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Postbariatric altered gastrointestinal (GI) anatomy/physiology may significantly harm oral drug absorption and overall bioavailability. In this work, sildenafil, the first phosphodiesterase-5 (PDE5) inhibitor, was investigated for impaired postbariatric solubility/dissolution and absorption; this research question is of particular relevance since erectile dysfunction (ED) is associated with higher body mass index (BMI). Sildenafil solubility was determined both in vitro and ex vivo, using pre- vs. postsurgery gastric contents aspirated from patients. Dissolution tests were done in conditions mimicking the stomach before surgery, after sleeve gastrectomy (post-SG, pH 5), and after one anastomosis gastric bypass (post-OAGB, pH 7). Finally, these data were included in physiologically based pharmacokinetic (PBPK) modelling (GastroPlus®) to simulate sildenafil PK before vs. after surgery. pH-dependent solubility was demonstrated with low solubility (0.3 mg/mL) at pH 7 vs. high solubility at pH 1–5, which was also confirmed ex vivo with much lower solubility values in postbariatric gastric samples. Hampered dissolution of all sildenafil doses was obtained under post-OAGB conditions compared with complete (100%) dissolution under both presurgery and post-SG conditions. PBPK simulations revealed delayed sildenafil absorption in postbariatric patients (increased tmax) and reduced Cmax, especially in post-OAGB patients, relative to a presurgery state. Hence, the effect of bariatric surgery on sildenafil PK is unpredictable and may depend on the specific bariatric procedure. This mechanistically based analysis suggests a potentially undesirable delayed onset of action of sildenafil following gastric bypass surgery. [ABSTRACT FROM AUTHOR]

[Display omitted] Anatomical/physiological gastrointestinal changes after bariatric surgery may influence the fate of orally administered drugs. Since non-selective NSAIDs are not well-tolerated post-surgery, selective cyclooxygenase-2 (COX-2) inhibitors may be important for these patients. In this work we investigated celecoxib, etoricoxib and etodolac, for impaired post-bariatric solubility/dissolution and absorption. Solubility was studied in-vitro, and ex-vivo in aspirated gastric contents from patients pre- vs. post-surgery. Dissolution was studied in conditions simulating pre- vs. post-surgery stomach. Finally, the experimental solubility data were used in physiologically-based biopharmaceutics model (PBBM) (GastroPlus®) to simulate pre- vs. post-surgery celecoxib/etoricoxib/etodolac pharmacokinetic (PK) profiles. For etoricoxib and etodolac (but not celecoxib), pH-dependent solubility was demonstrated: etoricoxib solubility decreased ∼1000-fold, and etodolac solubility increased 120-fold, as pH increased from 1 to 7, which was also confirmed ex-vivo. Hampered etoricoxib dissolution and improved etodolac dissolution post-surgery was revealed. Tablet crushing, clinically recommended after surgery, failed to improve post-bariatric dissolution. PBBM simulations revealed significantly impaired etoricoxib absorption post-surgery across all conditions; for instance, 79% lower C max and 53% decreased AUC was simulated post-gastric bypass procedure, after single 120 mg dose. Celecoxib and etodolac maintained unaffected absorption after bariatric surgery. This mechanistically-based analysis suggests to prefer the acidic drug etodolac or the neutral celecoxib as selective COX-2 inhibitors, over the basic drug etoricoxib, after bariatric surgery. [ABSTRACT FROM AUTHOR]

Peripheral blood is an easily accessed source for stem cell production; however, the number of cells produced is relatively low. We hypothesized that ischemic preconditioning may serve as a safe method to increase the number of CD34+ cells that can be harvested and cultured in a short period. This study was conducted to test this hypothesis by examining the safety and efficacy of brief, transient ischemia of the lower limbs to augment the number of cells that can be produced from blood of healthy volunteers. Following induction of ischemia, blood samples were withdrawn at baseline, 30 min, 12 h and 24 h. The number of progenitor cells was determined by flow cytometry after the harvested cells were cultured for 5 days. We also analyzed the blood samples to determine IL-8 and VEGF concentrations. No serious adverse events were observed. The total number of cells increased from 0.46 ± 0.1 × 10 cells/ml in the pretreatment blood samples to 0.7 ± 0.1 × 10 cells/ml in blood taken 12 h after the conclusion of transient ischemia, p = 0.0029. The number of CD34+ cells increased from 4.23 ± 0.8 × 10 cells/ml in the pretreatment samples to 7.17 ± 1.34 × 10 cells/ml in blood taken 12 h after ischemia, p = 0.0001. The harvested stem cells maintained their ability to construct tubular structures. The augmentation in the number of CD34+ cells was positively correlated with the increase of IL-8, but not with VEGF concentrations. Ischemic preconditioning is a safe and effective technique to increase the availability of stem cells for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Background: The primary aim was to determine the rate and nature of late postoperative complications in relation to the type of band used and the route through which it encircled the stomach in a retrospective review of postoperative complications that necessitated reoperation in 500 consecutive cases of laparoscopic adjustable gastric banding (LAGB) conducted over the past 48 months. Methods: The four study groups were: (A) Lap-Band® perigastric route, 186 cases; (B) Lap-Band® pars flaccida route 73 cases; (C) SAGB perigastric 70 cases, and (D) SAGB pars flaccida, 171 cases. There were 414 women and 86 men. The mean age was 39.2 ± 11.0 years (17–68). The mean weight was 126 kg, and mean BMI was 43.4 kg/m2 prior to operation. Results: There were 32 cases of slippage (17%) in group A and five cases (7%) in Group B ( P < 0.05). In group C there were 15 cases (21%) of slippage and in group D six cases (3%) ( P < 0.05). There were no significant differences between Groups A and C or Groups B and D. Except for one case of band erosion in Group C, erosion, tube disconnection and aneurysmatic balloon dilatation occurred only in groups A and B. Band erosion occurred in 2% each in groups A and B, tube disconnection in 3% and 4%, respectively, and balloon dilatation in 2% in each of groups A and B. Conclusions: Slippage was primarily route dependent. Erosion, tube disconnection and aneurysmatic dilatation of the balloon were encountered almost exclusively in the high-pressure system. We conclude that the pars flaccida route with the low-pressure system is more effective in reducing the rate of complications necessitating reoperation. [ABSTRACT FROM AUTHOR]

Seroma is a well-known complication of postoperative ventral hernia (POVH) repair. It occurs during the immediate postoperative period and usually resolves with or without drainage within 4–6 weeks. The case presented herein is interesting in that a huge seroma appeared 6 months postoperatively. Ten litres were evacuated in each of two consecutive hospitalisations. The final outcome was a complete recovery with no mesh infection and no residual seroma. Of interest are the diagnosis and treatment of this unusual clinical presentation of seroma after POVH repair. [ABSTRACT FROM AUTHOR]

Background: The extremely obese patient deserves special consideration: significant comorbidities, technical difficulties, and increased postoperative morbidity and mortality are all expected in this patient population. The study compared early postoperative complications (≤30‐day) following one‐anastomosis gastric bypass (OAGB) morbidity in patients with morbid obesity class IV obesity, body mass index (BMI) ≥50–59.9 kg/m2, and class V obesity, BMI ≥60 patients. Methods: We retrospectively reviewed perioperative OAGB outcomes in three BMI groups. Operative time, length of stay (LOS), and overall early postoperative complication rates were studied. Patient‐reported complications were ranked by Clavien–Dindo Classification (CDC). Results: Between January 2017–December 2021, consecutive patients with obesity class III (n = 2950), IV (n = 256), and V (n = 23) underwent OAGB. BMI groups were comparable in sex, age, and associated comorbidities. Mean operative time was significantly longer in the higher BMI groups: class III (66.5 ± 25.6 min), IV (70.5 ± 28.7 min), and V (80.0 ± 34.7 min), respectively (p = 0.018); no difference in LOS. In respective BMI classes, ≤30‐day complication rates were 3.2%, 3.5%, and 4.3% (p = 0.926). The respective number of patients with CDC grades of one to two were 45 (1.5%), 6 (2.3%), and 1 (4.3%), p = 0.500; and in grade ≥3a, 25 (0.8%), 1 (0.4%), 0 (0.0%), p = 0.669. There was 0.06% mortality (n = 2 in 3229), both in BMI class III. Conclusions: OAGB is a safe BS procedure in patients with class III, IV, and V obesity in the perioperative term with comparable ≤30‐day morbidity in the three BMI groups. [ABSTRACT FROM AUTHOR]

Laparoscopic one-anastomosis gastric bypass (LOAGB) has gained popularity as safe weight-reduction procedure. Bleeding is the common postoperative complication. We present a successful treatment of recurrent bleeding after LOAGB by embolization of the left gastric artery (LGA) and later development of necrotizing pancreatitis. A 41-year-old patient with previous bariatric surgeries undergone LOAGB surgery with development of massive intraluminal bleeding in the postoperative period. Attempts of unsuccessful endoscopic treatment were done and the bleeding was stopped by LGA embolization. In the post-embolization period, the patients developed necrotizing pancreatitis. Postoperative bleeding is the serious complications of the bariatric LOAGB procedure. Transcatheter Arterial Embolization (TAE) is the possible treatments after unsuccessful endoscopic attempts to stop the bleeding. The technical and clinical success rates of TAE in post-gastrectomy bleeding are 100 and 79%, respectively. TAE can be successfully used to stop obstinate recurrent postoperative bleeding after a LOAGB procedure. [ABSTRACT FROM AUTHOR]

Background: In a large nationwide mass vaccination setting, the SARS-CoV-2 vaccine was recently linked to myocarditis, lymphadenopathy, herpes zoster infection and appendicitis. We aimed to examine the characteristics and management of SARS-CoV-2 vaccine-related acute appendicitis. Methods: We performed a retrospective cohort study in a large tertiary medical centre in Israel. All patients presenting with acute appendicitis within 21 days of receiving their SARS-CoV-2 vaccination (PCVAA group) were compared with patients who presented with acute appendicitis not related to the vaccination (N-PCVAA group). Results: We reviewed the records of 421 patients with acute appendicitis from December 2020 to September 2021; 38 (9%) patients presented with acute appendicitis within 21 days of receiving their SARS-CoV-2 vaccination. Patients in the PCVAA group were older than those in the N-PCVAA group (mean 41 ± 19 yr v. 33 ± 15 yr, respectively, p = 0.008), with male predominance. More patients were managed nonsurgically during the pandemic than before the pandemic (24% v. 18%, p = 0.03). Conclusion: With the exception of older age, the clinical characteristics of patients presenting with acute appendicitis within 21 days of receiving the SARS-CoV-2 vaccination did not differ from those of patients who presented with acute appendicitis not related to the vaccination. This finding suggests that vaccine-related acute appendicitis is similar to "classic" acute appendicitis. [ABSTRACT FROM AUTHOR]

Objective: Up-regulated expression of transcription-factor E2F1 in human visceral adipose tissue (VAT) characterizes a dysmetabolic obesity sub-phenotype. An E2F1-miRNA network has been described in multiple cancers. Here we investigated whether elevated VAT-E2F1 in obesity is associated with VAT-miRNA alterations similar to, or distinct from, those described in cancer. Furthermore, we assessed if E2F1-associated miRNA changes may contribute to the link between high- VAT-E2F1 and a dysmetabolic obesity phenotype. Methods: We assembled a cohort of patients with obesity and high-VAT-E2F1, matched by age, sex, ±BMI to patients with low-VAT-E2F1, with and without obesity (8 patients/groupX3 groups). We performed Nanostring©-based miRNA profiling of VAT samples from all 24 patients. Candidate E2F1-related miRNAs were validated by qPCR in an independent cohort of patients with extreme obesity, with or without type-2-diabetes (T2DM) (n = 20). Bioinformatic tools and manipulation of E2F1 expression in cells were used to establish the plausibility of the functional VAT-E2F1-miRNA network in obesity. Results: Among n = 798 identified miRNAs, 17 were differentially expressed in relation to E2F1 and not to obesity itself. No evidence for the cancer-related E2F1-miRNA network was identified in human VAT in obesity. In HEK293-cells, overexpression/downregulation of E2F1 correspondingly altered the expression of miRNA-206 and miRNA-210-5p, two miRNAs with reported metabolic functions consistent with those of E2F1. In VAT from both cohorts, the expression of both miRNA-206 and 210-5p intercorrelated, and correlated with the expression of E2F1. In cohort 1 we did not detect significant associations with biochemical parameters. In cohort 2 of patients with extreme obesity, all those with high VAT-E2F1 showed a diabetes-complicated obesity phenotype and higher expression of miRNA-206 and miRNA-210-5p, which also correlated with fasting glucose levels (both miRNAs) and fasting insulin (miRNA-210-5p). Conclusions: Whilst the previously described cancer-related E2F1-miRNA network does not appear to operate in VAT in obesity, miRNAs-206 and 210-5p may link high-E2F1 expression in VAT with diabetes-complicated extreme obesity phenotype. [ABSTRACT FROM AUTHOR]

Objective: In a previous study, ketamine suppressed Escherichia coli-induced production of the cytokines interleukin (IL)-6 and tumor necrosis factor alpha (TNFα). In other previous studies ketamine improved survival after E. coli inoculation. However, the relationship between cytokines and survival following ketamine treatment is uncertain because no study has examined both cytokines and survival after E. coli inoculation. Methods: Rats were given E. coli (0.4×109 colony forming unit (CFU)) at time 0, followed by ketamine (50 mg/kg, n=30) or saline (n=30) at 5 min or 2 h. IL-6 and TNFα were measured in serum at 6 h, and mortality was recorded for 7 days. Results: Survival rate with ketamine was 57% (17/30) and was significantly increased compared to saline (27%, 8/30, P=0.01). IL-6 and TNFα were lower with ketamine than saline (15,197±3444 versus 30,725±4623 pg/ml [mean±S.E.M.], P=0.013 and 38.5±9.5 versus 122.5±14.0 pg/ml, P=0.001, respectively). With ketamine, IL-6 (but not TNFα) concentrations were lower in the survivors (10,900±776 pg/ml) as compared to the non-survivors (P=0.01). IL-6 in ketamine-treated survivors was not different from that in saline-treated survivors. Conclusion: We conclude that ketamine given 5 min or 2 h after induction of E. coli sepsis significantly improves survival, possibly by interfering with the inflammatory cascade (as evidenced by attenuation of cytokine production). [Copyright &y& Elsevier]

Stomach pH may vary following bariatric surgery, with implications for drug delivery/bioavailability. Yet, this parameter has not been studied. In this work, gastric content was aspirated from patients before, immediately after, and the day after different bariatric procedures, and pH was immediately measured. Compared to pre-surgery (1.8), pH was increased one day after one-anastomosis gastric bypass (OAGB) and sleeve gastrectomy (LSG) by 3–4 pH units; pH immediately after these procedures was in between the other 2 time points. Post-OAGB pH was significantly higher than post-LSG (6.4 and 4.9, respectively). Prior adjustable gastric band did not significantly alter baseline pH. We then performed drug dissolution studies of the antiplatelet drugs dipyridamole and aspirin, mimicking pre-surgery, post-LSG and post-OAGB conditions, implementing our pH results and other relevant physiological parameters. Dipyridamole, a weak base, completely dissolved (100% of dose) under pre-surgery conditions, while dissolution was hampered under post-LSG (5%) and post-OAGB (0.25%) conditions, due to solubility limit. Aspirin was not released from enteric-coated tablet under pre-surgery or post-LSG gastric conditions, however, >75% dissolved within 15 min under post-OAGB gastric conditions, indicating potential failure of enteric coating, depending on the bariatric procedure. In conclusion, special care should be taken when using pH-dependent drugs and drug products after bariatric surgery, and the use of pH-independent formulations should be preferred. Overall, this research revealed the interim gastric pH after different bariatric procedures, and potentially important effects on post-bariatric oral drug delivery and treatment. [ABSTRACT FROM AUTHOR]

Two suicide bombings in and around Taba, Egypt, on 7 October 2004 created a complex medical and organisational situation. Since most victims were Israeli tourists, the National Emergency and Disaster Management Division handled their evacuation and treatment. This paper describes the event chronologically, as well as the organisational and management challenges confronted and applied solutions. Forty-nine emergency personnel and physicians were flown early to the disaster area to reinforce scarce local medical resources. Two hundred casualties were recorded: 32 dead and 168 injured. Eilat hospital was transformed into a triage facility. Thirty-two seriously injured patients were flown to two remote trauma centres in central Israel. Management of mass casualty incidents is difficult when local resources are inadequate. An effective response should include: rapid transportation of experienced trauma teams to the disaster zone; conversion of local medical amenities into a triage centre; and rapid evacuation of the seriously injured to higher level medical facilities. [ABSTRACT FROM AUTHOR]

[Display omitted] Bariatric surgery is an effective treatment of obesity and related comorbidities. With surgery, the stomach undergoes major anatomical/physiological changes that may affect the oral exposure of drugs, especially marginally soluble weak bases, such as lamotrigine. The aim of this work was to study the solubility/dissolution of lamotrigine in conditions simulating the stomach before vs. after bariatric surgery. Lamotrigine solubility was studied in-vitro, as well as ex-vivo in gastric content aspirated from patients before vs. after bariatric surgery. We then compared the dissolution kinetics of various marketed lamotrigine products in pre- vs. post-operative stomach conditions, different in volume, pH, agitation strength and speed. Decreased lamotrigine solubility with increasing pH (from 1.37 ± 0.09 (pH = 1) to 0.22 ± 0.03 mg/mL (pH = 7)) was obtained. Twelve-fold higher lamotrigine solubility was revealed in gastric content aspirated before vs. after surgery (8.5 ± 0.7 and 0.7 ± 0.01 mg/mL, respectively). Dissolution studies showed that only the lowest dose (25 mg) fully dissolved in the post-surgery stomach conditions, while at higher doses, lamotrigine tablet dissolution was impaired. Neither fast-dissolving tablet, nor tablet crushing, helped resolving this problem. Based on these results, and given that dissolution of the drug dose governs the subsequent absorption, close monitoring of this essential drug is advised after bariatric surgery. [ABSTRACT FROM AUTHOR]