Therapeutic Strategies to Combat Increasing Rates of Multidrug Resistant Pathogens.

The emergence of antimicrobic-resistant infectious pathogens and the consequent rising in the incidence and prevalence of demises caused by or associated to infections which are not sensitive to drug treatments is one of today's major global health challenges. Antimicrobial resistance (AMR) can bring to therapeutic failure, infection's persistence and risk of serious illness, in particular in vulnerable populations such as the elderly, patients with neoplastic diseases or the immunocompromised. It is assessed that AMR will induce until 10 million deaths per year by 2050, becoming the leading cause of disease-related deaths. The World Health Organisation (WHO) and the United Nations General Assembly urgently call for new measures to combat the phenomenon. Research and development of new antimicrobial agents has decreased due to market failure. However, promising results are coming from new alternative therapeutic strategies such as monoclonal antibodies, microbiome modulators, nanomaterial-based therapeutics, vaccines, and phages. This narrative review aimed to analyse the benefits and weaknesses of alternative therapeutic strategies to antibiotics which treat multidrug-resistant bacterial infections.

The importance of antibiotic treatment duration in antimicrobial resistance.

Antimicrobial resistance (AMR) poses a significant threat to global health, leading to increased deaths from drug-resistant infections and escalates healthcare costs. Often termed a "silent pandemic," AMR occurs when pathogens become resistant to antimicrobial drugs, enabling their proliferation and spread. Inappropriate antibiotic usage is a major contributor to this phenomenon, which also extends to fungal infections. In particular, the duration of antibiotic therapy is a crucial aspect, with evidence suggesting that prolonged use can heighten bacterial resistance and harm the human microbiota. In fact, studies comparing short-term versus long-term antibiotic therapies show no significant difference in traditional treatments. In addition, therapeutic drug monitoring allows personalized antibiotic regimens, optimizing dosage and duration to minimize resistance and adverse effects. As a result, clinicians should regularly reassess treatment effectiveness, utilizing techniques like antibiotic timeout and de-escalation therapy to avoid prolonged antibiotic use and mitigate resistance. All these strategies are crucial to prevent and counter the phenomenon of antimicrobial resistance.

Advances in Therapeutic Strategies for the Management of Clostridioides difficile Infection.

The infection caused by Clostridioides difficile represents one of the bacterial infections with the greatest increase in incidence among nosocomial infections in recent years. C. difficile is a Gram-positive bacterium able to produce toxins and spores. In some cases, infection results in severe diarrhoea and fulminant colitis, which cause prolonged hospitalisation and can be fatal, with repercussions also in terms of health economics. C. difficile is the most common cause of antibiotic-associated diarrhoea in the healthcare setting. The problem of bacterial forms that are increasingly resistant to common antibiotic treatments is also reflected in C. difficile infection (CDI). One of the causes of CDI is intestinal dysmicrobialism induced by prolonged antibiotic therapy. Moreover, in recent years, the emergence of increasingly virulent strains resistant to antibiotic treatment has made the picture even more complex. Evidence on preventive treatments to avoid recurrence is unclear. Current guidelines indicate the following antibiotics for the treatment of CDI: metronidazole, vancomycin, and fidaxomycin. This short narrative review provides an overview of CDI, antibiotic resistance, and emerging treatments.

A Short Update on the Use of Monoclonal Antibodies in COVID-19.

Monoclonal antibodies in the prophylaxis and treatment of COVID-19 have been crucial in reducing severe infections when vaccines were unavailable. However, as the virus and its variants have changed over time, the effectiveness of monoclonal antibodies has been questioned. This technical note highlights the need to assess the antiviral activity of these antibodies against new variants and adapt treatment strategies accordingly. On the one hand, in vitro studies have suggested reduced susceptibility of the latest variants to monoclonal antibodies, whereas clinical data still show benefits in reducing severe illness and mortality, indicating that laboratory results do not always mirror real-world outcomes. As a result, although resistance to monoclonal antibodies can develop over time, they could still have an important role in COVID-19 treatment, especially when used in combination, and ongoing research aims to identify effective antibodies against new variants.

Could CT finding of gas in the sole mesenteric artery be a sign of a severe acute ischemia? Presentation of a rare fatal case and a literature review.

Contrast-enhanced abdominal CT is the gold standard for the diagnosis of acute mesenteric ischemia (AMI). CT findings include several anomalies like bowel wall thickening, thinning, attenuation, decreased enhancement, dilated fluid-filled loops, pneumatosis, and portal venous gas. A rare case of gas found only in the superior mesenteric artery (SMA) is presented. A contrast-enhanced CT scan was performed in emergency on an 80-year-old man with vague and diffuse abdominal pain, which showed findings of occlusive AMI. Gas was found in the context of the SMA and its branches, but not in the mesenteric and portal veins. The patient underwent emergency surgery but he died the next day in the intensive care unit for complications. The rare CT finding of gas in SMA during an AMI should be considered a radiological sign of irreversible intestinal damage: surgical prompt intervention is needed, even if the mortality rate is high.

Cost-effectiveness analysis of revisional Roux-en-Y gastric bypass: laparoscopic vs. robot assisted.

There is controversy over the possible advantages of the robotic technology in revisional bariatric surgery. The aim of this study is to report the experience of a high-volume bariatric center on revisional Roux-en-Y gastric bypass with robot-assisted (R-rRYGB) and laparoscopic (L-rRYGB) approaches, with regards to operative outcomes and costs. Patients who underwent R-rRYGB and L-rRYGB between 2008 and 2021 were included. Patients' baseline characteristics and perioperative data were recorded. The primary endpoint was the overall postoperative morbidity. A full economic evaluation was performed. One-way and two-way sensitivity analyses were performed on laparoscopic anastomotic leak and reoperation rates. A total of 194 patients were included: 44 (22.7%) L-rRYGB and 150 (77.3%) R-rRYGB. The robotic approach was associated with lower overall complication rate (10% vs. 22.7%, p = 0.038), longer operative time, and a reduced length of stay compared to L-rRYGB. R-rRYGB was more expensive than L-rRYGB (mean difference 2401.1€, p < 0.001). The incremental cost-effective ratio (ICER) was 18,906.3€/complication and the incremental cost-utility ratio was 48,022.0€/QALY (quality-adjusted life years), that is below the willingness-to-pay threshold. Decision tree analysis showed that L-rRYGB was the most cost-effective strategy in the base-case scenario; a probability of leak ≥ 13%, or a probability of reoperation ≥ 14% following L-rRYGB, or a 12.7% reduction in robotic costs would be required for R-rRYGB to become the most cost-effective strategy. R-rRYGB was associated with higher costs than L-rRYGB in our base-case scenario. However, it is an acceptable alternative from a cost-effectiveness perspective.

Multicenter retrospective cohort Italian study on elective laparoscopic cholecystectomy performed by the surgical residents.

PURPOSE: This retrospective multicenter cohort study aimed to evaluate the clinical outcomes (mortality rate, operative time, complications) of elective laparoscopic cholecystectomy (LC) when performed by a surgical resident in comparison to experienced consultant in the backdrop of Italian academic centers. METHODS: Retrospective review of all patients undergoing elective LC between January 2016 and January 2022 at six teaching hospitals across Italy was performed. Cases were identified using the Current Procedural Terminology (CPT) code 5123 (LC without cholangiogram). All cases of emergency surgery, ASA score > 3, or when cholecystectomy was performed with another surgical procedure, were excluded. All suitable cases were divided into 2 groups based on primary surgeon: consultant or senior resident. Main outcome was complication rates (intraoperative and peri/postoperative); secondary outcomes included operative time, the length of stay, and the rate of conversion to open. RESULTS: A total of 2331 cases (1425 females) were included, of which, consultants performed 1683 LCs (72%), while the residents performed 648 (28%) surgeries. The groups were statistically comparable regarding demographics, history of previous abdominal surgery, operative time, or intraoperative complications. The rate of conversion to open cholecystectomy was 1.42% for consultant and none for resident (p = 0.02). A statistically significant difference was observed between groups regarding the average length of stay (2.2 ± 3 vs 1.6 ± 1.3 days p = 0.03). Similarly, postoperative complications (1.7% vs 0.5%) resulted in statistically significant (p = 0.02) favoring resident group. CONCLUSIONS: Our study demonstrates that in selected patients, senior residents can safely perform LC when supervised by senior staff surgeons.

Robot-assisted minimally invasive esophagectomy (RAMIE) with side-to-side semi-mechanical anastomosis: analysis of a learning curve.

Minimally invasive esophagectomy (MIE) reduces mortality and morbidity related to esophageal surgery, but a long learning curve is necessary due to the technical difficulties of thoracoscopy (35 to 119 patients required as reported in literature). Robot-assisted minimally invasive esophagectomy (RAMIE) with side-to-side semi-mechanical (SM) anastomosis may shorten completion of the learning curve. We present the results of the first 40 RAMIEs performed by a single surgeon with experience in esophageal and minimally invasive surgery. Patients included in this study underwent RAMIE between April 1, 2018 and April 30, 2021. According to the risk-adjusted cumulative sum analysis for postoperative complications, the first 19 patients were compared to the last 21. Pulmonary complications and atrial fibrillation occurred in 2.5% and 5% of cases, respectively. A single case of anastomotic leak in the early group was registered. Thirty-day mortality was 2.5%. R0 resection was obtained in all cases. No anastomotic strictures occurred during the follow-up (median of 20 months). A significant difference between the early group and the late one was observed for median operative time (425 vs 393 min, p = 0.001), estimated intraoperative blood loss (100 vs 50 ml, p = 0.003), Intensive Care Unit stay (days 2 vs 1, p = 0.004), hospital stay (days 13 vs 10, p = 0.007) and number of lymph nodes harvested (17 vs 21, p = 0.020). In conclusion, this study showed RAMIE to be safe and effective even in the early phase of its application. The learning curve resulted shorter than in MIE, with 19 patients needed to gain proficiency in our series.

COVID-19 Related Acro-Ischemic Neuropathic-like Painful Lesions in Pediatric Patients: A Case Series.

BACKGROUND: A variety of skin manifestations have been associated with COVID-19 infection. Acral lesions on hands and feet, closely resembling chilblains, have been reported in association with COVID-19, which are nonspecific. These acro-ischemic painful lesions have been described mainly in asymptomatic and mildly symptomatic pediatric COVID-19 positive patients, without a precise pathogenetic mechanism. COVID-19-induced chilblains may portend an indolent course and a good outcome. In young patients, the IFN-1 response induces microangiopathic changes and produces a chilblain lupus erythematosus-like eruption with vasculitic neuropathic pain features. OBJECTIVES: This paper presented a case series of pediatric patients with COVID-19-related skin lesions and neuropathic-like pain. METHODS: Clinical outcomes were collected from 11 patients diagnosed with painful erythematous skin lesions with neuropathic-like pain and positive IgG for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RESULTS: It is a mildly symptomatic condition not related to severe pain rates, and it is treated with paracetamol due to the transitory nature of the problem, which provides good results. CONCLUSIONS: A particular point of interest is skin lesion manifestation as a further indirect sign of SARS-CoV-2 infection. Due to the initial manifestation of chilblains in pauci-symptomatic pediatric patients, they need to be immediately tested and isolated. Chilblains can be considered a clinical clue to suspect SARS-CoV-2 infection and help in early diagnosis, patient triage, and infection control.

Laparoscopic bariatric surgery is safe during phase 2-3 of COVID-19 pandemic in Italy: A multicenter, prospective, observational study.

BACKGROUND: Sars-Cov-2 epidemic in Italy caused one of the greatest 2020 European outbreaks, with suspension of elective bariatric/metabolic surgery (BMS). From May 2020 a significant decline of the epidemic has been observed (phase 2); National Health Service protocols permitted elective BMS' resumption. A new, more severe COVID-19 surge, the "second wave", started on October 2020 (phase 3). AIM: The primary end point was to analyze the outcomes of any Sars-Cov-2 infection and related morbidity/mortality within 30 POD after laparoscopic BMS during phase 2-3; secondary end points were readmission and reoperation rates. METHODS: Study design prospective, multicenter, observational. SETTING: Eight Italian high-volume bariatric centers. All patients undergoing BMS from July 2020 through January 2021 were enrolled according to the following criteria: no Sars-Cov-2 infection; primary procedures; no concomitant procedure; age > 18 < 60 years; compensated comorbidities; informed consent including COVID-19 addendum; adherence to specific admission, in-hospital and follow-up protocols. Data were collected in a prospective database. Patients undergone BMS during July-December 2019 were considered a control group. RESULTS: 1258 patients were enrolled and compared with 1451 operated on in 2019, with no differences for demographics, complications, readmission, and reintervention rates. Eight patients (0·6%) tested positive for Sars-Cov-2 infection after discharge, as well as and 15 healthcare professionals, with no related complications or mortality. CONCLUSIONS: Introduction of strict COVID-19 protocols concerning the protection of patients and health-care professionals guaranteed a safe resumption of elective BMS in Italy. The safety profile was, also, maintained during the second wave of outbreak, thus allowing access to a cure for the obese population.

Bariatric surgery in over 60 years old patients: is it worth it?

The high prevalence of obesity in the elderly and the increase in life expectancy pushed up the age limit as an indication to bariatric surgery. Nevertheless, results on safety and effectiveness of these procedures in over 60 years old population are still controversial. Objectives of the study were to evaluate the safety and effectiveness of bariatric surgery in the elderly. A prospectively collected database was queried for patients older than 60 years who underwent laparoscopic bariatric procedures between 2010 and 2017 at a single institution. These patients were matched with a group of younger patients who had the same procedure in the same period of time. Basal characteristic, intra- and post-operative data were compared. Patients were followed up at 36 months reporting the percentage of excess weight loss (%EWL) and comorbidities remission rate. A total of 100 patients ≥ 60 years old were included (Group 1) and matched with a control group of 96 patients < 60 years (Group 2). Post-operative complications rate was similar (15.0% versus 10.4% p = 0.395). %EWL at 36 months was significantly higher in Group 2 (44.6% versus 68.2% p < 0.001), while remission of medical morbidities was similar in both groups, with a higher rate for type 2 diabetes (T2D) remission among older people (p = 0.017). Patients older than 60 years have post-operative outcomes comparable to younger population. Long-term results are inferior in terms of %EWL, but similar regarding morbidities remission rates, with particular benefits on T2D.

Management of Hemorrhoidal Disease in Special Conditions: A Word of Caution.

BACKGROUND: Hemorrhoids are a common disease that is often considered an easy problem to solve. Unfortunately, some particular clinical conditions, including Inflammatory Bowel Diseases (IBD), pregnancy, immunosuppression, coagulopathy, cirrhosis with portal hypertension, and proctitis after radiotherapy, challenge hemorrhoids management and the outcomes. METHODS: Research and online contents related to hemorrhoids' treatment in special conditions are reviewed in order to help colorectal surgeons in daily practice. RESULTS: There are very limited data about the outcomes of hemorrhoids treatment in these subgroups of patients. Patients in pregnancy can be effectively treated with medical therapy, reserving surgical intervention in highly selected and urgent cases. In case of thrombosed haemorrhoids, the excision allows a fast symptoms' resolution, with a low incidence of recurrence and a long remission interval. In case of immunosuppressed patients, there is no consensus for the best treatment, even in most HIV positive patients, a surgical procedure can be safely proposed when indicated. There is no sufficient data in the literature related to transplanted patients. The surgical treatment of hemorrhoids in patients with IBD, especially Crohn's Disease, can be unsafe, although there is a paucity of literature on this topic. In case of previous pelvic radiotherapy, it must always be considered that severe complications, like abscesses and fistulas with subsequent pelvic and retroperitoneal sepsis, can occur after surgical treatment of hemorrhoids, so a conservative treatment is advocated. Moreover, caution is recommended in treating patients with coagulopathy, considering possible complications (mostly bleeding) also after outpatient treatments. In case of portal hypertension and cirrhosis, a 'conservative treatment' is recommended. Bleeding hemorrhoids can be treated with hemorrhoidectomy when they do not respond to other treatments. CONCLUSION: International literature is very scant about the treatment of patients affected by hemorrhoids in particular situations. A word of caution and concern even about the indication for minor outpatient procedures must be expressed in these patients, in order to avoid possible life-threatening complications. The first-line treatment is the conservative medical approach associated with the treatment of the primary disease.

Protracted low dose of oral vinorelbine and temozolomide with whole-brain radiotherapy in the treatment for breast cancer patients with brain metastases.

PURPOSE: The management of brain metastases (BM) from breast cancer (BC) needs to be improved, and new therapeutic strategies are urgently requested. In this view, we have evaluated the efficacy, tolerability, and safety of concurrent low protracted dose of temozolomide (TMZ), metronomic oral vinorelbine (VNB), and radiotherapy in BC women with previously untreated BM. METHODS: Thirty-six patients with newly diagnosed BM were treated with TMZ orally administered at a dose of 75 mg/m(2) during whole-brain radiotherapy, followed by 4 weeks off-therapy and a subsequent administration of oral 70 mg/m(2) VNB fractionated in days 1, 3, and 5, weekly for three consecutive weeks plus TMZ at 75 mg/m(2) on days 1-21, all every 4 weeks for up to 12 additional cycles. The primary end point was the evaluation of the objective response rate (ORR). RESULTS: Three complete responses and 16 partial responses have been achieved with an ORR of 52 % (95 % CI 38-67 %) that exceeded the target activity per study design. The median progression-free survival and overall survival were 8 and 11 months, respectively. The schedule appeared to be well tolerated, and side effects were generally mild. The functional assessment of cancer therapy-breast (FACT-B) analysis showed a significant positive change during the study. CONCLUSIONS: In conclusion, the treatment was safe and a significant number of objective responses were observed with a significant improvement in quality of life demonstrated by FACT-B. On the basis of the present results, a large randomized trial is warranted in BC patients with previously untreated BM.

Determination of dimethyl fumarate in desiccant and antimould sachets by reversed-phase liquid chromatography.

A method for the determination of dimethyl fumarate (DMF) in desiccant and antimould sachets, employed for protecting consumer products from humidity and mould, has been developed. The method is based on a solid-liquid extraction followed by HPLC-UV analysis. The method was validated with respect to recovery, linearity, limits of detection and quantitation and precision. The recovery was 98%. The correlation coefficient value (r) was equal to 0.94. Both intra- and inter-day precisions were studied at several concentration levels, being satisfactory in all cases (RSD < 5). Limits of detection and quantification values were in the low microgram per gram level, thus allowing the determination of DMF at concentrations below the limit established (0.1 mg/kg) by the recent EU Directive (Decision 2009/251/EC). The proposed procedure was applied for the determination of the target compound in 41 desiccant and antimould samples. DMF was detected in 39.0% of samples and its content in many samples exceeded the legal limits. The results of our analysis highlight the high risk of exposure to this powerful allergic sensitizer for consumers.

[Chronic pain after inguinal hernia mesh repair: possible role of surgical manipulation of the inguinal nerves. A prospective multicentre study of 973 cases]. / Il dolore cronico dopo ernioplas ica inguinale con protesi: il possibile ruolo della manipolazione chirurgica dei nervi del canale inguinale.

The aim of the study was to evaluate whether the surgical treatment reserved for the ilioinguinal, iliohypogastric and genital branches of the genitofemoral nerves, during open hernia mesh repair, is effective in reducing chronic post-operative pain. A multicentre prospective study involving 11 Italian Institutions led to the recruitment of 973 cases of hernioplasty. All surgeons were asked to report whether or not each nerve had been identified and preserved or divided. The main endpoint of the study was the evaluation of moderate-severe chronic pain at 6 months and 1 year. Overall, presence of groin pain at 6 months and 1 year follow-up was 9.7% and 4.1%, respectively. Pain was mild in 7.9% and moderate-to-severe in 2.1% at 6 months, and mild in 3.6% and moderate-to-severe in 0.5% at 1 year. Univariate and multivariate analysis showed that lack of identification of nerves is significantly correlated with presence of chronic pain, the risk of developing inguinal pain increasing with the number of nerves not detected. Likewise, division of nerves was clearly correlated with presence of chronic pain. The present findings indicate that identification and preservation of nerves during open inguinal hernia repair reduce chronic incapacitating groin pain.

Influence of preservation versus division of ilioinguinal, iliohypogastric, and genital nerves during open mesh herniorrhaphy: prospective multicentric study of chronic pain.

OBJECTIVE: To evaluate whether the various surgical treatment reserved for ilioinguinal, iliohypogastric, and genital branch of the genitofemoral nerves, during open hernia mesh repair, is effective in reducing chronic postoperative pain. BACKGROUND: Interest in chronic groin pain following herniorrhaphy has escalated, in recent years, due both to treatment and legal implications. However, much debate still exists concerning which treatment to reserve for the 3 inguinal sensory nerves. METHODS: A multicentric prospective study involving 11 Italian institutions led to the recruitment of 973 cases of hernioplasty. All surgeons were asked to report whether or not each nerve had been identified and preserved or divided. The main endpoint of the study was the evaluation of moderate to severe chronic pain at 6 months and 1 year. RESULTS: Overall, the presence of groin pain at the 6-month and 1-year follow-up was 9.7% and 4.1%, respectively. Pain was mild in 7.9% and moderate to severe in 2.1%, at 6 months, and mild in 3.6% and moderate to severe in 0.5%, at 1 year. Univariate and multivariate analysis showed that lack of identification of nerves is significantly correlated with presence of chronic pain, the risk of developing inguinal pain increasing with the number of nerves not detected. Likewise, division of nerves was clearly correlated with presence of chronic pain. CONCLUSIONS: The present findings indicate that identification and preservation of nerves during open inguinal hernia repair reduce chronic incapacitating groin pain and that, in the majority of patients with chronic pain at 6 months, the pain at 1 year is resolved only with conservative or medical treatment.