Italian guidelines for the management of adult individuals with overweight and obesity and metabolic comorbidities that are resistant to behavioral treatment.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of adult patients with overweight or obesity associated with metabolic complications who are resistant to lifestyle modification. METHODS: Surgeons, endocrinologists, gastroenterologists, psychologists, pharmacologists, a general practitioner, a nutritionist, a nurse and a patients' representative acted as multi-disciplinary panel. This GL has been developed following the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. A systematic review and network meta-analysis was performed by a methodologic group. For each question, the panel identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for clinical practice recommendations. Consensus on the direction (for or against) and strength (strong or conditional) of recommendations was reached through a majority vote. RESULTS: The present GL provides recommendations about the role of both pharmacological and surgical treatment for the clinical management of the adult patient population with BMI > 27 kg/m2 and < 40 kg/m2 associated with weight-related metabolic comorbidities, resistant to lifestyle changes. The panel: suggests the timely implementation of therapeutic interventions in addition to diet and physical activity; recommends the use of semaglutide 2.4 mg/week and suggests liraglutide 3 mg/day in patients with obesity or overweight also affected by diabetes or pre-diabetes; recommends semaglutide 2.4 mg/week in patients with obesity or overweight also affected by non-alcoholic fatty liver disease; recommends semaglutide 2.4 mg/week as first-line drug in patients with obesity or overweight that require a larger weight loss to reduce comorbidities; suggests the use of orlistat in patients with obesity or overweight also affected by hypertriglyceridemia that assume high-calorie and high-fat diet; suggests the use of naltrexone/bupropion combination in patients with obesity or overweight, with emotional eating; recommends surgical intervention (sleeve gastrectomy, Roux-en-Y gastric bypass, or metabolic gastric bypass/gastric bypass with single anastomosis/gastric mini bypass in patients with BMI ≥ 35 kg/m2 who are suitable for metabolic surgery; and suggests gastric banding as a possible, though less effective, surgical alternative. CONCLUSION: The present GL is directed to all physicians addressing people with obesity-working in hospitals, territorial services or private practice-and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Indications and Coverage of Metabolic and Bariatric Surgery: A Worldwide IFSO Survey Comparing Different National Guidelines.

INTRODUCTION: Knowing how metabolic and bariatric surgery (MBS) is indicated in different countries is essential information for the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO). AIM: To analyze the indications for MBS recommended by each of the national societies that comprise the IFSO and how MBS is financed in their countries. METHODS: All IFSO societies were asked to fill out a survey asking whether they have, and which are their national guidelines, and if MBS is covered by their public health service. RESULTS: Sixty-three out of the 72 IFSO national societies answered the form (87.5%). Among them, 74.6% have some kind of guidelines regarding indications for MBS. Twenty-two percent are still based on the US National Institute of Health (NIH) 1991 recommendations, 43.5% possess guidelines midway the 1991s and ASMBS/IFSO 2022 ones, and 34% have already adopted the latest ASMBS/IFSO 2022 guidelines. MBS was financially covered in 65% of the countries. CONCLUSIONS: Most of the IFSO member societies have MBS guidelines. While more than a third of them have already shifted to the most updated ASMBS/IFSO 2022 ones, another significant number of countries are still following the NIH 1991 guidelines or even do not have any at all. Besides, there is a significant number of countries in which surgical treatment is not yet financially covered. More effort is needed to standardize indications worldwide and to influence insurers and health policymakers to increase the coverage of MBS.

Allele-specific CRISPR-Cas9 editing of dominant epidermolysis bullosa simplex in human epidermal stem cells.

Epidermolysis bullosa simplex (EBS) is a rare skin disease inherited mostly in an autosomal dominant manner. Patients display a skin fragility that leads to blisters and erosions caused by minor mechanical trauma. EBS phenotypic and genotypic variants are caused by genetic defects in intracellular proteins whose function is to provide the attachment of basal keratinocytes to the basement membrane zone and most EBS cases display mutations in keratin 5 (KRT5) and keratin 14 (KRT14) genes. Besides palliative treatments, there is still no long-lasting effective cure to correct the mutant gene and abolish the dominant negative effect of the pathogenic protein over its wild-type counterpart. Here, we propose a molecular strategy for EBS01 patient's keratinocytes carrying a monoallelic c.475/495del21 mutation in KRT14 exon 1. Through the CRISPR-Cas9 system, we perform a specific cleavage only on the mutant allele and restore a normal cellular phenotype and a correct intermediate filament network, without affecting the epidermal stem cell, referred to as holoclones, which play a crucial role in epidermal regeneration.

Prophylactic surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC CO2) versus standard surgery for gastric carcinoma at high risk of peritoneal carcinomatosis: short and long-term outcomes (GOETH STUDY)-a collaborative randomized controlled trial by ACOI, FONDAZIONE AIOM, SIC, SICE, and SICO.

INTRODUCTION: At the time of diagnosis, 15-20% of gastric carcinomas are in stage T4 or T4b. Furthermore, 5-20% of patients undergoing potentially curative surgery suffer from synchronous or metachronous peritoneal metastases. To date, neither surgery nor systemic chemotherapy successfully controls peritoneal dissemination, offering a limited impact on survival. Peritoneal metastases are in fact responsible for death in around 60% of gastric cancer patients. Several Eastern studies in the past have focused on hyperthermic intraperitoneal chemotherapy (HIPEC) as a prophylactic measure in patients with serosal extension, nodal involvement, and positive peritoneal fluid cytology. Therefore, a new multimodal therapeutic strategy based on aggressive surgery plus new locoregional treatment may prolong survival in this particular clinical scenario. METHODS: This study compares the efficacy of prophylactic surgery (radical gastric resection, appendectomy, resection of the round ligament of the liver, and bilateral adnexectomy) plus hybrid CO2 HIPEC system versus standard surgery in patients with T3-T4 N0-N + gastric adenocarcinoma. Patients will be randomly assigned (1:1 ratio) to the experimental arm or standard surgery. The primary endpoint is to establish the difference in disease-free survival between the groups. The secondary objective is to compare the safety and tolerability of prophylactic surgery plus HIPEC CO2 versus standard surgery. DISCUSSION: Considering the poor prognosis of patients with peritoneal dissemination from gastric cancer, a prophylactic strategy to prevent peritoneal metastases may be beneficial. In patients with gastric cancer at high risk of peritoneal carcinomatosis, we propose aggressive surgical treatment with radical gastrectomy, removal of organs at risk of harbouring tumour cells, and HIPEC. TRIAL REGISTRATION: ClinicalTrials.gov NCT03917173. Registered on 16 April 2019. PROTOCOL VERSION: v1, March 27, 2019. Protocol number: IRFMN-GCC-7813. EudraCT number: 2019-001478-27.

Prevention of malocclusion and the importance of early diagnosis in the Italian young population.

AIM: Malocclusion is an alteration of the normal relationships between skeletal, muscle and dental structures that can lead to impaired functionality as well as aesthetic alteration of the stomatognathic system. Functional alteration can affect various aspects, ranging from chewing ability to respiratory disorders. Paediatricians and dentists are called to prevent and diagnose these conditions as early as possible in order to preserve the patient's health. The purpose of this research is to study the incidence of malocclusion and its relationship with Obstructive Sleep Apnea Syndrome (OSAS) in a young population. Also, the role of paediatricians and dentists in prevention and early diagnosis of this condition was evaluated METHODS: An anonymous survey was given through Google form to 300 Italian children (139 males and 161 females) from different private dental practices in Italy. No personal information that identifies the individuals was collected, and the data was analysed in aggregate form only. All data was collected and statistically analysed. CONCLUSION: The data highlight the patients' good attitude towards dental check-ups, which help to intercept malocclusions. Unlike the past, the knowledge of the importance of oral health and dental occlusion is high among young patients, parents and paediatricians. This study underlines the role of paediatricians as key players in the prevention of dental health problems.

Ischemic Lesions in the Brain of a Neonate With SARS-CoV-2 Infection.

AIM: To describe a term newborn with acquired severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and multisystem involvement including seizures associated to ischemic lesions in the brain. BACKGROUND: Coronavirus disease 2019 (COVID-19) is predominantly a respiratory infection, but it may affect many other systems. Most pediatric COVID-19 cases range from asymptomatic to mild-moderate disease. There are no specific clinical signs described for neonatal COVID-19 infections. In children, severe central nervous system compromise has been rarely reported. CASE DESCRIPTION: We describe a 17-day-old newborn who acquired a SARS-CoV-2 infection in a family meeting that was admitted for fever, seizures and lethargy and in whom consumption coagulopathy, ischemic lesions in the brain and cardiac involvement were documented. CONCLUSIONS: SARS-CoV-2 neonatal infection can be associated with multi-organic involvement. In our patient, significant central nervous system compromise associated to ischemic lesions and laboratory findings of consumption coagulopathy were found. CLINICAL SIGNIFICANCE: Although neonatal SARS-CoV-2 infections are infrequent, they can be associated with multi-organic involvement. Neonatologists and pediatricians should be aware of this unusual way of presentation of COVID-19 in newborn infants.

The epistatic interaction between the dopamine D3 receptor and dysbindin-1 modulates higher-order cognitive functions in mice and humans.

The dopamine D2 and D3 receptors are implicated in schizophrenia and its pharmacological treatments. These receptors undergo intracellular trafficking processes that are modulated by dysbindin-1 (Dys). Indeed, Dys variants alter cognitive responses to antipsychotic drugs through D2-mediated mechanisms. However, the mechanism by which Dys might selectively interfere with the D3 receptor subtype is unknown. Here, we revealed an interaction between functional genetic variants altering Dys and D3. Specifically, both in patients with schizophrenia and in genetically modified mice, concomitant reduction in D3 and Dys functionality was associated with improved executive and working memory abilities. This D3/Dys interaction produced a D2/D3 imbalance favoring increased D2 signaling in the prefrontal cortex (PFC) but not in the striatum. No epistatic effects on the clinical positive and negative syndrome scale (PANSS) scores were evident, while only marginal effects on sensorimotor gating, locomotor functions, and social behavior were observed in mice. This genetic interaction between D3 and Dys suggests the D2/D3 imbalance in the PFC as a target for patient stratification and procognitive treatments in schizophrenia.

Psychological status and role of caregivers in the neuro-rehabilitation of patients with severe Acquired Brain Injury (ABI).

OBJECTIVE: To investigate the relationships between (a) the psychological status of the caregiver, (b) the specific features of caregiving as perceived by the cognitive therapist in neuro-rehabilitation, (c) the caregivers' subjective approach to neuro-rehabilitation, and (d) the functional outcome of the patient. METHODS: Twenty-four patients with severe acquired brain injury and their 24 caregivers participated in this observational study. Caregivers underwent a psychological assessment examining emotional distress, burden and family strain; their subjective approach to neuro-rehabilitation has been evaluated by two specific answers. The patients' cognitive therapists responded to an ad-hoc questionnaire, namely the "Caregiving Impact on Neuro-Rehabilitation Scale" (CINRS), evaluating the features (i.e., amount and quality) of caregiving. Finally, the functional outcome of the patient was assessed through standardized scales of disability and cognitive functioning. RESULTS: The caregivers' psychological well-being was associated to the features of caregiving, to the subjective approach to neuro-rehabilitation, and to the functional recovery of their loved ones. A better caregivers' approach to neuro-rehabilitation was also associated to an overall positive impact of caregiving in neuro-rehabilitation and to a better functional outcome of the patients. CONCLUSIONS: We posited a virtuous circle involving caregivers within the neuro-rehabilitation process, according to which the caregivers' psychological well-being could be strictly associated to a better level of caregiving and to a better functional outcome of the patients that, in turn, could positively influence the caregivers' psychological well-being. Although preliminary, these results suggest a specific psycho-educational intervention, aimed at improving the caregivers' psychological well-being and at facilitating their caring of the loved one.

Evidence of taxonomy for Developmental Topographical Disorientation: Developmental Landmark Agnosia Case 1.

We report Developmental Landmark Agnosia (DLA) in a 6-year-old boy (L.G.) who was referred to us for congenital prosopagnosia (see Pizzamiglio et al., 2017 , in which both testing and rehabilitation of Congenital Prosopagnosia are reported). We investigated his performance using a neuropsychological battery and eye movement recordings. The assessment showed the presence of deficits in recognizing familiar places (along with Congenital Prosopagnosia), but not common objects. Eye movement recordings confirmed his problems in recognizing familiar landmarks and misrecognition of unfamiliar places. L.G. is the first evidence of a DLA, suggesting identification of taxonomy of navigational disorders in Developmental Topographical Disorientation is possible, as in the Acquired Topographical Disorientation.

Three-dimensional stereophotogrammetric analysis of nasolabial soft tissue effects of rapid maxillary expansion: a systematic review of clinical trials.

The aim of this systematic review is to analyse the quality and clinical evidence in the literature analysing, through 3D stereophotogrammetry, the nasolabial soft tissue modifications that may occur after rapid maxillary expansion (RME). This systematic literature review was based on the PRISMA-P statement and was registered in the PROSPERO database with the following protocol ID: CRD42017079875. Pubmed, Cochrane, EBSCO, Scopus, Web of Science databases were searched with no restriction of year or publication status. Selection criteria were: randomised clinical trials, controlled clinical trials, cohort studies, cross-sectional studies, case-control studies on patients with unilateral/bilateral crossbite, transverse maxillary deficiency and crowding, treated with RME and monitored by 3D stereophotogrammetry. 652 articles were retrieved in the initial search. After the review process, 11 full-text articles met inclusion criteria. After the evaluation process, 4 publications were included for the present literature review. Due to the heterogeneous methodology meta-analysis was not possible; consequently, a systematic assessment of the studies and summary of the findings from the available evidence were used to answer the research question. The maximum widening of the alar cartilage is 1.41 ± 0.95 mm, whose clinical significance is open to question. The effect of RME on the mouth width remains controversial. In Altindis et al., the difference between pre-treatment and post-treatment mouth width (1.80 mm increment in the banded RME group) was statistically significant, while in Baysal 1.86 mm was considered a non-significant value. Inconsistencies and limitations in the study population and measurement protocols were detected between studies. These data underline the necessity for updated guidelines that allow to standardise, for this type of study, sample selection, measurement methods and collection of results.

Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex.

The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (>50 days) while having unaltered recent memories (<24 h). COMT selectively and reversibly modulated the recall of remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC.

InP-InxGa1-xAs core-multi-shell nanowire quantum wells with tunable emission in the 1.3-1.55 µm wavelength range.

The usability and tunability of the essential InP-InGaAs material combination in nanowire-based quantum wells (QWs) are assessed. The wurtzite phase core-multi-shell InP-InGaAs-InP nanowire QWs are characterised using cross-section transmission electron microscopy and photoluminescence measurements. The InP-InGaAs direct interface is found to be sharp while the InGaAs-InP inverted interface is more diffused, in agreement with their planar counterpart. Bright emission is observed from the single nanowires containing the QWs at room temperature, with no emission from the InP core or outer barrier. The tunability of the QW emission wavelength in the 1.3-1.55 µm communication wavelength range is demonstrated by varying the QW thickness and in the 1.3 µm range by varying the composition. The experiments are supported by simulation of the emission wavelength of the wurtzite phase InP-InGaAs QWs in the thickness range considered. The radial heterostructure is further extended to design multiple QWs with bright emission, therefore establishing the capability of this material system for nanowire based optical devices for communication applications.

Predicting the Need for Intra-operative Large Volume Blood Transfusions During Thoraco-abdominal Aortic Aneurysm Repair.

OBJECTIVE: Thoraco-abdominal aortic aneurysm (TAAA) repair is a complex procedure performed in patients at high cardiovascular risk. High volume intra-operative bleeding is often recorded, and the amount of intra-operative blood product transfusion is associated with relevant morbidity and mortality. The aim of the study was to identify pre-operative predictors of intra-operative large volume blood transfusions (LVBT) to stratify patients pre-operatively. METHODS: This was a retrospective analysis of prospectively collected data of all patients who underwent open TAAA surgery at San Raffaele Scientific Institute from January 2009 to December 2015. Intra-operative red blood cell (RBC) transfusions were administered to maintain a hematocrit of at least 30%. A LVBT was defined as a transfusion of at least four RBC units, corresponding to 1000 mL. RESULTS: The study population included 428 patients: 260 (61%) received fewer than 4 RBC units, and 168 (39%) were transfused with at least 4 RBC units. In patients who underwent LVBT, higher mortality was observed after surgery (p=.003), longer intensive care unit admission (p=.004), and longer mechanical ventilation compared with less transfused patients (p=.0002). The patients who received fewer units were administered a higher dose of heparin during the surgical operation compared with patients of the LVBT group: 3400±1100 vs. 2900±1300 IU (international units) (p=.0004). Pre-operative chronic renal failure (OR 1.8), the pre-operative haemoglobin value (OR 0.8), and the need for urgent or emergent surgery (OR 3.15) were independent predictors of LVBT on multivariate analysis. CONCLUSIONS: The identification of patients at risk of intra-operative LVBT during TAAA surgery is critical as these patients experience a worse outcome. Nevertheless, only few independent predictors are available for clinical practice.

Congenital prosopagnosia in a child: Neuropsychological assessment, eye movement recordings and training.

Here we report the assessment and treatment of a 6-year-old boy (L.G.) who was referred to us for congenital prosopagnosia (CP). We investigated his performance using a test battery and eye movement recordings pre- and post-training. L.G. showed deficits in recognising relatives and learning new faces, and misrecognition of unfamiliar people. Eye movement recordings showed that L.G. focused on the lower part of stimuli in naming tasks based on familiar or unfamiliar incomplete or complete faces. The training focused on improving his ability to explore internal features of faces, to discriminate specific facial features of familiar and unfamiliar faces, and to provide his family with strategies to use in the future. At the end of the training programme L.G. no longer failed to recognise close and distant relatives and classmates and did not falsely recognise unknown people.

Value and Anisotropy of the Electron and Hole Mass in Pure Wurtzite InP Nanowires.

The effective mass of electrons and holes in semiconductors is pivotal in determining the dynamics of carriers and their confinement energy in nanostructured materials. Surprisingly, this quantity is still unknown in wurtzite (WZ) nanowires (NWs) made of III-V compounds (e.g., GaAs, InAs, GaP, InP), where the WZ phase has no bulk counterpart. Here, we investigate the magneto-optical properties of InP WZ NWs grown by selective-area epitaxy that provides perfectly ordered NWs featuring high-crystalline quality. The combined analysis of the energy of free exciton states and impurity levels under magnetic field (B up to 29 T) allows us to disentangle the dynamics of oppositely charged carriers from the Coulomb interaction and thus to determine the values of the electron and hole effective mass. By application of B⃗ along different crystallographic directions, we also assess the dependence of the transport properties with respect to the NW growth axis (namely, the WZ c axis). The effective mass of electrons along c is me∥ = (0.078 ± 0.002) m0 (m0 is the electron mass in vacuum) and perpendicular to c is me⊥ = (0.093 ± 0.001) m0, resulting in a 20% mass anisotropy. Holes exhibit a much larger (∼320%) and opposite mass anisotropy with their effective mass along and perpendicular to c equal to mh∥ = (0.81 ± 0.18) m0 and mh⊥ = (0.250 ± 0.016) m0, respectively. While no full consensus is found with current theoretical results on WZ InP, our findings show trends remarkably similar to the experimental data available in WZ bulk materials, such as InN, GaN, and ZnO.

Long-Lived Hot Carriers in III-V Nanowires.

Heat management mechanisms play a pivotal role in driving the design of nanowire (NW)-based devices. In particular, the rate at which charge carriers cool down after an external excitation is crucial for the efficiency of solar cells, lasers, and high-speed transistors. Here, we investigate the thermalization properties of photogenerated carriers by continuous-wave (cw) photoluminescence (PL) in InP and GaAs NWs. A quantitative analysis of the PL spectra recorded up to 310 K shows that carriers can thermalize at a temperature much higher than that of the lattice. We find that the mismatch between carrier and lattice temperature, ΔT, increases exponentially with lattice temperature and depends inversely on the NW diameter. ΔT is instead independent of other NW characteristics, such as crystal structure (wurtzite vs zincblende), chemical composition (InP vs GaAs), shape (tapered vs columnar NWs), and growth method (vapor-liquid-solid vs selective-area growth). Remarkably, carrier temperatures as high as 500 K are reached at the lattice temperature of 310 K in NWs with ∼70 nm diameter. While a population of nonequilibrium carriers, usually referred to as "hot carriers", is routinely generated by high-power laser pulses and detected by ultrafast spectroscopy, it is quite remarkable that it can be observed in cw PL measurements, when a steady-state population of carriers is established. Time-resolved PL measurements show that even in the thinnest NWs carriers have enough time (∼1 ns) after photoexcitation to interact with phonons and thus to release their excess energy. Nevertheless, the inability of carriers to reach a full thermal equilibrium with the lattice points to inhibited phonon emission primarily caused by the large surface-to-volume ratio of small diameter NWs.