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Background A new manometric classification of esophageal achalasia has recently been proposed that also suggests a correlation with the final outcome of treatment. The aim of this study was to investigate this hypothesis in a large group of achalasia patients undergoing laparoscopic Heller–Dor myotomy. Methods We evaluated 246 consecutive achalasia patients who underwent surgery as their first treatment from 2001 to 2009. Patients with sigmoid-shaped esophagus were excluded. Symptoms were scored and barium swallow X-ray, endoscopy, and esophageal manometry were performed before and again at 6 months after surgery. Patients were divided into three groups: (I) no distal esophageal pressurization (contraction wave amplitude <30 mmHg); (II) rapidly propagating compartmentalized pressurization (panesophageal pressurization >30 mmHg); and (III) rapidly propagating pressurization attributable to spastic contractions. Treatment failure was defined as a postoperative symptom score greater than the 10th percentile of the preoperative score (i.e., >7). Results Type III achalasia coincided with a longer overall lower esophageal sphincter (LES) length, a lower symptom score, and a smaller esophageal diameter. Treatment failure rates differed significantly in the three groups: I = 14.6% (14/96), II = 4.7% (6/127), and III = 30.4% (7/23; p  = 0.0007). At univariate analysis, the manometric pattern, a low LES resting pressure, and a high chest pain score were the only factors predicting treatment failure. At multivariate analysis, the manometric pattern and a LES resting pressure <30 mmHg predicted a negative outcome. Conclusion This is the first study by a surgical group to assess the outcome of surgery in 3 manometric achalasia subtypes: patients with panesophageal pressurization have the best outcome after laparoscopic Heller–Dor myotomy.

ᅟ Obstruction and perforation due to colorectal cancer represent challenging matters in terms of diagnosis, life-saving strategies, obstruction resolution and oncologic challenge. The aims of the current paper are to update the previous WSES guidelines for the management of large bowel perforation and obstructive left colon carcinoma (OLCC) and to develop new guidelines on obstructive right colon carcinoma (ORCC). Methods The literature was extensively queried for focused publication until December 2017. Precise analysis and grading of the literature has been performed by a working group formed by a pool of experts: the statements and literature review were presented, discussed and voted at the Consensus Conference of the 4th Congress of the World Society of Emergency Surgery (WSES) held in Campinas in May 2017. Results CT scan is the best imaging technique to evaluate large bowel obstruction and perforation. For OLCC, self-expandable metallic stent (SEMS), when available, offers interesting advantages as compared to emergency surgery; however, the positioning of SEMS for surgically treatable causes carries some long-term oncologic disadvantages, which are still under analysis. In the context of emergency surgery, resection and primary anastomosis (RPA) is preferable to Hartmann’s procedure, whenever the characteristics of the patient and the surgeon are permissive. Right-sided loop colostomy is preferable in rectal cancer, when preoperative therapies are predicted. With regards to the treatment of ORCC, right colectomy represents the procedure of choice; alternatives, such as internal bypass and loop ileostomy, are of limited value. Clinical scenarios in the case of perforation might be dramatic, especially in case of free faecal peritonitis. The importance of an appropriate balance between life-saving surgical procedures and respect of oncologic caveats must be stressed. In selected cases, a damage control approach may be required. Medical treatments including appropriate fluid resuscitation, early antibiotic treatment and management of co-existing medical conditions according to international guidelines must be delivered to all patients at presentation. Conclusions The current guidelines offer an extensive overview of available evidence and a qualitative consensus regarding management of large bowel obstruction and perforation due to colorectal cancer.

BackgroundPerforated peptic ulcer (PPU) remain a surgical emergency accounting for 37% of all peptic ulcer-related deaths. Surgery remains the standard of care. The benefits of laparoscopic approach have been well-established even in the elderly. However, because of inconsistent results with specific regard to some technical aspects of such technique surgeons questioned the adoption of laparoscopic approach. This leads to choose the type of approach based on personal experience. The aim of our study was to critically appraise the use of the laparoscopic approach in PPU treatment comparing it with open procedure.MethodsA retrospective study with propensity score matching analysis of patients underwent surgical procedure for PPU was performed. Patients undergoing PPU repair were divided into: Laparoscopic approach (LapA) and Open approach (OpenA) groups and clinical-pathological features of patients in the both groups were compared.ResultsA total of 453 patients underwent PPU simple repair. Among these, a LapA was adopted in 49% (222/453 patients). After propensity score matching, 172 patients were included in each group (the LapA and the OpenA). Analysis demonstrated increased operative times in the OpenA [OpenA: 96.4 ± 37.2 vs LapA 88.47 ± 33 min, p = 0.035], with shorter overall length of stay in the LapA group [OpenA 13 ± 12 vs LapA 10.3 ± 11.4 days p = 0.038]. There was no statistically significant difference in mortality [OpenA 26 (15.1%) vs LapA 18 (10.5%), p = 0.258]. Focusing on morbidity, the overall rate of 30-day postoperative morbidity was significantly lower in the LapA group [OpenA 67 patients (39.0%) vs LapA 37 patients (21.5%) p = 0.002]. When stratified using the Clavien–Dindo classification, the severity of postoperative complications was statistically different only for C–D 1–2.ConclusionsBased on the present study, we can support that laparoscopic suturing of perforated peptic ulcers, apart from being a safe technique, could provide significant advantages in terms of postoperative complications and hospital stay.

Introduction Laparoscopic Heller-Dor surgery is the current treatment of choice for patients with esophageal achalasia, but elderly patients are generally referred for less invasive treatments (pneumatic dilations or botulinum toxin injections). Aim To assess the effect of age on the surgical outcome of patients receiving laparoscopic Heller-Dor as primary treatment. Methods Demographic and clinical findings were prospectively collected on patients undergoing laparoscopic Heller-Dor from 1992 to 2012. Patients were classified in three age brackets: group A (≤45 years), group B (45–70), and group C (≥70). Treatment was defined as a failure if the postoperative symptom score was >10th percentile of the preoperative score (i.e., >8). We consecutively performed the Heller-Dor in 571 achalasia patients, 305 (53.4 %) in group A, 226 (39.6 %) in group B, and 40 (7 %) in group C. Results The mortality was nil; the conversion and morbidity rates were both 1.1 %. Group C patients had higher preoperative symptom scores ( p  = 0.02), while the symptom duration was similar in all three groups. Mucosal tears occurred in 17 patients (3 %): 6 (2 %) in group A, 8 (3.5 %) in group B, and 3 (7.5 %) in group C ( p  = 0.09). The postoperative hospital stay was slightly longer for group C ( p  = 0.06). Discussion The treatment failure rate was quite similar: 31 failures in group A (10.1 %), 19 in group B (8.4 %), and 3 in group C (7.5 %; p  = 0.80). These failures were seen more in manometric pattern III (22.2 %, p  = 0.002). Laparoscopic Heller-Dor can be used as the first therapeutic approach to achalasia even in elderly patients with an acceptable surgical risk.

Background Zenker’s diverticula (ZD) can be treated by transoral diverticulostomy or open surgery (upper esophageal sphincter myotomy and diverticulectomy or diverticulopexy). The aim of this study was to compare the effectiveness of a minimally invasive (group A) versus a traditional open surgical approach (group B) in the treatment of ZD. Material and Methods Between 1993 and September 2007, 128 ZD patients underwent transoral diverticulostomy ( n  = 51) or cricopharyngeal myotomy and diverticulectomy or diverticulopexy ( n  = 77). All patients were evaluated for symptoms using a detailed questionnaire. Manometry recorded upper esophageal sphincter (UES) pressure, relaxations, and intrabolus pharyngeal pressure. The size of the pouch was measured on the barium swallow. The choice of treatment was based on the size of the diverticulum and the patients’ preference. Long-term follow-up data were available for 121/128 (94.5%) patients with a median follow-up of 40 months (interquartile range, 17–83). Results Mortality was nil. Three patients in group A (5.8%) and ten in group B (13%) had postoperative complications ( p  = n.s.). Hospital stays were markedly shorter for patients after diverticulostomy ( p  < 0.01). Postoperative manometry showed a reduction in UES pressure, improved UES relaxation, and lower intrabolus pressure in both groups ( p  < 0.05). Four patients in the open surgery group (5.2%) complained of severe dysphagia after surgery (three of them required endoscopic dilations). In the transoral diverticulostomy group, 11 patients (21.5%) required additional septal reduction ( n  = 8) or a surgical myotomy ( n  = 3) for persistent symptoms ( p  < 0.01); nine of these 11 patients had a ZD ≤ 3 cm in size. After primary and complementary treatments, symptoms disappeared or improved significantly at long-term follow-up in 93.5% of patients in group A and 96% of those in group B. Conclusion Diverticulostomy is safe, quick, and effective for most patients with medium-sized ZD, but open surgery offers better long-term results as a primary treatment and should be recommended for younger, healthy patients, especially those with small diverticula. Small ZD may represent a formal contraindication to the transoral approach because an excessively short septum prevents a complete division of the sphincter fibers.

As an inherited disorder characterized by severe pulmonary disease, cystic fibrosis could be considered a comorbidity for coronavirus disease 2019. Instead, current clinical evidence seems to be heading in the opposite direction. To clarify whether host factors expressed by the Cystic Fibrosis epithelia may influence coronavirus disease 2019 progression, here we describe the expression of SARS-CoV-2 receptors in primary airway epithelial cells. We show that angiotensin converting enzyme 2 (ACE2) expression and localization are regulated by Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) channel. Consistently, our results indicate that dysfunctional CFTR channels alter susceptibility to SARS-CoV-2 infection, resulting in reduced viral entry and replication in Cystic Fibrosis cells. Depending on the pattern of ACE2 expression, the SARS-CoV-2 spike (S) protein induced high levels of Interleukin 6 in healthy donor-derived primary airway epithelial cells, but a very weak response in primary Cystic Fibrosis cells. Collectively, these data support that Cystic Fibrosis condition may be at least partially protecting from SARS-CoV-2 infection. Patients with cystic fibrosis are not reporting particularly sever outcomes upon SARS-CoV-2 infection. Here, the authors demonstrate decreased ACE2 levels is cystic fibrosis airway epithelia associated with impaired viral entry and replication.

Immune mechanisms contribute to the neuropathology of Alzheimer’s disease (AD) but the role of adaptive immune cells is unclear. Here we show that the brain CD8 + T cell compartment is dysregulated in AD patients and in the 3xTg-AD mouse model, accumulating activated CD103 – tissue-resident memory T cells that produce large amounts of granzyme K (GrK). These CD103 – CD8 + T cells originate from the circulation and migrate into the brain using LFA-1 integrin. Ablation of brain CD103 – CD8 + T cells in 3xTg-AD mice ameliorates cognitive decline and reduces neuropathology. GrK induces neuronal dysfunction and tau hyperphosphorylation in human and mouse cells via protease-activated receptor-1 (PAR-1), which is expressed at higher levels in the AD brain, revealing a key immune-mediated neurotoxic axis. We conclude that communication between CD8 + T cells and the nervous system is altered in AD, paving the way for therapies targeting T cell-dependent neurotoxic inflammation. Neuroimmune communication in Alzheimer’s disease (AD) is poorly understood. Here, the authors show that CD103–CD8+ resident memory T cells induce neurotoxicity and neuroinflammation in AD via the granzyme K–PAR-1 axis.

This paper describes the development and validation of an innovative protection system based on medium-voltage fuses for a high-power switching conversion system. This special conversion system, rated to deliver about 56 MW to the load, is based on neutral-point clamped IGCT inverters, connected to the same dc link through a set of distributed busbars, with a dc-link voltage of 6.5 kV and a capacitive stored energy up to 837 kJ. The sudden release of this energy in case of a switch failure in one inverter and the subsequent short circuit of one leg can lead to destructive consequences. From the analysis of different protection strategies, performed by numerical simulations of the fault evolutions, the developed solution based on medium-voltage fuses was found the only provision able to cope with such high stored energy and uncommon circuit topology. Custom fuses were developed for this application, and a specially tailored test was designed for validating the fuse selection. The paper, after summarizing the work carried out to simulate the fault evolution and select the protection, presents the analyses carried out to set up the validation test, and describes and discusses the results of the test and the complementing numerical simulations, which demonstrated the effectiveness of the protection system.

MicroRNAs are a family of small noncoding RNAs regulating gene expression by sequence-selective mRNA targeting, leading to a translational repression or mRNA degradation. The oncomiR miR-221 is highly expressed in human gliomas, as confirmed in this study in samples of low and high grade gliomas, as well in the cell lines U251, U373 and T98G. In order to alter the biological functions of miR-221, a peptide nucleic acid targeting miR-221 (R8-PNA-a221) was produced, bearing a oligoarginine peptide (R8) to facilitate uptake by glioma cells. The effects of R8-PNA-a221 were analyzed in U251, U373 and T98G glioma cells and found to strongly inhibit miR-221. In addition, the effects of R8-PNA-a221 on p27 Kip1 (a target of miR-221) were analyzed in U251 and T98G cells by RT-qPCR and by Western blotting. No change of p27 Kip1 mRNA content occurs in U251 cells in the presence of PNA-a221 (lacking the R8 peptide), whereas significant increase of p27 Kip1 mRNA was observed with the R8-PNA-a221. These data were confirmed by Western blot assay. A clear increment of p27 Kip1 protein expression in the samples treated with R8-PNA-a221 was detected. In addition, R8-PNA-a221 was found able to increase TIMP3 expression (another target of miR-221) in T98G cells. These results suggest that PNAs against oncomiRNA miR-221 might be proposed for experimental treatment of human gliomas.