The Impact of Climate Change and Extreme Weather Conditions on Cardiovascular Health and Acute Cardiovascular Diseases.

Climate change is widely recognized as one of the most significant challenges facing our planet and human civilization. Human activities such as the burning of fossil fuels, deforestation, and industrial processes release greenhouse gases into the atmosphere, leading to a warming of the Earth's climate. The relationship between climate change and cardiovascular (CV) health, mediated by air pollution and increased ambient temperatures, is complex and very heterogeneous. The main mechanisms underlying the pathogenesis of CV disease at extreme temperatures involve several regulatory pathways, including temperature-sympathetic reactivity, the cold-activated renin-angiotensin system, dehydration, extreme temperature-induced electrolyte imbalances, and heat stroke-induced systemic inflammatory responses. The interplay of these mechanisms may vary based on individual factors, environmental conditions, and an overall health background. The net outcome is a significant increase in CV mortality and a higher incidence of hypertension, type II diabetes mellitus, acute myocardial infarction (AMI), heart failure, and cardiac arrhythmias. Patients with pre-existing CV disorders may be more vulnerable to the effects of global warming and extreme temperatures. There is an urgent need for a comprehensive intervention that spans from the individual level to a systemic or global approach to effectively address this existential problem. Future programs aimed at reducing CV and environmental burdens should require cross-disciplinary collaboration involving physicians, researchers, public health workers, political scientists, legislators, and national leaders to mitigate the effects of climate change.

Average treatment effect of robotic versus laparoscopic rectal surgery for rectal cancer.

BACKGROUND: The aim of this study is to estimate what would have happened if all patients treated with laparoscopy for rectal cancer had instead been treated with the robotic technique. METHODS: To estimate the average treatment effect (ATE) of the robotic technique over the laparoscopic approach, data from patients treated at two centres between 2007 and 2018 were used to obtain counterfactual outcomes using an inverse probability weighting (IPW) adjustment. RESULTS: This study enrolled 261 patients, of which 177 and 84 patients had undergone robotic surgery and standard laparoscopy, respectively. After IPW adjustment, the difference between the groups was similar in the pseudo-population. The average conversion rate would fall by an estimated 6.1% if all procedures had been robotic (p = 0.045). All other post-operative variables showed no differences regardless of the approach. CONCLUSION: ATE estimation suggests that robotic rectal cancer surgery could be associated with a lower conversion rate. The approach did not affect the post-operative morbidity rates or the operative time.

Expression levels of circulating miRNAs as biomarkers during multimodal treatment of rectal cancer - TiMiSNAR-mirna: a substudy of the TiMiSNAR Trial (NCT03962088).

BACKGROUND: Neoadjuvant chemoradiotherapy followed by surgery is the mainstay treatment for locally advanced rectal cancer, leading to significant decrease in tumor size (downsizing) and a shift towards earlier disease stage (downstaging). Extensive histopathological work-up of the tumor specimen after surgery including tumor regression grading and lymph node status helped to visualize individual tumor sensitivity to chemoradiotherapy, retrospectively. As the response to neoadjuvant chemoradiotherapy is heterogeneous, however, valid biomarkers are needed to monitor tumor response. A relevant number of studies aimed to identify molecular markers retrieved from tumor tissue while the relevance of blood-based biomarkers is less stringent assessed. MicroRNAs are currently under investigation to serve as blood-based biomarkers. To date, no screening approach to identify relevant miRNAs as biomarkers in blood of patients with rectal cancer was undertaken. The aim of the study is to investigate the role of circulating miRNAs as biomarkers in those patients included in the TiMiSNAR Trial (NCT03465982). This is a biomolecular substudy of TiMiSNAR Trial (NCT03962088). METHODS: All included patients in the TiMiSNAR Trial are supposed to undergo blood collection at the time of diagnosis, after neoadjuvant treatment, after 1 month from surgery, and after adjuvant chemotherapy whenever indicated. DISCUSSION: TiMiSNAR-MIRNA will evaluate the association of variation between preneoadjuvant and postneoadjuvant expression levels of miRNA with pathological complete response. Moreover, the study will evaluate the role of liquid biopsies in the monitoring of treatment, correlate changes in expression levels of miRNA following complete surgical resection with disease-free survival, and evaluate the relation between changes in miRNA during surveillance and tumor relapse. TRIAL REGISTRATION: Clinicaltrials.gov NCT03962088 . Registered on 23 May 2019.

Correction to: Standard (8 weeks) vs long (12 weeks) timing to minimally-invasive surgery after NeoAdjuvant Chemoradiotherapy for rectal cancer: a multicenter randomized controlled parallel group trial (TiMiSNAR).

Following publication of the original article [1], the authors reported that the family name of the author, Ludovica Baldari, was misspelled.

Naïve/Effector CD4 T cell ratio as a useful predictive marker of immune reconstitution in late presenter HIV patients: A multicenter study.

A significant proportion of HIV-infected patients experiencing a late diagnosis highlights the need to define immunological protocols able to help the clinicians in identifying patients at higher risk for immunological failure. The aim of the study was to evaluate the feasibility of easy cytometric tests in defining the effect of antiretroviral treatment (cART) on immunological homeostasis and in identifying predictive markers of early immune recovery. Chronic HIV infected patients (n = 202) were enrolled in a prospective multicentric study, and their immunological profile was studied before (w0) and after 24 weeks (w24) of antiretroviral treatment (cART) using a standardized flow cytometric panel. Based on CD4 T cell count before treatment, patients were divided in late (LP: CD4 <350/mmc), intermediate (IP: 350/mmc500/mmc) presenters. In all groups, cART introduction increased CD4 and CD4/CD8 T cell ratio, naïve T cell (CD4 and CD8) and CD127-expressing CD4 T cells. In parallel, cART significantly reduced effector memory T cells (CD4 and CD8) and T cell activation (CD38+CD8 and CD95+CD4 T cells). Moreover, the frequency of Naïve and Effector CD4 T cells before treatment correlated with several immune parameters key associated with the pathogenesis of HIV, thus mirroring the health of immune system. Interestingly, we identified the Naïve/Effector CD4 T cell ratio (N/EM) at w0 as a marker able to predict early immune recovery. Specifically, in LP, N/EM ratio was significantly higher in immunological responder patients (CD4>500/mmc at w24) when compared to immunological non responder (CD4 T cells <500/mmc at w24). Finally, a multivariate analysis indicates that after 24w patients with N/EM ratio higher than 1.86 at w0 recovered 96 CD4 T cells more than those with N/EM ratio lower than 0.46. Altogether, our data define an easy protocol able to define reliable immunological markers useful for the characterization of immune profile in viremic HIV patients and identify the naïve/effector CD4 T cell ratio as a new tool able to predict an early immune reconstitution potential.

Standard (8 weeks) vs long (12 weeks) timing to minimally-invasive surgery after NeoAdjuvant Chemoradiotherapy for rectal cancer: a multicenter randomized controlled parallel group trial (TiMiSNAR).

BACKGROUND: The optimal timing of surgery in relation to chemoradiation is still controversial. Retrospective analysis has demonstrated in the recent decades that the regression of adenocarcinoma can be slow and not complete until after several months. More recently, increasing pathologic Complete Response rates have been demonstrated to be correlated with longer time interval. The purpose of the trial is to demonstrate if delayed timing of surgery after neoadjuvant chemoradiotherapy actually affects pathologic Complete Response and reflects on disease-free survival and overall survival rather than standard timing. METHODS: The trial is a multicenter, prospective, randomized controlled, unblinded, parallel-group trial comparing standard and delayed surgery after neoadjuvant chemoradiotherapy for the curative treatment of rectal cancer. Three-hundred and forty patients will be randomized on an equal basis to either robotic-assisted/standard laparoscopic rectal cancer surgery after 8 weeks or robotic-assisted/standard laparoscopic rectal cancer surgery after 12 weeks. DISCUSSION: To date, it is well-know that pathologic Complete Response is associated with excellent prognosis and an overall survival of 90%. In the Lyon trial the rate of pCR or near pathologic Complete Response increased from 10.3 to 26% and in retrospective studies the increase rate was about 23-30%. These results may be explained on the relationship between radiation therapy and tumor regression: DNA damage occurs during irradiation, but cellular lysis occurs within the next weeks. Study results, whether confirmed that performing surgery after 12 weeks from neoadjuvant treatment is advantageous from a technical and oncological point of view, may change the current pathway of the treatment in those patient suffering from rectal cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT3465982.

The use of intra-abdominal drain in minimally invasive right colectomy: a propensity score matched analysis on postoperative outcomes.

PURPOSE: No evidences supporting or not the use of intra-abdominal drain (AD) in minimally invasive right colectomies have been published. This study aims to assess the outcomes on its use after robotic or laparoscopic right colectomies. METHODS: This is a multicenter propensity score matched study including patients who underwent minimally invasive right colectomy with (AD group) or without (no-AD group) the use of AD between February 1, 2007, and January 31, 2018. AD patients were matched to no-AD patients in a 1:1 ratio. Main outcomes were postoperative morbidity and mortality and anastomotic leak. RESULTS: A total of 653 patients were included. Of 149 (22.8%) no-AD patients, 124 could be matched. The rate of postoperative complications (AD n = 26, 21% vs. no-AD n = 26, 21%; p = 1.000), mortality (AD n = 2, 1.6% vs. no-AD n = 1, 0.8%; p = 1.000), anastomotic leak (AD n = 2, 1.6% vs. no-AD n = 5, 4.0%; p = 0.453), and wound infection (AD n = 9, 7.3% vs. no-AD n = 6, 4.8%; p = 0.581) did not significantly differ between the groups. Time to oral feeding was significantly shorter in the no-AD group [2 (1-3) vs. 3 (2-3), p = 0.0001]. The median length of hospital stay was 8 (IQR 7-9) in the AD group while it was 6 (IQR 5-9) in the no-AD group (p = 0.010). CONCLUSIONS: In conclusion, the use of AD after minimally invasive right colectomies has no influence on postoperative morbidity and mortality rates.

Robotic versus laparoscopic right colectomy with intracorporeal anastomosis: a multicenter comparative analysis on short-term outcomes.

BACKGROUND: In literature, most of the comparative studies of robotic (RRC) versus laparoscopic (LRC) right colectomy are biased by the type of the anastomotic technique adopted. With this study, we aim to understand whether there is a role for robotics in performing right colectomies, comparing RRC versus LRC, both performed with intracorporeal anastomosis. METHODS: In this retrospective cohort study, all consecutive patients who underwent minimally invasive right colectomy (robotic or laparoscopic) with intracorporeal anastomosis in three Italian high-volume centers between February 1, 2007 and December 31, 2017 were included. Patients were grouped according to the method of surgery: RRC or LRC. RESULTS: A total of 389 patients were included in the study (305 RRC vs. 84 LRC). Patients' baseline characteristics were comparable between the groups. Operative time was significantly longer in RRC (250 min, IQR 209-305) group than LRC group (160 min, IQR 130-200) (p < 0.001). The median number of lymph nodes harvested was 22 (IQR 18-29) in RRC group while it was 19 (IQR 15-27) in LRC one (p = 0.028). No significant differences between the groups were seen in terms of time-to-first flatus, postoperative complications and length of hospital stay. Re-admission rate was significantly higher in LRC (n = 3, 3.6%) group than in RRC group (n = 1, 0.3%) (p = 0.033). CONCLUSIONS: In conclusion, RRC and LRC are comparable in terms of functional postoperative outcomes and length of hospital stay. RRC requires longer operative time, but the number of lymph nodes harvested may be higher.

Robotic Rectal Resection With a Single-docking Technique Thanks to the Rotation of the R3 Arm.

BACKGROUND: Robotic surgery for rectal resection presents some advantages compared with the traditional technique; however, it also presents some limitations, especially due to the multiple changes of surgical fields. We describe a new technique to perform low-anterior resection using single docking with the rotation of the third arm and our perioperative results. MATERIALS AND METHODS: A total of 31 patients who underwent low-anterior rectal robotic resection with single-docking technique using robotic daVinci SI (Surgical Intuitive System) were included in the study. RESULTS: The mean operative time was 338 minutes. The conversion rate was 3%. The mean time of refeeding was 1.4 days and the mean time of hospital stay was 6 days. CONCLUSIONS: Our technique allowed to use the robot for all surgical steps with a single docking, thereby reducing the cost of the hybrid technique and facilitating the operative team in the management of the robotic cart.

Does robotics improve minimally invasive rectal surgery? Functional and oncological implications.

OBJECTIVE: Robot-assisted surgery has been reported to be a safe and effective alternative to conventional laparoscopy for the treatment of rectal cancer in a minimally invasive manner. Nevertheless, substantial data concerning functional outcomes and long-term oncological adequacy is still lacking. We aimed to assess the current role of robotics in rectal surgery focusing on patients' functional and oncological outcomes. METHODS: A comprehensive review was conducted to search articles published in English up to 11 September 2015 concerning functional and/or oncological outcomes of patients who received robot-assisted rectal surgery. All relevant papers were evaluated on functional implications such as postoperative sexual and urinary dysfunction and oncological outcomes. RESULTS: Robotics showed a general trend towards lower rates of sexual and urinary postoperative dysfunction and earlier recovery compared with laparoscopy. The rates of 3-year local recurrence, disease-free survival and overall survival of robotic-assisted rectal surgery compared favourably with those of laparoscopy. CONCLUSIONS: This study fails to provide solid evidence to draw definitive conclusions on whether robotic systems could be useful in ameliorating the outcomes of minimally invasive surgery for rectal cancer. However, the available data suggest potential advantages over conventional laparoscopy with reference to functional outcomes.

Robotic pylorus-preserving pancreaticoduodenectomy: Technical considerations.

Laparoscopy has revolutionized the way of thinking abdominal surgery, however, to date there are still limitations making it difficult to apply this technique to some types of surgical procedures considered technically demanding even when performed by open surgery, such as the pancreaticoduodenectomy. This technical note provides a complete description of the surgical procedure performed for the execution of a robotic pancreaticoduodenectomy through the use of the "Da Vinci Si" robotic system. Robotic systems represent a real evolution in minimally invasive surgery. We wish to emphasize this concept, highlighting the application of this technology to complex procedures in digestive surgery.

A combination of faecal tests for the detection of colon cancer: a new strategy for an appropriate selection of referrals to colonoscopy? A prospective multicentre Italian study.

INTRODUCTION: Colonoscopy workload for endoscopy services in Western countries is increasing markedly because of the implementation of faecal occult blood-based mass screening programmes against colorectal cancer (CRC). We therefore explored the possibility of using a combination of faecal tests to prioritize the access to colonoscopy with criteria other than symptoms and/or time of referral. AIMS AND METHODS: We tested a combination of faecal tests [immunochemical faecal occult blood test (i-FOBT), M2-PK, calprotectin] as markers for advanced neoplasia in a selected series of patients requiring colonoscopy for the suspicion of CRC. All the tests were performed in a 1-day stool sample of patients aged 50-80 years, without any dietary restriction, before colonoscopy. RESULTS: A total of 280 patients' stool single samples were analysed. Forty-seven patients had CRC and 85 patients had one or more advanced adenoma(s) at colonoscopy/histology. CRCs were associated with a highly significant increase (P<0.001) in faecal tumour M2-PK (mean 24.2 kU/l), which correlated with Dukes' staging. For CRC detection, i-FOBT was the test with the highest specificity and positive predictive value (0.89 and 0.53), whereas M2-PK had the highest sensitivity and negative predictive value (0.87 and 0.96). Calprotectin showed performance similar to M2-PK in terms of sensitivity and negative predictive value (0.93), but had lower specificity (0.39). The best combination of tests to predict the risk of CRC in this series was i-FOBT+M2-PK, as in patients showing positivity to both markers, the risk of cancer was as high as 79%. CONCLUSION: The combination of i-FOBT and M2-PK is a sensitive tool in clinical practice for the appropriate management of waiting lists for colonoscopy, as it allows the classification of patients into different degrees of priority for investigation, according to their foreseeable risk of CRC.

A new 24 h ELISA culture based method for Helicobacter pylori chemosusceptibility.

BACKGROUND: Clarithromycin (CH) and metronidazole (MZ) are routinely used in Helicobacter pylori treatment regimes. Recently, treatment with these antibiotics has been reported to fail in >30% of patients due to increasing resistance. The common chemosusceptibility methods are cumbersome and take up to 14 days. Chemosusceptibility of H pylori is therefore rarely checked. AIM: To develop a rapid susceptibility test (RST) for H pylori. METHODS: Preliminary experiments were performed to find a broth medium able to support the growth of H pylori in 20 h and a reliable detection method to quickly detect the amount of H pylori grown in the media. A mixture of different components was the best broth medium; ELISA was chosen as the detection technique. Performance of the new RST was compared to a gold standard (break point agar dilution method). 200 consecutive patients were tested for H pylori infection and chemosusceptibility to CH and MZ by the gold standard and RST. RESULTS: 111 patients were infected with H pylori. 105 of these were positive by both RST and the gold standard culture method; 75/105 and 68/105 strains were susceptible to CH and MZ, respectively. RST misdiagnosed 2 strains of CH and 10 strains of MZ. CONCLUSIONS: A new simple and rapid chemosusceptibility test for H pylori has been validated, which is simple to perform and reduces the procedure time from 6-14 days to 24 h.

Helicobacter pylori antibiotic resistance and [13C]urea breath test values.

A correlation between delta over baseline (DOB) values of the [(13)C]urea breath test (UBT) and Helicobacter pylori clarithromycin resistance has been reported, suggesting a possible predictive role of UBT in therapeutic outcome. However, available data are limited and conflicting. This study aimed to clarify this issue, assessing the possible relationship between H. pylori resistance towards different antibiotics (clarithromycin, metronidazole and levofloxacin) and UBT values. The data showed similar DOB values between susceptible and resistant strains for clarithromycin (46.9+/-32.3 vs 45.7+/-30.6; P=0.8), metronidazole (46.4+/-29.6 vs 47.4+/-37.9; P=0.8), and levofloxacin (45.0+/-30.2 vs 54.2+/-38.4; P=0.08). Likewise, comparable DOB values were observed between susceptible and multidrug-resistant strains (45.4+/-29.6 vs 54.8+/-44.8; P=0.1). In conclusion, our data failed to find a significant correlation between UBT values and H. pylori antibiotic resistance.

A comparison amongst three rapid urease tests to diagnose Helicobacter pylori infection in 375 consecutive dyspeptic.

Rapid diagnostic tools for Helicobacter pylori are important in endoscopy. To assess the accuracy of a new 5-min rapid urease test (UFT300, ABS Cernusco, sul Naviglio, Italy) compared with the 1-h Pyloritek (Serim Laboratories, Elkhart, IN) and the 24-h CLO test (Kimberly-Clark Ballard Medical Products, Roswell, GA), consecutive dyspeptic patients referred to our unit for endoscopy were prospectively studied. All patients underwent a 13C-urea-breath test, histology and the UFT300 (ABS; Cernusco, sul Naviglio, Italy). Two additional rapid urease tests were performed. Patients were deemed infected when both 13C-UBT and histology were positive. Rapid urease tests were read at 1, 5, and 60 min, respectively. Of the 375 enrolled patients, 45.3% were infected with H. pylori. The sensitivity of the new 5-min rapid urease test 300 was 90.3, 94.5, and 96.2% at 1, 5, and 60 min, respectively (specificity 100%). The Pyloritek and the new 5-min rapid urease test were comparable, but the CLO test was not reliable at 5 and 60 min. In conclusion, the new 5-min rapid urease test is comparable to the Pyloritek test, but the CLO test is significantly less sensitive at early time points. Reading the test results at 1 min may increase false-negative results with decreasing sensitivity.

Phenotypic and genotypic Helicobacter pylori clarithromycin resistance and therapeutic outcome: benefits and limits.

INTRODUCTION: Primary clarithromycin resistance is increasing worldwide, and it has been regarded as the main factor reducing the efficacy of Helicobacter pylori therapy. However, the clinical consequence of either phenotypic or genotypic resistance still remains unclear. This study aimed to evaluate: (i) the concordance between phenotypic (culture) and genotypic (real-time PCR) tests in assessing primary clarithromycin resistance; and (ii) the role of both in therapeutic outcome. METHODS: A post hoc subgroup study was selected from a double-blind, placebo-controlled trial, enrolling 146 patients with dyspepsia or peptic ulcers never previously treated. Real-time PCR and Etest on bacterial culture for assessing clarithromycin resistance were performed. [(13)C]urea breath test (UBT), histology and rapid urease tests at entry and UBT after 4-8 weeks were used to assess infection and eradication. All patients received a 10 day therapy. RESULTS: Prevalence of clarithromycin phenotypic resistance was significantly lower as compared with genotypic resistance (18.4% versus 37.6%, P < 0.001). A concordance between the two methods was present in 71.2% of cases. A significant difference in the eradication rate was seen between clarithromycin-susceptible and -resistant strains, when assessed with either Etest (92.4% versus 55.5%, P < 0.001) or a PCR-based method (94.5% versus 70.9%; P < 0.001). Of note, the eradication rate showed the lowest value (30.7%) when phenotypic bacterial resistance was genetically linked to the A2143G point mutation. CONCLUSIONS: This study showed that: (i) there is a relevant discordance between the two methods; and (ii) phenotypic clarithromycin resistance markedly reduces H. pylori eradication when it is linked to a specific point mutation.

13C-urea breath test values and Helicobacter pylori eradication.

Delta over baseline (DOB) values of 13C-urea breath test (UBT) have been shown to be predictive of H. pylori eradication following therapy. This was a post hoc analysis of a large, double-blind, randomized trial. Consecutive patients with a positive UBT underwent upper endoscopy. H. pylori strains were tested for clarithromycin resistance. All patients received an eradication therapy with either a standard 10-day triple therapy or a 10-day sequential regimen. The infection was considered cured when two consecutive UBTs were negative. Basal DOB values were categorized as low (<16), intermediate (16-35), or high (>35). A total of 282 patients were selected. Eradication rates did not differ between patients with high and low DOB values. No significant difference in DOB values emerged between patients infected with clarithromycin-susceptible and clarithromycin-resistant strains. Under multivariate analysis, DOB values did not influence the bacterial eradication, which was significantly affected only by the presence of clarithromycin resistance. This large analysis failed to demonstrate a role for DOB value in H. pylori eradication with either a 10-day triple or sequential therapy.