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Abstract Background The addition of pertuzumab (P) to trastuzumab (H) and standard chemotherapy (CT) as neoadjuvant treatment (NaT) for patients with HER2 + breast cancer (BC), has shown to increase the pathological complete response (pCR) rate, without main safety concerns. The aim of NeoPowER trial is to evaluate safety and efficacy of P + H + CT in a real–world population. Methods We retrospectively reviewed the medical records of stage II–III, HER2 + BC patients treated with NaT: who received P + H + CT (neopower group) in 5 Emilia Romagna institutions were compared with an historical group who received H + CT (control group). The primary endpoint was the safety, secondary endpoints were pCR rate, DRFS and OS and their correlation to NaT and other potential variables. Results 260 patients were included, 48% received P + H + CT, of whom 44% was given anthraciclynes as part of CT, compared to 83% in the control group. The toxicity profile was similar, excluding diarrhea more frequent in the neopower group (20% vs. 9%). Three patients experienced significant reductions in left ventricular ejection fraction (LVEF), all receiving anthracyclines. The pCR rate was 46% (P + H + CT) and 40% (H + CT) (p = 0.39). The addition of P had statistically correlation with pCR only in the patients receiving anthra-free regimens (OR = 3.05,p = 0.047). Preoperative use of anthracyclines (OR = 1.81,p = 0.03) and duration of NaT (OR = 1.18,p = 0.02) were statistically related to pCR. 12/21 distant-relapse events and 14/17 deaths occurred in the control group. Patients who achieve pCR had a significant increase in DRFS (HR = 0.23,p = 0.009). Conclusions Adding neoadjuvant P to H and CT is safe. With the exception of diarrhea, rate of adverse events of grade > 2 did not differ between the two groups. P did not increase the cardiotoxicity when added to H + CT, nevertheless in our population all cardiac events occurred in patients who received anthracycline-containing regimens. Not statistically significant, higher pCR rate is achievable in patients receiving neoadjuvant P + H + CT. The study did not show a statistically significant correlation between the addition of P and long-term outcomes.

Ilaria Ottonelli,1,* Elisa Adani,2,* Andrea Bighinati,2 Sabrina Cuoghi,1 Giovanni Tosi,1,3 Maria Angela Vandelli,1 Barbara Ruozi,1 Valeria Marigo,2,3 Jason Thomas Duskey1 1Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; 2Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; 3Center for Neuroscience and Neurotechnology, Modena, Italy*These authors contributed equally to this workCorrespondence: Jason Thomas Duskey, Nanotech Lab, Te.Far.T.I., Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, Modena, MO, Italy, 41125, Tel +390592058573, Email jtduskey@unimore.it Valeria Marigo, Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 287, Modena, MO, 41125, Italy, Tel +390592055392, Email vmarigo@unimore.itPurpose: In recent years, microfluidic technologies have become mainstream in producing gene therapy nanomedicines (NMeds) following the Covid-19 vaccine; however, extensive optimizations are needed for each NMed type and genetic material. This article strives to improve LNPs for pDNA loading, protection, and delivery, while minimizing toxicity.Methods: The microfluidic technique was optimized to form cationic or neutral LNPs to load pDNA. Classical “post-formulation” DNA addition vs “pre” addition in the aqueous phase were compared. All formulations were characterized (size, homogeneity, zeta potential, morphology, weight yield, and stability), then tested for loading efficiency, nuclease protection, toxicity, and cell uptake.Results: Optimized LNPs formulated with DPPC: Chol:DOTAP 1:1:0.1 molar ratio and 10 μg of DOPE-Rhod, had a size of 160 nm and good homogeneity. The chemico-physical characteristics of cationic LNPs worsened when adding 15 μg/mL of pDNA with the “post” method, while maintaining their characteristics up to 100 μg/mL of pDNA with the “pre” addition remaining stable for 30 days. Interestingly, neutral LNPs formulated with the same method loaded up to 50% of the DNA. Both particles could protect the DNA from nucleases even after one month of storage, and low cell toxicity was found up to 40 μg/mL LNPs. Cell uptake occurred within 2 hours for both formulations with the DNA intact in the cytoplasm, outside of the lysosomes.Conclusion: In this study, the upcoming microfluidic technique was applied to two strategies to generate pDNA-LNPs. Cationic LNPs could load 10x the amount of DNA as the classical approach, while neutral LNPs, which also loaded and protected DNA, showed lower toxicity and good DNA protection. This is a big step forward at minimizing doses and toxicity of LNP-based gene therapy.Keywords: gene therapy, lipid nanoparticles, microfluidics, lipoplexes, DNA delivery

Background and Aims: Hypoalbuminemia, as defined by serum albumin (SA) levels ≤35 g/L, is associated to venous and arterial thrombosis in general population and in patients at risk of cardiovascular disease. It is unknown if SA ≤35 g/L is also associated to portal vein thrombosis (PVT) in cirrhosis. Methods: Cirrhotic patients enrolled in the Portal vein thrombosis Relevance On Liver cirrhosis: Italian Venous thrombotic Events Registry (PRO-LIVER) study (n = 753), were followed-up for 2 years to assess the risk of PVT, that was diagnosed by Doppler ultrasonography. Child-Pugh classes, Model for End-Stage Liver Disease score, presence of hepatocellular carcinoma and laboratory variables including SA, D-dimer, and high-sensitivity C-reactive protein (hs-CRP) were measured at baseline. Results: SA ≤35 g/L was detected in 52% of patients. A logistic multivariate regression analysis showed that higher Child-Pugh class, hepatocellular carcinoma and thrombocytopenia were significantly associated to SA ≤35 g/L. In a subgroup of patients where data regarding hs-CRP and D-dimer were available, SA ≤35 g/L was inversely associated with hs-CRP and D-dimer. During the follow-up, a total of 61 patients experienced PVT. A Kaplan Meier survival analysis showed SA ≤35 g/L was associated to increased risk of PVT compared to SA >35 g/L (P = .005). A multivariate Cox proportional hazards regression analysis showed that male sex, lower platelet count, and SA ≤35 g/L remained associated to PVT after adjusting for confounding factors. Conclusion: Cirrhotic patients with SA ≤35 g/L are at higher risk of experiencing PVT compared to those with SA >35 g/L and could be considered as potential candidates to anticoagulant prophylaxis for PVT prevention.

IntroductionThe effectiveness of early interventions in young autistic children is well established, but there is great interindividual variability in treatment response. Predictors of response to naturalistic developmental behavioral interventions (NDBI), like the Early Start Denver Model (ESDM), are needed.MethodsWe conducted an exploratory study to prospectively seek predictors of response in 32 young children treated with ESDM after receiving an ASD diagnosis. All children were less than 39 months old (mean age: 29.7 mo), and received individualized ESDM for nine months. Tests were administered at the beginning, after 4 months, and at the end of treatment.ResultsFour children (12.5%) were “strong responders”, 8 children (25.0%) were “moderate responders”, and 20 children (62.5%) were “poor responders”. A more favorable response to ESDM was significantly predicted by higher PEP-3 Expressive Language, Receptive Language, Cognitive Verbal/Preverbal, Visuo-Motor Imitation scores, higher GMDS-ER Personal/Social, and VABS-II Communication scores, by lower ADI-R C restricted/stereotypic behaviors, and by joint attention level.DiscussionMost predictors showed a linear association with increasing response to ESDM, but GMDS-ER Personal-Social and joint attention level predicted strong response, while PEP-3 receptive language equally predicted moderate or strong response. Although larger samples will be necessary to reach definitive conclusions, in conjunction with prior reports our findings begin providing information able to assist clinicians in choosing the most appropriate treatment program for young autistic children.

To describe the orthodontic, periodontal and prosthetic management of a case with a 3 mm root fracture below the crest of the alveolar bone.

ObjectiveWe investigated the performance of enzyme linked immunospot (ELISpot) assay for the diagnosis of invasive aspergillosis (IA) in high-risk patients with hematologic malignancies.MethodsWe prospectively enrolled two cohorts of patients undergoing intensive myelosuppressive or immunosuppressive treatments at high risk for IA. ELISpot was performed to detect Aspergillus-specific T cells producing Interleukin-10.ResultsIn the discovery cohort, a derived cut-off of 40 spot forming cells (SFCs)/106 PBMCs has shown to correctly classify IA cases with a sensitivity and specificity of 89.5% and 88.6%, respectively. This cut-off is lowered to 25 SFC when considering the subset of possible IA patients, with sensitivity and specificity of 76% and 93%, respectively. The application of the 40 SFCs cut-off to the validation cohort resulted in a positivity rate of 83.3% in proven/probable cases and a negativity rate of 92.5% in possible/non-IA cases. Adopting the 25 SCFs cut-off, the assay resulted positive in 83.3% of proven/probable cases while it resulted negative in 66.7% of possible/non-IA cases.ConclusionsELISpot shows promises in the diagnosis of IA and the possibility to use two distinct cut-offs with similar diagnostic performances according to patients' different pre-test probability of infection can widen its use in patients at risk.

ObjectivesTo standardize the diagnosis of patent ductus arteriosus (PDA) and report its association with adverse neonatal outcomes in very low birth weight infants (VLBW, birth weight < 1500 g).Study designA multicenter prospective observational study was conducted in Emilia Romagna from March 2018 to October 2019. The association between ultrasound grading of PDA and adverse neonatal outcomes was evaluated after correction for gestational age. A diagnosis of hemodynamically significant PDA (hsPDA) was established when the PDA diameter was ≥ 1.6 mm at the pulmonary end with growing or pulsatile flow pattern, and at least 2 of 3 indexes of pulmonary overcirculation and/or systemic hypoperfusion were present.Results218 VLBW infants were included. Among infants treated for PDA closure in the first postnatal week, up to 40% did not have hsPDA on ultrasound, but experienced clinical worsening. The risk of death was 15 times higher among neonates with non-hemodynamically significant PDA (non-hsPDA) compared to neonates with no PDA. In contrast, the risk of death was similar between neonates with hsPDA and neonates with no PDA. The occurrence of BPD was 6-fold higher among neonates with hsPDA, with no apparent beneficial role of early treatment for PDA closure. The risk of IVH (grade ≥ 3) and ROP (grade ≥ 3) increased by 8.7-fold and 18-fold, respectively, when both systemic hypoperfusion and pulmonary overcirculation were present in hsPDA.ConclusionsThe increased risk of mortality in neonates with non-hsPDA underscores the potential inadequacy of criteria for defining hsPDA within the first 3 postnatal days (as they may be adversely affected by other clinically severe factors, i.e. persistent pulmonary hypertension and mechanical ventilation). Parameters such as length, diameter, and morphology may serve as more suitable ultrasound indicators during this period, to be combined with clinical data for individualized management. Additionally, BPD, IVH (grade ≥ 3) and ROP (grade ≥ 3) are associated with hsPDA. The existence of an optimal timeframe for closing PDA to minimize these adverse neonatal outcomes remains uncertain.

Introduction Pain is a multidimensional experience that varies among individuals and has a significant impact on their health. A biopsychosocial approach is recommended for effective pain management; however, health professionals’ education is weak on this issue. Patient involvement is a promising didactic methodology in developing a more holistic perspective, however there is a lack of reliable evidence on this topic. The aim of the present study is to evaluate the effectiveness of patient involvement in pain education in undergraduate medicine and nursing students.Methods and analysis An open-label randomised controlled trial including qualitative data will be conducted. After an introductory lesson, each student will be randomly assigned to the intervention group, which includes an educational session conducted by a patient–partner along with an educator, or to the control group in which the session is exclusively conducted by an educator. Both sessions will be carried out according to the Case-Based Learning approach. Primary outcomes will be students’ knowledge, attitudes, opinions and beliefs about pain management, whereas the secondary outcome will be students’ satisfaction. The Pain Knowledge and Attitudes (PAK) and Chronic Pain Myth Scale (CPMS) will be administered preintervention and postintervention to measure primary outcomes. Students’ satisfaction will be measured by a questionnaire at the end of the session. Two focus groups will be conducted to evaluate non-quantifiable aspects of learning.Ethics and dissemination The protocol of this study was approved by the independent Area Vasta Emilia Nord ethics committee.Adherence to The Declaration of Helsinki and Good Clinical Practice will ensure that the rights, safety and well-being of the participants in the study are safeguarded, as well as data reliability. The results will be disseminated through scientific publications and used to improve the educational offer. A version of the anonymised data set will be released for public access.Trial registration Trial was not registered on ClinicalTrials.gov as the interventions being compared only concern educational programmes and the outcomes considered do not refer to any clinical dimension.

Angiosarcoma is a rare and aggressive neoplasia of endothelial cells which represents only 2% of all soft-tissue tumors and frequently occurs in the skin and subcutaneous tissues. It is classified in two groups: the first is represented by primary angiosarcoma, which includes cutaneous and breast angiosarcoma; the second is constituted by secondary angiosarcoma, which is related to radiation therapy, lymphedema, exposure to some chemical toxins, and familiar syndromes. Post-radiation intestinal angiosarcoma is a special type of secondary angiosarcoma, and only a few cases have been reported in the literature. We present a case of radiation-induced small bowel angiosarcoma in an 88-year-old female patient who was admitted to our department for abdominal pain and signs of intestinal obstruction. Her clinical history included previous radiotherapy treatments after a hysterectomy for uterine fibroids, excision of the vaginal stump for squamous cell carcinoma, and the surgical removal of a left-leg cutaneous angiosarcoma. She underwent emergency surgery, and features of peritoneal carcinomatosis were detected. A histological examination showed the presence of a small intestinal angiosarcoma. At the histochemical analysis, MYC amplification was detected, suggesting that her small bowel angiosarcoma was related to past radiation treatments.

This study investigates the role of body composition parameters in patients with pancreatic cancer undergoing surgical treatment. The research involved 88 patients diagnosed with pancreatic cancer who underwent surgery at the Modena Cancer Center between June 2015 and October 2023. Body composition parameters were obtained from CT scans performed before and after surgery. The percentage of sarcopenic patients at the time of diagnosis of pancreatic cancer is 56.82%. Of the patients who died between the first and second CT evaluated, 58% were sarcopenic, thus confirming the role of sarcopenia on outcome. The study found that all body composition parameters (TAMA, SMI, VFI, and SFI) demonstrated a trend towards reduction between two examinations, indicating an overall depletion in muscle and adipose tissue. We then evaluated the relationships between fat-related parameters (VFI, SFI and VSR) and survival outcomes: overall survival and progression-free survival. Cox univariate regression model show significant parameter related to outcomes was adipose tissue, specifically VFI. The study found that higher VFI levels were associated with greater survival rates. This research holds promise for advancing our understanding of the link between body composition and the prognosis of pancreatic cancer patients.

The administration of TKIs after Allo-SCT in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) remains controversial, and the TKI approach (prophylactic, pre-emptive or salvage) is still heterogeneous in transplant centers. In this context, very little is known about the feasibility and safety of third-generation TKIs. In this paper, we analyze the efficacy and safety of ponatinib (PONA) administered after Allo-SCT to prevent cytologic relapse of Ph + ALL. This is a multicenter observational study including 48 patients (pts) with Ph + ALL (median age 49 years) who received PONA after Allo-SCT while in complete cytological remission (cCR); 26 (54%) had positive minimal residual disease (MRD pos) before Allo-SCT. PONA was administered after Allo-SCT prophylactically (starting with MRD neg) in 26 pts or pre-emptively (starting with MRD pos post-SCT and without hematological relapse) in 22 pts. Patients treated prophylactically with PONA started treatment earlier, at a median of 4.3 months (range 1.5–6) after Allo-SCT, than those treated pre-emptively, who started PONA at a median of 7.4 months (range 2–63) after Allo-SCT (p = 0.01). The median starting dose of PONA was 30 mg/day (range 15–45). A dose reduction was required in 10/48 (21%) of cases, but a permanent discontinuation of PONA, due to toxicity, was required in only 5/48 pts (10.5%). No deaths due to PONA-related adverse events (AEs) were reported. The median follow-up time after Allo-SCT was 34 months (range 7.7–118). At the last follow-up, the median duration of PONA therapy was 22 months (range 2–100). The 5-year OS and RFS after Allo-SCT were 92% and 71%, respectively. The 5-year RFS after Allo-SCT of pts who received PONA prophylaxis was 95%, and it was 57% for those who received PONA pre-emptively (log-rank p = 0.02). In conclusion, this multicenter analysis of 48 patients with Ph + ALL undergoing Allo-SCT while in CcR, although with the caution of the retrospective data, supports the feasibility of PONA maintenance strategy after Allo-SCT with a low rate of discontinuations (10.5%) due to PONA-related AE.

Malignant gastrointestinal neuroectodermal tumor (GNET) is an infrequent soft-tissue sarcoma, formerly referred to as clear-cell sarcoma-like gastrointestinal tumor (CCSLGT) and frequently reported in the literature as clear-cell sarcoma of the gastrointestinal tract (CCS-GI); it is characterized by an absence of melanocytic differentiation and the presence of nontumoral osteoclast-like giant cells (OLGCs). The current study reports a case of a 79 year old woman admitted to the emergency department (ED) with symptoms of constipation and intestinal obstruction; a mass was found within the ileal wall necessitating of surgical approach. Immunohistochemically, tumor cells surprisingly had the hallmark of GNETs. Unfamiliarity with tumors with the features of GNETs can easily lead to a misdiagnosis by surgical pathologist. Therefore, comprehensive evaluation, including morphology and additional studies, is required for an appropriated diagnosis. Furthermore, without a high index of suspicion, there is actually no consensus on staging or treatment.

A 70-year-old man was admitted to the Emergency Department (ED) for marked asthenia and severe anemia. In addition, a high level of lipase was found. During hospitalization, a locally advanced gastric cancer was diagnosed, with endoscopic evidence of a large polyploid formation originating under the cardias that occupied most of the gastric lumen. A total body CT scan was performed before surgery; the tumor affected the posterior gastric wall, with tenacious infiltration of the pancreatic body. Therefore, we performed a total gastrectomy with esophageal jejunum anastomosis and reconstruction of intestinal continuity according to Roux, distal spleno-pancreatectomy, and cholecystectomy. At histology, a pancreatic acinar cell carcinoma (PACC) with full thickness infiltration of the gastric wall was diagnosed. Acinar cell carcinomas are highly aggressive neoplasms, and surgical resection, when feasible, is the treatment of choice regardless of size, also because the role of neoadjuvant or adjuvant chemo- or radiotherapy remains uncodified.

Background: There are wide variations in antibiotic use in neonatal intensive care units (NICUs). Limited data are available on antimicrobial stewardship (AS) programs and long-term maintenance of AS interventions in preterm very-low-birth-weight (VLBW) infants. Methods: We extended a single-centre observational study carried out in an Italian NICU. Three periods were compared: I. “baseline” (2011–2012), II. “intervention” (2016–2017), and III. “maintenance” (2020–2021). Intensive training of medical and nursing staff on AS occurred between periods I and II. AS protocols and algorithms were maintained and implemented between periods II and III. Results: There were 111, 119, and 100 VLBW infants in periods I, II, and III, respectively. In the “intervention period”, there was a reduction in antibiotic use, reported as days of antibiotic therapy per 1000 patient days (215 vs. 302, p < 0.01). In the “maintenance period”, the number of culture-proven sepsis increased. Nevertheless, antibiotic exposure of uninfected VLBW infants was lower, while no sepsis-related deaths occurred. Our restriction was mostly directed at shortening antibiotic regimens with a policy of 48 h rule-out sepsis (median days of early empiric antibiotics: 6 vs. 3 vs. 2 in periods I, II, and III, respectively, p < 0.001). Moreover, antibiotics administered for so-called culture-negative sepsis were reduced (22% vs. 11% vs. 6%, p = 0.002), especially in infants with a birth weight between 1000 and 1499 g. Conclusions: AS is feasible in preterm VLBW infants, and antibiotic use can be safely reduced. AS interventions, namely, the shortening of antibiotic courses in uninfected infants, can be sustained over time with periodic clinical audits and daily discussion of antimicrobial therapies among staff members.

Este trabalho reflete sobre a produção de dados e gestão de riscos e desastres, na última década, em relação à afetação de pessoas idosas, em especial as residentes em Instituições de Longa Permanência para Idosos (ILPIs). Para isso são utilizados dados secundários, legislações e levantamento de literatura. Dentre os resultados, observa-se que para o funcionamento, estas devem seguir as legislações, as instruções normativas e as resoluções para a garantia de proteção e cuidados aos seus residentes. Em situações de desastres, emergências e calamidades públicas, a situação torna-se complexa com a falta de dados a envolver idosos institucionalizados, a falta de orientações de como ILPIs e serviços da rede de cuidado ao idoso poderiam proceder, de modo a garantir a proteção desse segmento. O artigo mostra que as ações de proteção aos idosos institucionalizados e monitoramento da afetação são prejudicadas, visto que o tema passa desapercebido. Para o enfrentamento dos desafios da invisibilidade da gestão de riscos e desastres envolvendo ILPIs, demanda-se produção de dados, comunicação, embasamento técnico-científico em gerontologia e proteção e defesa civil, assim como instruções normativas para orientar ILPIs e órgãos públicos na prevenção, preparação, resposta e recuperação envolvendo esse segmento populacional.

Abstract Background Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease that typically affects multiple organs and can lead to potentially fatal complications. Central nervous system (CNS) involvement in SLE is common, especially in children, and can present nonspecifically with various neuropsychiatric manifestations, described as neuropsychiatric SLE (NPSLE). Chronic headache is a common feature of NPSLE, secondary to increased intracranial pressure (also called pseudotumor cerebri (PTC)) due to inflammation or medication. Here, we highlight the importance of evaluating refractory headache (HA) in SLE patients to rule out PTC as a cause of severe morbidity. Methods Single tertiary care pediatric center case series of 8 children who developed NPSLE in the form of intracranial hypertension at or after SLE diagnosis. Conclusion Neurologic and ophthalmologic evaluation of refractory HA in patients with SLE, especially children, is warranted to decrease the burden of the disease and rule out treatable causes like PTC.

Abstract Acute hepatic porphyrias (AHPs) are a family of four rare genetic diseases resulting from a deficiency in one of the enzymes involved in heme biosynthesis. AHP patients can experience potentially life-threatening acute attacks, characterized by severe abdominal pain, along with other signs and symptoms including nausea, mental confusion, hyponatraemia, hypertension, tachycardia and muscle weakness. Some patients also experience chronic manifestations and long-term complications, such as chronic pain syndrome, neuropathy and porphyria-associated kidney disease. Most symptomatic patients have only a few attacks in their lifetime; nevertheless, some experience frequent attacks that result in ongoing symptoms and a significant negative impact on their quality of life (QoL). Initial diagnosis of AHP can be made with a test for urinary porphobilinogen, $$\delta$$ δ -aminolaevulinic acid and porphyrins using a single random (spot) sample. However, diagnosis is frequently missed or delayed, often for years, because the clinical symptoms of AHP are non-specific and mimic other more common disorders. Delayed diagnosis is of concern as some commonly used medications can trigger or exacerbate acute attacks, and untreated attacks can become severe, potentially leading to permanent neurological damage or fatality. Other attack triggers include hormonal fluctuations in women, stress, alcohol and low-calorie diets, which should be avoided in patients where possible. For the management of attacks, intravenous hemin is approved, whereas new therapeutic approaches are currently being investigated as a baseline therapy for prevention of attacks and improvement of QoL. Among these, a novel siRNA-based agent, givosiran, has shown very promising results in a recently concluded Phase III trial and has been approved for the management of AHPs. Here, we propose a challenging case study-with a very unusual pediatric onset of variegate porphyria-as a starting point to summarize the main clinical aspects (namely, clinical manifestations, diagnostic challenges, and therapeutic management) of AHPs, with a focus on the latest therapeutic innovations.

Introduction: Oral cancer refers to malignant tumors, of which 90% are squamous cell carcinomas (OSCCs). These malignancies exhibit rapid progression, poor prognosis, and often mutilating therapeutical approaches. The determination of a prophylactic and/or therapeutic antitumor role of the polyphenolic extract Polypodium leucotomos(PL) would be relevant in developing new tools for prevention and treatment.Methods: We aimed to determine the antitumor effect of PL by treating OSCC cell lines with PL metabolites and evaluating its action during OSCC progression in vivo.Results: PL treatment successfully impaired cell cycling and proliferation, migration, and invasion, enhanced apoptosis, and modulated macrophage polarization associated with the tumoral immune-inflammatory response of tongue cancer cell lines (TSCC). PL treatment significantly decreased the expression of MMP1 (p < 0.01) and MMP2 (p < 0.001), and increased the expression of TIMP1 (p < 0.001) and TIMP2 (p < 0.0001) in these cells. The mesenchymal-epithelial transition phenotype was promoted in cells treated with PL, through upregulation of E-CAD (p < 0.001) and reduction of N-CAD (p < 0.05). PL restrained OSCC progression in vivo by inhibiting tumor volume growth and decreasing the number of severe dysplasia lesions and squamous cell carcinomas. Ki-67 was significantly higher expressed in tongue tissues of animals not treated with PL(p < 0.05), and a notable reduction in Bcl2 (p < 0.05) and Pcna (p < 0.05) cell proliferation-associated genes was found in dysplastic lesions and TSCCs of PL-treated mice. Finally, N-cad(Cdh2), Vim, and Twist were significantly reduced in tongue tissues treated with PL.Conclusion: PL significantly decreased OSCC carcinogenic processes in vitro and inhibited tumor progression in vivo. PL also appears to contribute to the modulation of immune-inflammatory oral tumor-associated responses. Taken together, these results suggest that PL plays an important antitumor role in processes associated with oral carcinogenesis and may be a potential phytotherapeutic target for the prevention and/or adjuvant treatment of TSCCs

OBJECTIVES: To map the number and geospatial distribution of Brazilian long-term care facilities (LTCFs) for older adults. Additionally, we sought to highlight the relationship between these findings and the number of older people in the country's 27 Federation Units, demonstrating the growth of these facilities in the last decade. METHODS: This is a descriptive observational study, using secondary data, which was performed in 3 stages: 1) searching and consolidating national and subnational data from different sources and mapping LTCFs; 2) preparing a geospatial map using Brazilian postal codes; and 3) triangulating the number of facilities and of older people in each state and all 5 Brazilian regions. RESULTS: We found 7029 LTCFs in the country, mostly in the Southeast and South regions: São Paulo, Minas Gerais and Rio Grande do Sul had the highest numbers of facilities while states in the North region represented only 1.12% of Brazilian LTCFs. Geospatial mapping highlighted that 64% of the 5 570 Brazilian municipalities did not have any LTCFs for older adults. CONCLUSIONS: We observed a large difference between Brazilian regions regarding the provision of long-term care.

Background: Small (SGA) and large (LGA) for gestational age infants have higher risks of infant morbidity when compared to those who are appropriate for gestational age (AGA). Increasing pre-pregnancy maternal BMI and gestational weight gain (GWG) are associated with higher risks of LGA and lower risks of SGA infants; however, their direct effects on infant morbidity are unknown. Therefore, we intended to 1) assess how maternal pre-pregnancy BMI, GWG, and birthweight (categorized as SGA, AGA or LGA) affect infant morbidity and 2) estimate at entry of care the risk of infant morbidity according to pre-pregnancy BMI and possible GWG. Methods: we used Consortium on Safe Labor data, a retrospective observational cohort study collecting pregnancy and birth data from 2002 to 2008 in 12 US centers. The association between maternal BMI, GWG and infant morbidity was estimated in singleton gestations delivering ≥ 37 weeks using binomial logistic regression. Hypoxic composite neonatal morbidity was defined as any the following: stillbirth, neonatal death, resuscitation at birth, NICU admission, intracranial hemorrhage, PVH grade III and IV, neonatal seizures, NEC, meconium aspiration, CPAP or mechanical ventilation, RDS, and sepsis. Traumatic composite neonatal morbidity included shoulder dystocia or birth injuries. Results: In this study of 110,594 mother-infant dyads, a total of 8,369 (7.6%) infants experienced hypoxic, while 2,134 (1.9%) developed traumatic morbidity. The risk of hypoxic morbidity among SGA, AGA and LGA infants increased when mothers were overweight (aOR 1.26 [95%CI 1.18–1.34]) or obese (class 1: aOR 1.3 [1.2–1.4]; class 2: aOR 1.7 [1.5–1.9]; class 3: aOR 1.8 [1.6–2]) as opposed to normal weight, and when GWG exceeded (aOR 1.08 [1.02–1.014]) rather than remained within recommendations. The risk of traumatic morbidity increased with maternal obesity (class 1: aOR 1.3 [1.1–1.5]), whilst it dropped with GWG below recommendations (aOR 0.7 [0.6–0.8]). The risk of hypoxic events estimated at entry of care increased with maternal overweight (aOR 1.27 [1.19–1.35]) or obesity (class 1: aOR 1.4 [1.2–1.5]; class 2: aOR 1.7 [1.5–1.9]; class 3: aOR 1.8 [1.6–2.1]), and with possible GWG above (aOR 1.09 [1.03–1.015]) recommendations. The risk of traumatic morbidity increased with overweight (aOR 1.1 [1–1.3]) or obesity (class 1: aOR 1.4 [1.2–1.6]; class 2: aOR 1.3 [1–1.6]), with possible GWG above (aOR 1.2 [1–1.3]), as opposed to below recommendations (aOR 0.7 [0.6–0.8]). Conclusions: While maternal pre-pregnancy BMI and GWG equally affected traumatic morbidity, the former had a greater impact on hypoxic complications. Therefore, weight control prior to pregnancy is at least as effective as avoiding excessive gestational weight gain to prevent neonatal morbidity. [ABSTRACT FROM AUTHOR]

Objectives: To standardize the diagnosis of patent ductus arteriosus (PDA) and report its association with adverse neonatal outcomes in very low birth weight infants (VLBW, birth weight < 1500 g). Study design: A multicenter prospective observational study was conducted in Emilia Romagna from March 2018 to October 2019. The association between ultrasound grading of PDA and adverse neonatal outcomes was evaluated after correction for gestational age. A diagnosis of hemodynamically significant PDA (hsPDA) was established when the PDA diameter was ≥ 1.6 mm at the pulmonary end with growing or pulsatile flow pattern, and at least 2 of 3 indexes of pulmonary overcirculation and/or systemic hypoperfusion were present. Results: 218 VLBW infants were included. Among infants treated for PDA closure in the first postnatal week, up to 40% did not have hsPDA on ultrasound, but experienced clinical worsening. The risk of death was 15 times higher among neonates with non-hemodynamically significant PDA (non-hsPDA) compared to neonates with no PDA. In contrast, the risk of death was similar between neonates with hsPDA and neonates with no PDA. The occurrence of BPD was 6-fold higher among neonates with hsPDA, with no apparent beneficial role of early treatment for PDA closure. The risk of IVH (grade ≥ 3) and ROP (grade ≥ 3) increased by 8.7-fold and 18-fold, respectively, when both systemic hypoperfusion and pulmonary overcirculation were present in hsPDA. Conclusions: The increased risk of mortality in neonates with non-hsPDA underscores the potential inadequacy of criteria for defining hsPDA within the first 3 postnatal days (as they may be adversely affected by other clinically severe factors, i.e. persistent pulmonary hypertension and mechanical ventilation). Parameters such as length, diameter, and morphology may serve as more suitable ultrasound indicators during this period, to be combined with clinical data for individualized management. Additionally, BPD, IVH (grade ≥ 3) and ROP (grade ≥ 3) are associated with hsPDA. The existence of an optimal timeframe for closing PDA to minimize these adverse neonatal outcomes remains uncertain. [ABSTRACT FROM AUTHOR]

Objective: We investigated the performance of enzyme linked immunospot (ELISpot) assay for the diagnosis of invasive aspergillosis (IA) in high-risk patients with hematologic malignancies. Methods: We prospectively enrolled two cohorts of patients undergoing intensive myelosuppressive or immunosuppressive treatments at high risk for IA. ELISpot was performed to detect Aspergillus-specific T cells producing Interleukin-10. Results: In the discovery cohort, a derived cut-off of 40 spot forming cells (SFCs)/106 PBMCs has shown to correctly classify IA cases with a sensitivity and specificity of 89.5% and 88.6%, respectively. This cut-off is lowered to 25 SFC when considering the subset of possible IA patients, with sensitivity and specificity of 76% and 93%, respectively. The application of the 40 SFCs cut-off to the validation cohort resulted in a positivity rate of 83.3% in proven/probable cases and a negativity rate of 92.5% in possible/non-IA cases. Adopting the 25 SCFs cut-off, the assay resulted positive in 83.3% of proven/probable cases while it resulted negative in 66.7% of possible/non-IA cases. Conclusions: ELISpot shows promises in the diagnosis of IA and the possibility to use two distinct cut-offs with similar diagnostic performances according to patients' different pre-test probability of infection can widen its use in patients at risk. [ABSTRACT FROM AUTHOR]

Enzyme‐based therapy has garnered significant attention for its current applications in various diseases. Despite the notable advantages associated with the use of enzymes as therapeutic agents, that could have high selectivity, affinity, and specificity for the target, their application faces challenges linked to physico‐chemical and pharmacological properties. These limitations can be addressed through the encapsulation of enzymes in nanoplatforms as a comprehensive solution to mitigate their degradation, loss of activity, off‐target accumulation, and immunogenicity, thus enhancing bioavailability, therapeutic efficacy, and circulation time, thereby reducing the number of administrations, and ameliorating patient compliance. The exploration of novel nanomedicine‐based enzyme therapeutics for the treatment of challenging diseases stands as a paramount goal in the contemporary scientific landscape, but even then it is often not enough. Combining an enzyme with another therapeutic (e.g., a small molecule, another enzyme or protein, a monoclonal antibody, or a nucleic acid) within a single nanocarrier provides innovative multidrug‐integrated therapy and ensures that both the actives arrive at the target site and exert their therapeutic effect, leading to synergistic action and superior therapeutic efficacy. Moreover, this strategic approach could be extended to gene therapy, a field that nowadays has gained increasing attention, as enzymes acting at genomic level and nucleic acids may be combined for synergistic therapy. This multicomponent therapeutic approach opens opportunities for promising future developments. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological DiseaseTherapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic DiseaseTherapeutic Approaches and Drug Discovery > Emerging Technologies [ABSTRACT FROM AUTHOR]

With the clear need for better cancer treatment, naturally occurring molecules represent a powerful inspiration. Recently, curcumin has attracted attention for its pleiotropic anticancer activity in vitro, especially against colorectal and prostate cancer cells. Unfortunately, these encouraging results were disappointing in vivo due to curcumin’s low stability and poor bioavailability. To overcome these issues, herein, the synthesis of eight new pyrimidine–curcumin derivatives is reported. The compounds were fully characterized (1H/13C NMR (Nuclear Magnetic Resonance), LC-MS (Liquid Chromatography-Mass Spectrometri), UV-Vis spectroscopy), particularly their acid/base behavior; overall protonation constants were estimated, and species distribution, as a function of pH, was predicted, suggesting that all the compounds are in their neutral form at pH 7.4. All the compounds were extremely stable in simulated physiological media (phosphate-buffered saline and simulated plasma). The compounds were tested in vitro (48 h incubation treatment) to assess their effect on cell viability in prostate cancer (LNCaP and PC3) and colorectal cancer (HT29 and HCT116) cell lines. Two compounds showed the same anti-proliferative activity as curcumin against HCT116 cells and improved cytotoxicity against PC3 cells.