule STN). The collected data included patients age, gender, systemic comorbidities, family history of thyroid malignancy, previous neck radiation, type of disease (multinodular or single), size of the dominant nodule by the US, operative time, and detection of significant lymph nodes during operation. Based on the histopathological analysis, the cases were allocated into benign and malignant groups. Results: Malignancy was detected in 21 patients (21.43%). Although age distribution was comparable between the two groups, males showed a significant increase in association with malignancy. Medical comorbidities and family history of cancer did not differ between the two groups. However, TMNG showed a statistically higher prevalence in the malignant group. Operative data, including operative time and lymph node detection, were comparable between the two groups. On regression analysis, both male gender and TMNG were significant predictors of malignancy. Conclusion: The presence of thyroid hyperfunction is not a protective factor against malignancy, as malignancy was detected in about 1/5 of cases. Male gender and TMNG were significant risk factors of malignancy in such patients.

Incidence and factors associated with acute kidney injury among children with type 1 diabetes hospitalized with diabetic ketoacidosis: A prospective study.

BACKGROUND AND OBJECTIVES: Acute kidney injury (AKI) is frequent among critically ill children. This study aimed to assess the incidence and factors associated with AKI among children with type 1 diabetes mellitus (T1DM) hospitalized with diabetic ketoacidosis (DKA). METHODS: This prospective observational study was conducted at Sohag University Hospital, Egypt over 1 year. Children aged 6 months to 12 years, diagnosed with T1DM and hospitalized with the criteria of DKA were included. The study participants received intravenous fluid therapy and intravenous insulin infusion for DKA management. Serum creatinine levels were measured at admission, 24 and 48 h after admission. AKI was defined and staged using the Kidney Disease Improving Global Outcomes serum creatinine criteria. RESULTS: The study included 265 DKA episodes in 240 participants. AKI was found in 110 (41.5%) DKA episodes. Moderated to severe AKI developed in 41 (15.5%) episodes. Multivariate regression analysis revealed that age (adjusted odds ratio = 0.78, 95% confidence interval (CI): 0.69-0.89, p < 0.001), Glasgow-Coma scale (GCS) < 14 at admission (adjusted odds ratio = 4.66, 95% CI: 1.66-13.14, p = 0.004) and serum chloride level at 12 h (adjusted odds ratio = 1.10, 95% CI: 1.02-1.18, p = 0.01) were the most significant factors associated with moderate to severe AKI development. CONCLUSIONS: AKI is common among T1DM children hospitalized with DKA. Younger age, low GCS at hospital admission and increased serum chloride level during DKA management were associated with increased risk for moderate to severe AKI development.

Diurnal Variation of Real-Life Insulin Sensitivity Factor Among Children and Adolescents With Type 1 Diabetes Using Ultra-Long-Acting Basal Insulin Analogs.

Background: Estimation of insulin sensitivity factor (ISF) is essential for correction insulin doses calculation. This study aimed to assess real-life ISF among children and adolescents with type 1 diabetes using ultra-long-acting basal insulin analogs and to detect factors associated with ISF among those patients. Methods: This prospective observational study was conducted at Sohag University Hospital, Egypt, and included 93 participants aged 6-18 years, diagnosed with T1DM for at least 1 year and using insulin glargine 300 Units/mL or insulin degludec 100 Units/mL as basal insulin. The ISF, insulin-to-carbohydrate ratio (ICR) and insulin doses were initially assessed then adjusted as required. The participants were regularly contacted throughout the follow-up period. Glycemic control parameters were assessed after 3 months. Results: The ISF showed diurnal variation with higher correction dose requirements for the morning than for the rest of the day (p < 0.001). This pattern of diurnal variation was found in participants with different pubertal stages and in participants using either type of ultra-long acting basal insulin analogs. There was no significant difference between the ISF calculated according to the 1800 rule [1800/Total daily insulin dose (TDD)] and the morning ISF (p = 0.25). The 1800 rule-calculated ISF was significantly lower than the actual ISF for the afternoon (p < 0.001) and the evening (p < 0.001). ISF at different times of the day were significantly correlated with age, body mass index, pubertal stage, diabetes duration, TDD, and ICR. Multiple regression analysis revealed that ICR was the most significant factor associated with ISF. Linear regression analysis revealed that the ISF (in mg/dL) for any time of the day could be estimated as 5.14 × ICR for the same time of the day (coefficient = 5.14, 95% confidence interval: 5.10-5.19, R 2 = 0.95, p < 0.001). Conclusion: Diurnal variation of ISF that had to be considered for proper calculation of correction doses. This diurnal variation was found in children and adolescents with different pubertal stages. The 1800 rule was appropriate for the morning correction doses but not in the afternoon or the evening. The TDD and the ICR could be used for ISF estimation.

Short-term intermittent cigarette smoke exposure enhances alveolar type 2 cell stemness via fatty acid oxidation.

BACKGROUND: Cigarette smoke (CS) is associated with chronic obstructive pulmonary disease (COPD) and cancer. However, the underlying pathological mechanisms are not well understood. We recently reported that mice exposed to long-term intermittent CS for 3 months developed more severe emphysema and higher incidence of adenocarcinoma than mice exposed to long-term continuous CS for 3 months and long-term continuous CS exposure activated alveolar stem cell proliferation. However, the influence of variations in the CS exposure pattern in alveolar stem cell in unknown. Here, we exposed mice to 3 weeks of continuous or intermittent CS to identify whether different CS exposure patterns would result in differential effects on stem cells and the mechanisms underlying these potential differences. METHODS: Female mice expressing GFP in alveolar type 2 (AT2) cells, which are stem cells of the alveolar compartment, were exposed to mainstream CS via nasal inhalation. AT2 cells were collected based on their GFP expression by flow cytometry and co-cultured with fibroblasts in stem cell 3D organoid/colony-forming assays. We compared gene expression profiles of continuous and intermittent CS-exposed AT2 cells using microarray analysis and performed a functional assessment of a differentially expressed gene to confirm its involvement in the process using activator and inhibitor studies. RESULTS: AT2 cells sorted from intermittent CS-exposed mice formed significantly more colonies compared to those from continuous CS-exposed mice, and both CS-exposed groups formed significantly more colonies when compared to air-exposed cells. Comparative microarray analysis revealed the upregulation of genes related to fatty acid oxidation (FAO) pathways in AT2 cells from intermittent CS-exposed mice. Treatment of intermittent CS-exposed mice with etomoxir, an inhibitor of the FAO regulator Cpt1a, for 5 weeks resulted in a significant suppression of the efficiency of AT2 cell colony formation. In vitro treatment of naïve AT2 cells with a FAO activator and inhibitor further confirmed the relationship between FAO and AT2 stem cell function. CONCLUSIONS: Alveolar stem cell function was more strongly activated by intermittent CS exposure than by continuous CS exposure. We provide evidence that AT2 stem cells respond to intermittent CS exposure by activating stem cell proliferation via the activation of FAO.

Combined opioid free and loco-regional anaesthesia enhances the quality of recovery in sleeve gastrectomy done under ERAS protocol: a randomized controlled trial.

BACKGROUND: It is debatable whether opioid-free anaesthesia (OFA) is better suited than multimodal analgesia (MMA) to achieve the goals of enhanced recovery after surgery (ERAS) in patients undergoing laparoscopic sleeve gastrectomy. METHODS: In all patients, anaesthesia was conducted with an i.v. induction with propofol (2 mg. kg-1), myorelaxation with cisatracurium (0.15 mg.kg-1), in addition to an ultrasound-guided bilateral oblique subcostal transverse abdominis plane block. In addition, patients in the OFA group (n = 51) received i.v. dexmedetomidine 0.1 µg.kg-1 and ketamine (0.5 mg. kg-1) at induction, then dexmedetomidine 0.5 µg. kg-1.h-1, ketamine 0.5 mg.kg-1.h-1, and lidocaine 1 mg. kg-1.h-1 for maintenance, while patients in the MMA group (n = 52) had only i.v. fentanyl (1 µg. kg-1) at induction. The primary outcome was the quality of recovery assessed by QoR-40, at the 6th and the 24th postoperative hour. Secondary outcomes were postoperative opioid consumption, time to ambulate, time to tolerate oral fluid, and time to readiness for discharge. RESULTS: At the 6th hour, the QoR-40 was higher in the OFA than in the MMA group (respective median [IQR] values: 180 [173-195] vs. 185 [173-191], p < 0.0001), but no longer difference was found at the 24th hour (median values = 191 in both groups). OFA also significantly reduced postoperative pain and morphine consumption (20 mg [1-21] vs. 10 mg [1-11], p = 0.005), as well as time to oral fluid tolerance (238 [151-346] vs. 175 min [98-275], p = 0.022), and readiness for discharge (505 [439-626] vs. 444 min [356-529], p = 0.001), but did not influence time to ambulate. CONCLUSION: While regional anaesthesia achieved most of the intraoperative analgesia, avoiding intraoperative opioids with the help of this OFA protocol was able to improve several sensible parameters of postoperative functional recovery, thus improving our knowledge on the OFA effects. CLINICAL TRIAL NUMBER: Registration number NCT04285255.

Teaching "medical interview and physical examination" from the very beginning of medical school and using "escape rooms" during the final assessment: achievements and educational impact in Japan.

BACKGROUND: There is no consensus regarding the best time to teach two fundamental pillars of clinical medicine: medical interview and physical examination. We investigated the impacts of teaching the course "Medical Interview and Physical Examination" in Japan from the very beginning of medical school. In addition, we also evaluated the educational value of using "Escape Rooms", a series of timed, game-based scenarios using simulators, as a part of the final assessment of the course. METHODS: At the end of the course, the interview capabilities of 140 first year medical students at International University of Health and Welfare (Japan) were assessed by physicians who acted as simulated patients. Physical examination skills were assessed using the "Escape Room" team task method. Students also self-assessed their confidence in their physical examination skills pre and post "Escape Rooms." A day prior to the final assessment, students completed an anonymous course evaluation. RESULTS: The average global rating of the students' medical interview skills using a rating scale from 1 to 6 (1-fail 6-outstanding, no different from practicing junior physician's level) was 4.6. Twenty-two students scored the highest mark of 6. An average of 89% of "Escape Room" teams finished all the physical examination tasks correctly within the allotted time. All teams that could not finish in time completed all tasks correctly when given an additional 3 to 5 min. Students' self-assessed confidence in their physical examination skills increased from 49 to 73 (out of 100) pre and post "Escape Rooms." In the course evaluation questionnaire, 99% of students answered "this course enhanced their motivation" (response rate 89%) and 99% also answered "this course was interesting and useful" (response rate 86%). CONCLUSIONS: This descriptive study analyzing both quantitative and qualitative data showed that the course not only achieved the intended objectives of successfully conducting comprehensive medical interview and basic physical examination skills, but also enhanced student motivation. "Escape Rooms", used for the course assessment, in itself enhanced students' self-perceived physical examination skills and had an added educational value.

Effect of laparoscopic sleeve gastrectomy vs laparoscopic Roux-en-Y gastric bypass on weight loss in Egyptian patients with morbid obesity.

BACKGROUND: Bariatric surgical operation is taken into consideration to be the handiest remedy for extreme obesity. Durability is the main requirement for the broad usage of bariatric surgery. According to several factors, the present work tries to match the SG and RYGB techniques. METHODS: This is a retrospective work that studied 200 morbid obese patients randomized and categorized into two groups according to the treatment method: the laparoscopic sleeve gastrectomy (LSG) and LRYGB groups, within the period from 2014 to 2019 and matched weight dissipation, complications, quality of life, and adverse events. RESULTS: BMI had a mean value of 39.66 ± 3.770 kg/m2 in the RYGB group versus 39.38 ± 3.648 kg/m2. No significant differences were found according to comorbidity, height, and weight. There was no significant difference between the study groups according to complications and morbidity-no recorded unexpected histopathology results in the excised LSG specimens. CONCLUSION: There was no significant change in weight dissipation, fluctuations in comorbidities, increase in Quality of Life (QoL), and complications for pathological obesity patients according to the treatment methods of laparoscopic SG (sleeve gastrectomy) and RYGB at 2-years postoperative follow-up.

ADAM10 partially protects mice against influenza pneumonia by suppressing specific myeloid cell population.

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene (Adam10)flox/flox/Lyz2-Cre (Adam10ΔLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10ΔLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines, such as TNF-α, IL-1ß, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10ΔLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10ΔLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10ΔLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10ΔLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10ΔLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.

Effect of High Fat Diet on the Severity and Repair of Lung Fibrosis in Mice.

Lung fibrosis is a progressive fatal disease, and the underlying mechanisms remain unclear. These involve a combination of altered fibroblasts, excessive accumulation of extracellular matrix, inflammation, and aberrant activation of epithelial cells. Previously, we showed that high-fat diet (HFD) induces lung inflammation, aberrant activation of stem cells, and lung mitochondria impairment. Therefore, we hypothesized that HFD-induced changes would influence lung fibrosis. Mice were fed standard diet (SD) or HFD, administered bleomycin, then examined for fibrosis severity and the start of repair 3 weeks after injury, and for fibrosis repair/resolution 6-9 weeks after injury. At 3 weeks, no significant differences in inflammation and fibrosis severity were observed between SD- and HFD-fed mice. However, infiltration of alveolar type (AT)-2 cells and bronchioalveolar stem cells (BASCs) into the fibrotic areas (the start of repair) was impaired in HFD-fed mice. At 6 weeks, SD-fed mice showed near-complete resolution/repair of fibrosis and inflammation, while HFD-fed mice still showed residual fibrosis and inflammation. Infiltration of the fibrotic areas with AT2 cells was observed, but very few BASCs were detectable. At 9 weeks, mice from both groups showed complete resolution/repair of fibrosis and inflammation, indicating that HFD induced delayed, rather than failed, resolution of fibrosis and alveolar repair. To further confirm the direct role of enhanced fatty-acid oxidation (FAO) in delayed resolution/repair, we administered etomoxir, a FAO inhibitor, to HFD-fed mice for 3-6 weeks after bleomycin injury. Inhibition of FAO abolished the HFD-induced delay in alveolar repair and fibrosis resolution at both time points. In conclusion, after a fibrosis-inducing injury, HFD slows resolution of fibrosis/inflammation and delays alveolar repair by slowing the contribution of AT2 stem cells and abolishing the contribution of BASCs in the repair process. FAO activation appears to be involved in this delay mechanism; thus, inhibiting FAO may be useful in the treatment of lung injury and fibrosis.

Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer.

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9-FGFR axis as a therapeutic target for transdifferentiated SCLC. SIGNIFICANCE: This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.

Prevalence and factors associated with stunting among school children in Egypt.

BACKGROUND: Stunting adversely affects children's health and development. Few studies on the prevalence of stunting and factors associated with stunting have been done in Upper Egypt. AIMS: This study aimed to determine the prevalence of and factors associated with stunting in schoolchildren in Sohag, Egypt. METHODS: This was a cross-sectional study conducted in 2017 in Sohag governorate. Two public schools were randomly selected (one urban, one rural) and all children in these schools aged 4-12 years whose parents consented were included in the study. Parents were interviewed to collect data on child and family characteristics. The children were examined for vitamin deficiency, anaemia and parasitic infection, and body mass index was calculated. Multivariate logistic regression analysis was done to determine factors significantly associated with stunting; odds ratios (ORs) and 95% confidence intervals (CIs) are given. RESULTS: A total of 1786 children were included (response rate 69%), of whom 329 (18.4%) were stunted (-2 z-score and below). Factors significantly associated with stunting were: parasite infestation (OR = 1.8, 95% CI: 1.3-2.5), anaemia (OR = 1.7, 95% CI: 1.3-2.7), low body mass index (OR = 1.2, 95% CI: 1.1-1.3), frequent gastroenteritis (OR = 1.1, 95% CI: 1.06-1.2), first-cousin consanguinity of parents (OR = 1.3, 95% CI: 1.2-1.6) and familial short stature (OR = 1.5, 95% CI: 1.2-2.1). CONCLUSION: Screening and treatment of parasitic infestation, provision of iron/multivitamin supplementation and education on healthy nutrition should be part of school health programmes to prevent stunting in schoolchildren in Sohag.

Exposure to Cigarette Smoke Enhances the Stemness of Alveolar Type 2 Cells.

Chronic exposure to cigarette smoke (CS) causes chronic inflammation, oxidative stress, and apoptosis of epithelial cells, which results in destruction of the lung matrix. However, the mechanism by which the lung fails to repair the CS-induced damage, thereby succumbing to emphysema, remains unclear. Alveolar type 2 (AT2) cells comprise the stem cells of the alveolar compartments and are responsible for repairing and maintaining lung tissues. In this study, we examined the effect of chronic CS on AT2 stem cells. Adult mice expressing GFP in their AT2 cells were exposed to CS for > 3 months. Histological assessment showed that CS not only induced emphysematous changes but also increased the number of AT2 cells compared with that of air-exposed lungs. Assessment of sorted GFP+/AT2 cells via the stem cell three-dimensional organoid/colony-forming assay revealed that the number and size of the colonies formed by the CS-exposed AT2 stem cells were significantly higher than those of air-exposed control AT2 cells. Although CS-exposed lungs had more apoptotic cells, examination of the surviving AT2 stem cells in two-dimensional in vitro culture revealed that they developed a higher ability to resist apoptosis. Microarray analysis of CS-exposed AT2 stem cells revealed the upregulation of genes related to circadian rhythm and inflammatory pathways. In conclusion, we provide evidence that AT2 stem cells respond to chronic CS exposure by activating their stem cell function, thereby proliferating and differentiating faster and becoming more resistant to apoptosis. Disturbances in expression levels of several circadian rhythm-related genes might be involved in these changes.

ADAM17 protects against elastase-induced emphysema by suppressing CD62L+ leukocyte infiltration in mice.

Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease and is associated with chronic pulmonary inflammation caused by cigarette smoking, with contributions from immune cells such as neutrophils, macrophages, and lymphocytes. Although matrix metalloproteinases are well known to contribute to emphysema progression, the role of a disintegrin and metalloproteinase (ADAM) family proteins, other major metalloproteinases, in disease pathogenesis is largely unknown. ADAM17 is a major sheddase that cleaves various cell surface proteins, including CD62L, an adhesion molecule that plays a critical role in promoting the migration of immune cells to the site of inflammation. In the present study, we aimed to investigate the potential role of ADAM17 and CD62L in the development of elastase-induced emphysema. Control and Adam17flox/flox/Mx1-Cre (Adam17ΔMx1) mice (8-10 wk old) were intratracheally injected with 5 units of porcine pancreas elastase and monitored for 35 days after injection. Lung alveolar destruction was evaluated by analyzing the mean linear intercepts of lung tissue specimens and by histopathological examination. Mean linear intercepts data indicated that the degree of elastase-induced emphysema was significantly more severe in Adam17ΔMx1 mice. Furthermore, flow cytometry showed that CD62L+ neutrophil, CD62L+ macrophage, and CD62L+ B lymphocyte numbers were significantly increased in Adam17ΔMx1 mice. Moreover, the pharmacological depletion of CD62L+ cells with a CD62L-neutralizing antibody ameliorated the extent of emphysema in Adam17ΔMx1 mice. Collectively, these results suggest that ADAM17 possibly suppresses the progression of emphysema by proteolytically processing CD62L in immune cells and that ADAM17 and CD62L could be novel therapeutic targets for treating pulmonary emphysema.

Optimizing the in vitro colony-forming assay for more efficient delineation of the interaction between lung epithelial stem cells and their niche.

The use of in vitro 3D organoid/colony forming assay (CFA); which mimics the in vivo environment have provided insight into the mechanisms by which lung stem cells maintain and repair the lung. In recent years, the use of CFA has markedly expanded. However, variations among laboratories in lung cell isolation methods, media used, type, origin, and processing methods of mesenchymal cells used as feeders for the epithelial colonies, and terms utilized to describe and quantify the growing colonies, have caused difficulty in reproducing results among different labs. In this study, we compared several previously described methods for lung cell isolation and culture media, to identify their influence on retrieved cells and growing colonies. We also characterized the effect of freeze/thaw, and propagation of fibroblasts on their ability to support epithelial colonies. Importantly, we suggested markers to identify fibroblast subtypes that offer the best support to alveolar stem cell proliferation. Then, we used our optimized assay to confirm the in vitro identity of recently described epithelial progenitors. We also tested the effect of hyperoxia on lung stem cells, and examined the expression of the receptors for the SARS-COV-2 virus's entry into epithelial cells, on our organoids. In summary, our findings facilitate CFA standardization, help understand how niche cell variations influence growing colonies, and confirm some of the recently described lung stem cells.