Investigating cortical excitability and inhibition in patients with schizophrenia: A TMS-EEG study.

BACKGROUND: Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) has widely been used as a non-invasive brain stimulation tool to assess excitation/inhibition (E/I) balance. E/I imbalance is a putative mechanism underlying symptoms in patients with schizophrenia. Combined TMS-electroencephalography (TMS-EEG) provides a detailed examination of cortical excitability to assess the pathophysiology of schizophrenia. This study aimed to investigate differences in TMS-evoked potentials (TEPs), TMS-related spectral perturbations (TRSP) and intertrial coherence (ITC) between patients with schizophrenia and healthy controls. MATERIALS AND METHODS: TMS was applied over the motor cortex during EEG recording. Differences in TEPs, TRSP and ITC between the patient and healthy subjects were analysed for all electrodes at each time point, by applying multiple independent sample t-tests with a cluster-based permutation analysis to correct for multiple comparisons. RESULTS: Patients demonstrated significantly reduced amplitudes of early and late TEP components compared to healthy controls. Patients also showed a significant reduction of early delta (50-160 ms) and theta TRSP (30-250ms),followed by a reduction in alpha and beta suppression (220-560 ms; 190-420 ms). Patients showed a reduction of both early (50-110 ms) gamma increase and later (180-230 ms) gamma suppression. Finally, the ITC was significantly lower in patients in the alpha band, from 30 to 260 ms. CONCLUSION: Our findings support the putative role of impaired GABA-receptor mediated inhibition in schizophrenia impacting excitatory neurotransmission. Further studies can usefully elucidate mechanisms underlying specific symptoms clusters using TMS-EEG biometrics.

Functional outcomes after transanal total mesorectal excision (TaTME): a random forest analysis to predict patients' outcomes.

PURPOSE: Anorectal, sexual, and urinary dysfunction are common issues after rectal cancer surgery, although seldom explored. The primary aim of this study was to investigate postoperative anorectal functional results. METHODS: Patients with mid/low-rectal cancer treated with transanal TME (TaTME) with primary anastomosis with/without diverting stoma between 2015 and 2020 were reviewed and selected if they had a minimum follow-up of 6 months (from the primary procedure or stoma reversal). Patients were interviewed using validated questionnaires and the primary outcome was bowel function based on Low Anterior Resection Syndrome (LARS) scores. Statistical analyses were performed to identify clinical/operative variables correlated with worse outcomes. A random forest (RF) algorithm was computed to classify patients at a greater risk of minor/major LARS. RESULTS: Ninety-seven patients were selected out of 154 TaTME performed. Overall, 88.7% of the patients had a protective stoma and 25.8% reported major LARS at mean follow-up of 19.0 months. Statistical analyses documented that age, operative time, and interval to stoma reversal correlated with LARS outcomes. The RF analysis disclosed worse LARS symptoms in patients with longer operative time (> 295 min) and stoma reversal interval (> 5.6 months). If the interval ranged between 3 and 5.6 months, older patients (> 65 years) reported worse outcomes. Finally, no statistical difference was documented when comparing the rate of minor/major LARS in the first 27 cases versus others. CONCLUSION: One-quarter of the patients developed major LARS after TaTME. An algorithm based on clinical/operative variables, such as age, operative time, and time to stoma reversal, was developed to identify categories at risk for LARS symptoms.

Surgical or Endovascular Treatment of MCA Aneurysms: An Agreement Study.

BACKGROUND AND PURPOSE: MCA aneurysms are still commonly clipped surgically despite the recent development of a number of endovascular tools and techniques. We measured clinical uncertainty by studying the reliability of decisions made for patients with middle cerebral artery (MCA) aneurysms. MATERIALS AND METHODS: A portfolio of 60 MCA aneurysms was presented to surgical and endovascular specialists who were asked whether they considered surgery or endovascular treatment to be an option, whether they would consider recruitment of the patient in a randomized trial, and whether they would provide their final management recommendation. Agreement was studied using κ statistics. Intrarater reliability was assessed with the same, permuted portfolio of cases of MCA aneurysm sent to the same specialists 1 month later. RESULTS: Surgical management was the preferred option for neurosurgeons (n = 844/1320; [64%] responses/22 raters), while endovascular treatment was more commonly chosen by interventional neuroradiologists (1149/1500 [76.6%] responses/25 raters). Interrater agreement was only "slight" for all cases and all judges (κ = 0.094; 95% CI, 0.068-0.130). Agreement was no better within specialties or with more experience. On delayed requestioning, 11 of 35 raters (31%) disagreed with themselves on at least 20% of cases. Surgical management and endovascular treatment were always judged to be a treatment option, for all patients. Trial participation was offered to patients 65% of the time. CONCLUSIONS: Individual clinicians did not agree regarding the best management of patients with MCA aneurysms. A randomized trial comparing endovascular with surgical management of patients with MCA aneurysms is in order.

Open versus laparoscopic gastrectomy for advanced gastric cancer: a propensity score matching analysis of survival in a western population-on behalf of the Italian Research Group for Gastric Cancer.

BACKGROUND: Oncologic outcomes after laparoscopic gastrectomy for advanced gastric cancer in the West have been poorly investigated. The aim of the present study was to compare survival outcomes in patients undergoing curative-intent laparoscopic and open gastrectomy for advanced gastric cancer in several centres belonging to the Italian Research Group for Gastric Cancer. METHODS: Data of patients operated between 2015 and 2018 were retrospectively analysed. Propensity Score Matching was performed to balance baseline characteristics of patients undergoing laparoscopic and open gastrectomy. The primary endpoint was 3-year overall survival. Secondary endpoints were 3-year disease-free survival and short-term outcomes. Multivariable regression analyses for survival were conducted. RESULTS: Data were retrieved from 20 centres. Of the 717 patients included, 438 patients were correctly matched, 219 per group. The 3-year overall survival was 73.6% and 68.7% in the laparoscopic and open group, respectively (p = 0.40). When compared with open gastrectomy, laparoscopic gastrectomy showed comparable 3-year disease-free survival (62.8%, vs 58.9%, p = 0.40), higher rate of return to intended oncologic treatment (56.9% vs 40.2%, p = 0.001), similar 30-day morbidity/mortality. Prognostic factors for survival were ASA Score ≥ 3, age-adjusted Charlson Comorbidity Index ≥ 5, lymph node ratio ≥ 0.15, p/ypTNM Stage III and return to intended oncologic treatment. CONCLUSIONS: Laparoscopic gastrectomy for advanced gastric cancer offers similar rates of survival when compared to open gastrectomy, with higher rates of return to intended oncologic treatment. ASA score, age-adjusted Charlson Comorbidity Index, lymph node ratio, return to intended oncologic treatment and p/ypTNM Stage, but not surgical approach, are prognostic factors for survival.

From mothership to drip-and-ship: Effects of staff shortages at a comprehensive stroke center.

BACKGROUND: Mechanical thrombectomy (MT) has been shown to be effective in the acute phase of ischemic stroke. Current data suggests that the drip-and-ship and mothership telestroke models are equally effective for its administration. We describe the consequences of changing the telestroke model due to staff shortages in a comprehensive stroke center (Besançon), which was replaced by a more distant one (Dijon). METHODS: We conducted a retrospective analysis of all patients referred for MT from January 2015 to December 2018. We analyzed the time between symptom onset and arrival in the angiography suite. We also calculated number of thrombectomies divided by number of days on call, and rate of thrombectomies relative to the number of strokes in each group. RESULTS: In Besançon, 205 patients underwent an MT procedure, versus 43 patients in Dijon. A further four patients were transferred to Dijon but not treated. The time from symptom onset to arrival in the angiography suite was longer for Dijon; 334min versus 281min for Besançon (p<0.001). The percentage of thrombectomies performed per day on call was higher for Besançon: 18.6% versus 13.2% in Dijon (p=0.026). CONCLUSIONS: Over the study period, the time from symptom onset to angiography suite was longer for patients who were transferred to Dijon. The period in which the Besançon hospital experienced the greatest lack of personnel corresponded to a decrease in the number of MTs performed.

Secondary hemophagocytic lymphohystiocytosis in a Rubinstein Taybi syndrome patient.

Rubinstein-Taybi syndrome (RSTS) is an autosomal dominant disorder, caused by variants in CREBBP or EP300. Affected individuals present with distinctive craniofacial features, broad thumbs and/or halluces, intellectual disability and immunodeficiency. Here we report on one RSTS patient who experienced hemophagocytic lymphohystiocytosis (HLH) and disseminated herpes virus 1 ( HSV-1) disease. The clinical picture of RSTS is expanding to include autoinflammatory, autoimmune, and infectious complications. Prompt treatment of HLH and disseminated HSV-1 can lower the mortality rate of these life-threatening conditions.

Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol.

BACKGROUND: The outcome of infants with KMT2A-germline acute lymphoblastic leukaemia (ALL) is superior to that of infants with KMT2A-rearranged ALL but has been inferior to non-infant ALL patients. Here, we describe the outcome and prognostic factors for 167 infants with KMT2A-germline ALL enrolled in the Interfant-06 study. METHODS: Univariate analysis on prognostic factors (age, white blood cell count at diagnosis, prednisolone response and CD10 expression) was performed on KMT2A-germline infants in complete remission at the end of induction (EOI; n = 163). Bone marrow minimal residual disease (MRD) was measured in 73 patients by real-time quantitative polymerase chain reaction at various time points (EOI, n = 68; end of consolidation, n = 56; and before OCTADAD, n = 57). MRD results were classified as negative, intermediate (<5∗10-4), and high (≥5∗10-4). RESULTS: The 6-year event-free and overall survival was 73.9% (standard error [SE] = 3.6) and 87.2% (SE = 2.7). Relapses occurred early, within 36 months from diagnosis in 28 of 31 (90%) infants. Treatment-related mortality was 3.6%. Age <6 months was a favourable prognostic factor with a 6-year disease-free survival (DFS) of 91% (SE = 9.0) compared with 71.7% (SE = 4.2) in infants >6 months of age (P = 0.04). Patients with high EOI MRD ≥5 × 10-4 had a worse outcome (6-year DFS 61.4% [SE = 12.4], n = 16), compared with patients with undetectable EOI MRD (6-year DFS 87.9% [SE = 6.6], n = 28) or intermediate EOI MRD <5 × 10-4 (6-year DFS 76.4% [SE = 11.3], n = 24; P = 0.02). CONCLUSION: We conclude that young age at diagnosis and low EOI MRD seem favourable prognostic factors in infants with KMT2A-germline ALL and should be considered for risk stratification in future clinical trials.

Skip pattern approach toward the early access of innovative anticancer drugs.

BACKGROUND: With the rapid development of innovative anticancer treatments, the optimization of tools able to accelerate the access of new drugs to the market by the regulatory authority is a major issue. The aim of the project was to propose a reliable methodological pathway for the assessment of clinical value of new therapeutic innovative options, to objectively identify drugs which deserve early access (EA) priority for solid and possibly in other cancer scenarios, such as the hematological ones. MATERIALS AND METHODS: After a comprehensive review of the European Public Assessment Report of 21 drugs, to which innovation had previously been attributed by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA), an expert panel formulated an algorithm for the balanced use of three parameters: Unmet Medical Need (UMN) according to AIFA criteria, Added Benefit (AB) according to the European Society for Medical Oncology's Magnitude of Clinical Benefit Scale (ESMO-MCBS) criteria and Quality of Evidence (QE) assessed by the Grades of Recommendation Assessment, Development and Evaluation (GRADE) method. By sequentially combining the above indicators, a final priority status (i.e. EA or not) was obtained using the skip pattern approach (SPA). RESULTS: By applying the SPA to the non-curative setting in solid cancers, the EA status was obtained by 5 out of 14 investigated drugs (36%); by enhancing the role of some categories of the UMN, additional 4 drugs, for a total of 9 (64%), reached the EA status: 2 and 3 drugs were excluded for not achieving an adequate score according to AB and QE criteria, respectively. For hematology cancer, only the UMN criteria were found to be adequate. CONCLUSIONS: The use of this model may represent a reliable tool for assessment available to the various stakeholders involved in the EA process and may help regulatory agencies in a more comprehensive and objective definition of new treatments' value in these contexts. Its generalizability in other national contexts needs further evaluation.

Interobserver Agreement in Scoring Angiographic Results of Basilar Artery Occlusion Stroke Therapy.

BACKGROUND AND PURPOSE: The modified TICI Infarction grading system is a metric currently used to evaluate angiographic results of thrombectomy for large-vessel occlusion in ischemic stroke. Originally designed for evaluating MCA territories, it is currently used for other vessel occlusions, including the posterior circulation. We postulate that the modified TICI use for the posterior circulation is not accurate due to the different vascular territories supplied by vertebrobasilar vasculature, making grading more complex. MATERIALS AND METHODS: We collected angiographic results from 30 patients who presented with acute posterior circulation occlusions between 2015 and 2018 and underwent thrombectomy in our institution. Eight observers were asked to evaluate the TICI scores before and after thrombectomy. The multirater statistics were computed using Fleiss κ analysis. Further data were collected regarding the potential brain territories at risk and the existence of atherosclerotic disease in the basilar artery. RESULTS: The overall agreement κ reached 0.277 (SD, 0.013), which suggests a "fair" agreement among the raters. On average, 45% of observers achieved a high accuracy in predicting brain areas at risk of ischemia. As for the existence of basilar atherosclerotic disease, a high agreement (defined as at least 5 of 6 observers) was seen in 20 of the 30 patients. CONCLUSIONS: Despite TICI being ubiquitous in stroke diagnostics, the high variability of posterior circulation TICI scores calls into question its use in these strokes. Other methods should be developed to assess recanalization in the posterior circulation.

Probiotic intake unmasking a gastro-pleural fistula.

OBJECTIVE: Gastropleural fistula represents a rare clinical event often resulting in an iatrogenic complication of gastrointestinal surgery. Clinical presentation is insidious, patients complain of chronic and non-specific respiratory symptoms and may be conservatively treated for lung infections for several months until detailed tests finally reveal the correct diagnosis. PATIENTS AND METHODS: We describe a case of a healthy patient with an unexpected diagnosis of empyema due to a gastropleural fistula. RESULTS: A 51-year-old man with a past history of splenectomy for cyst was admitted because of high fever and cough. A chest radiography and CT-scan revealed a left-side pneumonia complicated with pleural empyema. Broad spectrum empirical antibiotics and pleural drainage did not significantly improve the clinical picture. While the need for a surgical complex thoracic approach becomes a collective awareness, questions about causes of empyema and its unfavorable evolution in our patient did not initially find a common satisfactory answer. It was only by the identification of probiotics bacteria in the pleural fluid that a gastropleural fistula was suspected, and then, it was confirmed by CT-scan and by digestive endoscopy. A combined thoraco-abdominal surgical treatment was therefore scheduled, leading to progressive improvement till total healing. CONCLUSIONS: Although gastropleural fistula is rare, it is necessary to include this pathological condition in the differential diagnosis of a persistent complicated pneumonia, because early diagnosis and, consequently, surgical management, may significantly impact on the prognosis of these patients. In our case, the detection of probiotics bacteria in the pleural fluid helped us to suspect and to look for the fistula.

Association between colorectal cancer and Streptococcus gallolyticus subsp. pasteuranus (former S. bovis) endocarditis: clinical relevance and cues for microbiota science. Case report and review of the literature.

OBJECTIVE: The purpose of this paper is to contextualize the case of a patient with a synchronous diagnosis of colorectal cancer (CRC) and endocarditis from S. gallolyticus subsp. pasteuranus (former S. Bovis) within the current evidence, in order to determine if this condition is indicative of an underlying CRC and if it has any pathophysiologic significance. PATIENTS AND METHODS: First, we describe the clinical case. Then, we review the literature focused on the association between infections from the former S. Bovis group and CRC and on the possible role of certain microbiota species on the occurrence of CRC. At last, we discuss the implications of this case considering the current evidence. RESULTS: There is a strong association between all the species of the former S. Bovis group and CRC. There is initial evidence that these bacteria may contribute to CRC by a genomic passenger mechanism. CONCLUSIONS: There are two main conclusions for this paper. The first one is that CRC neoplasms and endocarditis from all species of the former S. bovis group have a strong association. Any case of infection by these subspecies should prompt to a diagnostic completion by colonoscopy. The second one is that there is an increased need for detailed reports/series and original articles based on the evaluation of gut microbiota in patients with CRC, with the aim to clarify if the association between bacteria and CRC is causative or sporadic and to better understand the possible causative mechanism of specific bacteria in initiating and promoting CRC.

Safeguard pressure assisted device for local femoral hemostasis in neuroendovascular procedures: A single center study of 879 patients.

BACKGROUND: Various vascular closure devices (VCDs) are available for local hemostasis after percutaneous transfemoral approach for neuroendovascular procedures but they have been associated with an increased complication rate and limitations to a re-puncture of the artery. We evaluated the safety and efficacy of Safeguard® 24 cm pressure assisted device (Merit Medical, West Jordan, UT, USA) and the associated complications. METHODS: From September 2016 to December 2019, 879 patients underwent neuroendovascular procedures via transfemoral approach using an introducer sheath ranging from 4 to 6-French and they were included in a prospective database. We registered the demographic characteristics and procedural factors. We evaluated the device failure and associated complications. RESULTS: The Safeguard® was successful in 862 cases (98.1 %) with post-procedural local bleeding in 17 patients (1.9%). On univariate analysis, an association with local bleeding was observed with age >60 years (Odds ratio [OR] = 3.2, P = 0.04) and the use of an introducer sheath >4 F ([OR] = 3.1, P = 0.007). Female gender, antithrombotic medication and type of procedure (diagnostic or interventional) were not associated with local bleeding. On binary logistic regression analysis, there was association only for age >60 years ([OR] = 3, P = 0.04). CONCLUSION: The Safeguard® 24 cm is safe and efficient. It is simple to use and it can be applied independently from vessel anatomic characteristics. It should though be used with caution in case of a femoral introducer sheath larger than 4 Fr and patients older than 60 years.

When math meets surgery: how to improve femoral interference screw alignment in ACL reconstruction. A cadaveric study.

Transtibial femoral tunnel drilling is still an alternative technique in ACL reconstruction. Femoral interference screw divergence is a potential pitfall associated with transtibial tunnel technique, as angles greater than 15° jeopardize graft fixation. Our mathematical model theorizes the proper degrees of knee flexion during femoral screw insertion and the correct screwdriver position to obtain a minimal divergence of the screw in the femoral tunnel. The cadaveric study confirms our method. Mathematical model: using rototranslation matrices, a correlation is demonstrated between the ACLtibial- guide angle, the knee flexion, and the screwdriver position. A theoretical minimal divergence between femoral interference screw and the femoral tunnel is obtainable following these assumptions: 1) knee hyperflexion during femoral screw insertion is obtained adding a flexion corresponding to the ACL-tibial-guide angle to the flexion while drilling the femoral tunnel; 2) screwdriver position (through the AM portal) is kept parallel to tibial plateau at a rotation of 15° medial to tibial sagittal plane. Cadaveric study: 24 cadaver knees were used. The transtibial tunnel was drilled with an 8 mm drill bit with the help of an ACL tibial guide set at 55°. To simulate femoral tunnel direction, a 2.4 mm K. wire was drilled through the femur with a transtibial 7 mm offset femoral drill guide. To simulate the femoral screw direction, a second 2.4 mm K. wire was drilled from the femoral entry point of the first wire through the femur, with a cannulated screwdriver. Screwdriver direction and knee flexion during the simulation were obtained following two different methods: GROUP A (mathematical model group, 12 knees), screwdriver direction and knee flexion were calculated following the mathematical model; in GROUP B (control group, 12 knees), knee hyperflexion and screwdriver medialization were manually obtained by a senior surgeon. The divergence between the femoral interference screw and the femoral tunnel was identified as the angle formed by the two wires, measured on the plane formed by the direction of the wires. Mean divergence angles between the K. wires were significantly different (p< 0.05) between the groups: GROUP 1 (mathematical rule): 7.25° (SD 2.2); GROUP 2 (free-hand technique): 17.3° (SD 2.9). Our study shows that a minimal divergence between the femoral tunnel and the screwdriver can be achieved simply by following a mathematical rule for correct intraoperative knee flexion and screwdriver position without the need for any specialized instrumentation. Namely, during femoral interference screw insertion through the anteromedial portal: 1) the correct knee flexion is the sum between the knee flexion angle while drilling the transtibial femoral tunnel AND the ACL tibial guide angle used during tibial tunnel drilling; 2) Correct screwdriver position is parallel to the tibial plateau, engaging the femoral tunnel with a position of 15° medial to tibial sagittal plane. This simple concept has clinical relevance in helping the surgeons in obtaining an optimal alignment between the femoral tunnel and the femoral interference screw during transtibial ACL reconstruction. Furthermore, following the assumptions of this study, a starting knee flexion angle around 70° during femoral tunnel drilling seems preferable for ACL reconstruction when the transtibial tunnel technique is used. Indeed, because ACL-tibial-guide angles range commonly from 50° to 60° and in vivo, the maximal intraoperative knee flexion attainable is 130°, a starting knee flexion around 70° is optimal to allows for adding flexion angles up to 60° before reaching the physiological limit value of 130°.

Patients self-mastery of wearable devices for seizure detection: A direct user-experience.

PURPOSE: wearable devices aimed at detecting seizures are rapidly emerging. Continuous collection and optimal data quality are paramount to guarantee the acquisition of clinically meaningful data. It is still unknown how successfully patients can self-manage new technologies and which factors have an impact on this. We assessed the performance of patients managing a wrist-worn device. METHOD: patients wearing a wrist-worn device received a single training session to perform 5 tasks: (1) fitting the device correctly; (2) switching the device on and off; (3) charging the device on a daily basis; (4) pairing the device with a phone or tablet; (5) seeking assistance. Participants were then reviewed every 24 h and, at the end of the study, a Wearable technology Self-management Score (WSS) was calculated according to their performance in the different tasks (0-12). The association between WSS, seizure capture, demographics and clinical characteristics was analysed. RESULTS: Thirty patients were included. The mean WSS score was 9.4 ± 2.1 points. The task more often performed inaccurately was pairing the device with a phone or tablet, followed by performing charging procedures. A strong association was found between WSS and seizure capture (p = 0.019), with higher scores strongly associated with more seizures captured. A WSS of ≥9 was the minimum value of WSS that allowed the device to record all the seizures. Number of AEDs and illness-perception related factors (perceived disease timeline and personal control) were significantly associated with WSS. CONCLUSIONS: Overall, participants demonstrated good performances in self-managing a wrist-worn device. Digital inequalities may extend to variations in how different individuals feel about their own disease and, consequently, manage the technology. These aspects should be addressed when technological solutions are delivered to users.

Precision-based exercise as a new therapeutic option for children and adolescents with haematological malignancies.

Children and adolescents with haematological malignancies (PedHM) are characterized by a severe loss of exercise ability during cancer treatment, lasting throughout their lives once healed and impacting their social inclusion prospects. The investigation of the effect of a precision-based exercise program on the connections between systems of the body in PedHM patients is the new frontier in clinical exercise physiology. This study is aimed at evaluating the effects of 11 weeks (3 times weekly) of combined training (cardiorespiratory, resistance, balance and flexibility) on the exercise intolerance in PedHM patients. Two-hundred twenty-six PedHM patients were recruited (47% F). High or medium frequency participation (HAd and MAd) was considered when a participant joined; > 65% or between 30% and < 64% of training sessions, respectively. The "up and down stairs'' test (TUDS), "6 min walking" test (6MWT), the "5 Repetition Maximum strength" leg extension and arm lateral raise test (5RM-LE and 5RM-ALR), flexibility (stand and reach), and balance (stabilometry), were performed and evaluated before and after training. The TUDS, the 5RM-LE and 5RM-ALR, and the flexibility exercises showed an increase in HAd and MAd groups (P < 0.05), while the 6MWT and balance tests showed improvement only in HAd group (P < 0.0001). These results support the ever-growing theory that, in the case of the treatment of PedHM, 'exercise is medicine' and it has the potential to increase the patient's chances of social inclusion.

Two siblings presenting with novel ADA2 variants, lymphoproliferation, persistence of large granular lymphocytes, and T-cell perturbations.

The presence of large granular lymphocytes has been reported in patients with ADA2 deficiency and T-LGL leukemia. Here we describe two siblings with novel ADA2 variants, expanding the mutational spectrum of ADA2 deficiency. We show that lymphoproliferation, persistence of large granular lymphocytes, T-cell perturbations, and activation of PI3K pathway, measured by means of phosphorylation levels of S6, are detectable in DADA2 patients without T-LGL leukemia.