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We retrospectively analyzed real-world data from the ARON-1 project for patients with papillary renal cell carcinoma who received first-line immune-based combinations or tyrosine kinase inhibitors. Immune-based combinations were associated with better 1-yr and 2-yr overall survival rates, better median progression-free survival, and a better objective response rate. Immune-based combinations are the preferable option for first-line treatment in this setting.

Background: DDH is 1 of the most important causes of childhood disability. A diagnosis of instability can be made in the neonatal period via the Ortolani and Barlow manoeuvres. However, clinical examination, although highly specific, has poor sensitivity as compared to ultrasound. There is controversy between the necessity of universal screening for dysplasia of all newborns or selective screening reserved for those with clinical signs of instability or known risk factors of DDH.Aim: To analyse the risk factors of congenital hip dysplasia in a consecutive case series of children referred for diagnosis and treatment of DDH.Materials and methods: This was a cross-sectional study on infants consecutively examined between January 2000 and December 2019 at the Marino Ortolani Centre in Ferrara, Italy. The first 3 types on Graf’s classification were considered physiological (1A, 1B, 2A+), while the last 6 pathological (2A-, 2B, 2C, 2D, 3, 4).Results: 18,954 infants met the inclusion criteria and were therefore considered eligible for the study. Of these 18,954 infants, 56% (n= 10,629) were females and 44% (n= 8325) were males. According to Graf classification, 34.9% (n= 6621) were 1A, 52.7% (n= 9999) were 1B, 4.0% (n= 753) were 2A+, 2.5% (n= 478) were 2A-, 1.5% (n= 284) were 2B, 1% (n= 196) were 2C, 1.3% (n= 243) were 2D, 1% (n= 193) were 3 and 1.0% (n= 187) were 4. The most significant risk factor was the female gender (OR 5.36; 95% CI, 4.63–6.20) followed by a family history (OR 2.35; 95% CI, 2.08–2.65), then skeletal pathologies (OR 2.04; 95% CI, 1.21–3.42), oligohydramnios (OR 1.75; 95% CI, 1.44–2.13), and finally breech presentation (OR 1.42: 95% CI, 1.27–1.60).Conclusions: Based on our data, family history, musculoskeletal disease, oligohydramnios and breech presentation are the main risk factors for DDH development, as is the female sex.

ABSTRACTBackgroundSwitch patterns among different biologics and from originators to biosimilars (and vice versa) can be complex in patients with psoriasis (PsO) and psoriatic arthritis (PsA).ObjectiveThe aim of this study was to describe switching patterns of biological drugs in PsO/PsA patients and to explore predictors of multiple switches and switch-back.Research design and methodsA large-scale retrospective cohort study was conducted using the Italian VALORE database. Bio-naïve users treated for PsO/PsA during 2010–2022 were included. Time to switch/swap and predictors of multiple switches and switch-back were analyzed.ResultsThirty-thousand seven hundred bio-naïve users were included. At 3 and 5 years of follow-up, patients with at least one switch/swap were 37.1% and 47.8%, respectively. The median time to first switch/swap was significantly shorter (p< 0.001) for TNF-α inhibitors (2,068 days) than anti-IL (2,780 days). At 1 year of follow-up patients starting with IL-23 switched/swapped biological therapy less frequently than those with anti-IL-12/23 and anti-IL-17 (4.9% vs. 8.7% and 9.4%, respectively). Patients starting with anti-IL-12/23 reported a significantly lower risk of multiple switches and switch-back (0.74, 95% CI, 0.67–0.83; 0.58, 95% CI, 0.44–0.77, respectively) than those with TNF-α inhibitors.ConclusionsPatients with PsO/PsA starting with TNF-α inhibitors switch/swap more rapidly and frequently than those with anti-IL, which are also associated with a reduced risk of multiple switches during follow-up.

Recently, we described synthetic sulfolipids named Sulfavants as a novel class of molecular adjuvants based on the sulfoquinovosyl-diacylglycerol skeleton. The members of this family, Sulfavant A (1), Sulfavant R (2), and Sulfavant S (3), showed important effects on triggering receptor expressed on myeloid cells 2 (TREM2)-induced differentiation and maturation of human dendritic cells (hDC), through a novel cell mechanism underlying the regulation of the immune response. As these molecules are involved in biological TREM2-mediated processes crucial for cell survival, here, we report the synthesis and application of a fluorescent analogue of Sulfavant A bearing the 4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene moiety (Me4-BODIPY). The fluorescent derivative, named PB-SULF A (4), preserving the biological activity of Sulfavants, opens the way to chemical biology and cell biology experiments to better understand the interactions with cellular and in vivoorgan targets and to improve our comprehension of complex molecular mechanisms underlying the not fully understood ligand-induced TREM2 activity.

Background: Immunotherapy has revolutionized the approach to metastatic triple-negative breast cancers. Atezolizumab was approved for patients with metastatic triple-negative breast cancers whose tumors express PD-L1, determined by SP 142 assay. To assess the availability and practice of SP142 test we administered a survey to all the 15 pathology departments of the Lazio Region during a six-month period.Methods: The survey comprised 12 questions regarding the availability of SP142 in the pathology departments, the percentage of positive tests, the difficulties of pathologists in cases close to cut-off value and the tested samples.Results: The SP142 assay was available in only eight centers. In case of positive result, most centers (5/8, 62.5%) reported values of PD-L1 expression ranging from > 1 to ⩽ 5%, with values close to the cut-off point (⩾ 1% or < 1%) being the greatest challenge. Most of the centers (6/8, 75%) tested material from both their own and other hospitals. In most centers, the evaluations were performed either on primary tumors or metastasis, in particular lymph nodes (5/8, 62.5%), followed by lung (3/8, 37.5%) and liver (1/8, 12.5%) metastasis.Conclusion: Our results raise some important issues concerning the evaluation of PD-L1 in the “real-life” setting, providing strategies for its implementation.

ObjectiveSelected populations of patients with chronic hepatitis B (CHB) may benefit from a combined use of pegylated interferon-alpha (pegIFN-α) and nucleos(t)ides (NUCs). The aim of our study was to assess the immunomodulatory effect of pegIFN-α on T and natural killer (NK) cell responses in NUC-suppressed patients to identify cellular and/or serological parameters to predict better T cell-restoring effect and better control of infection in response to pegIFN-α for a tailored application of IFN-α add-on.Design53 HBeAg-negative NUC-treated patients with CHB were randomised at a 1:1 ratio to receive pegIFN-α-2a for 48 weeks, or to continue NUC therapy and then followed up for at least 6 months maintaining NUCs. Serum hepatitis B surface antigen (HBsAg) and hepatitis B core‐related antigen (HBcrAg) levels as well as peripheral blood NK cell phenotype and function and HBV-specific T cell responses upon in vitro stimulation with overlapping HBV peptides were measured longitudinally before, during and after pegIFN-α therapy.ResultsTwo cohorts of pegIFN-α treated patients were identified according to HBsAg decline greater or less than 0.5 log at week 24 post-treatment. PegIFN-α add-on did not significantly improve HBV-specific T cell responses during therapy but elicited a significant multispecific and polyfunctional T cell improvement at week 24 post-pegIFN-α treatment compared with baseline. This improvement was maximal in patients who had a higher drop in serum HBsAg levels and a lower basal HBcrAg values.ConclusionsPegIFN-α treatment can induce greater functional T cell improvement and HBsAg decline in patients with lower baseline HBcrAg levels. Thus, HBcrAg may represent an easily and reliably applicable parameter to select patients who are more likely to achieve better response to pegIFN-α add-on to virally suppressed patients.

Background: Currently, several therapies are available for metastatic castration-resistant prostate cancer (mCRPC) but no specific clinical factors to personalize treatment. We first sought the prognostic value of duration on androgen-deprivation therapy (ADT) for hormone-sensitive prostate cancer (HSPC) in patients receiving androgen-receptor-signaling inhibitors (ARSI) for mCRPC. Methods: A multicenter cohort of mCRPC patients who started ARSI between July 2011 and October 2021 was identified. Based on their initial disease burden and duration on ADT for HSPC, primary progressive (PP) men were classified into four groups: low/intermediate-risk localized disease (LOC) and high-risk localized/locally advanced disease (LAD) and short-term (ST) &lt; 24 vs. long-term (LT) ADT ≥ 24 months, whereas de novo (DN) mHSPC were subdivided into short-time vs. long-time to CRPC. Results: We included 919 mCRPC patients with a median age of 77 years [interquartile range (IQR) = 71–82)]. Median ADT duration in HSPC was 24 months (IQR = 14–40). Median follow-up was 91 months (IQR = 62–138), median OS and PFS from ARSI start were 20 (IQR 10–32) and 10 months (IQR = 5–19), respectively. In PP developing metastatic disease (n= 655, 71.3%), LOC and LAD with ST ADT had a greater than almost double-risk of death compared to LT ADT (LOC/ST: hazard ratio [HR] = 2.01; 95% CI 1.54–2.64; LAD/ST: HR = 1.73; 95% CI 1.34–2.24; p&lt; 0.001). In the multivariate analysis including age, prognostic cohort, Gleason, ECOG, radical radiotherapy and prostatectomy, groups with ST ADT were associated with worse OS compared to LT ADT (LOC/ST: HR = 1.84; 95% CI 1.38–2.45; p&lt; 0.001; LAD/ST: HR = 1.59; 95% CI 1.21–2.10; p&lt; 0.001), along with ECOG > 2 (HR = 1.55; 95% CI 1.06–2.26; p= 0.03). There were also similar results of PFS. Moreover, long-time to CRPC in patients with history of DN mHSPC (n= 264, 28.7%) resulted in a better OS/PFS (HR = 0.76, 95% CI 0.56–1.02, p= 0.064 and HR = 0.74, 95% CI 0.55–0.99, p= 0.042, respectively). Conclusions: Our study showed that duration on ADT for mHSPC was significantly associated with survival in mCRPC undergoing ARSI. These findings suggest a possible connection between initial management of prostate tumour and a better prognostication in mCRPC. Prospective trials are warranted.

Carotid stenosis due to severely calcified plaque can pose a significant therapeutic challenge. Extremely calcified scars/stenosis plaques can be challenging from an endovascular treatment perspective as severely calcified lesions are prone to technical failure, stent re-coil and restenosis. Intravascular lithotripsy, approved for treatment of severely calcified coronary lesions, can be used for breaking up the calcium build up in the intimal and medial layers of the vessel wall prior to stenting. This was designated as a breakthrough device innovation by the Food and Drug Administration. This new technique addresses the challenge of the disease without compromising patient safety during the procedure. We here report procedural set-up, execution and early patient follow up from our first use of this emerging technology in a neurointerventional practice setting.

IMPORTANCE: Sentinel lymph node biopsy (SLNB) is the standard of care for axillary node staging of patients with early breast cancer (BC), but its necessity can be questioned since surgery for examination of axillary nodes is not performed with curative intent. OBJECTIVE: To determine whether the omission of axillary surgery is noninferior to SLNB in patients with small BC and a negative result on preoperative axillary lymph node ultrasonography. DESIGN, SETTING, AND PARTICIPANTS: The SOUND (Sentinel Node vs Observation After Axillary Ultra-Sound) trial was a prospective noninferiority phase 3 randomized clinical trial conducted in Italy, Switzerland, Spain, and Chile. A total of 1463 women of any age with BC up to 2 cm and a negative preoperative axillary ultrasonography result were enrolled and randomized between February 6, 2012, and June 30, 2017. Of those, 1405 were included in the intention-to-treat analysis. Data were analyzed from October 10, 2022, to January 13, 2023. INTERVENTION: Eligible patients were randomized on a 1:1 ratio to receive SLNB (SLNB group) or no axillary surgery (no axillary surgery group). MAIN OUTCOMES AND MEASURES: The primary end point of the study was distant disease–free survival (DDFS) at 5 years, analyzed as intention to treat. Secondary end points were the cumulative incidence of distant recurrences, the cumulative incidence of axillary recurrences, DFS, overall survival (OS), and the adjuvant treatment recommendations. RESULTS: Among 1405 women (median [IQR] age, 60 [52-68] years) included in the intention-to-treat analysis, 708 were randomized to the SLNB group, and 697 were randomized to the no axillary surgery group. Overall, the median (IQR) tumor size was 1.1 (0.8-1.5) cm, and 1234 patients (87.8%) had estrogen receptor–positive ERBB2 (formerly HER2 or HER2/neu), nonoverexpressing BC. In the SLNB group, 97 patients (13.7%) had positive axillary nodes. The median (IQR) follow-up for disease assessment was 5.7 (5.0-6.8) years in the SLNB group and 5.7 (5.0-6.6) years in the no axillary surgery group. Five-year distant DDFS was 97.7% in the SLNB group and 98.0% in the no axillary surgery group (log-rank P = .67; hazard ratio, 0.84; 90% CI, 0.45-1.54; noninferiority P = .02). A total of 12 (1.7%) locoregional relapses, 13 (1.8%) distant metastases, and 21 (3.0%) deaths were observed in the SLNB group, and 11 (1.6%) locoregional relapses, 14 (2.0%) distant metastases, and 18 (2.6%) deaths were observed in the no axillary surgery group. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, omission of axillary surgery was noninferior to SLNB in patients with small BC and a negative result on ultrasonography of the axillary lymph nodes. These results suggest that patients with these features can be safely spared any axillary surgery whenever the lack of pathological information does not affect the postoperative treatment plan. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02167490

The opportunity to foresee how a physical system might work in advance, resorting to its digital model, explains the general attractiveness of digital twins. The use of digital twins, especially in the manufacturing context, encourages the investigation of the benefits that may bring in many circumstances, ranging from medical to commercial applications. In this work, however, we do not introduce yet another field where digital twins may be applied but, instead, propose digital twins as part of a convergence of technologies that may be put to good use to foster advanced distributed collaboration platforms to support humans in the loop. To clarify our proposal, we contextualize the proposed methodology by providing a conceptual framework related to a Virtual Hackable City, where we explain the advantages of such an approach.

Obesity has been associated with improved response to immunotherapy in cancer patients. We investigated the role of body mass index (BMI) in patients from the ARON-1 study (NCT05287464) treated by dual immuno-oncology agents (IO+IO) or a combination of immuno-oncology drug and a tyrosine kinase inhibitors (TKI) as first-line therapy for metastatic renal cell carcinoma (mRCC).

•Adjuvant systemic treatment with sunitinib for patients with renal cell carcinoma (RCC) is controversial.•Systemic adjuvant treatment with Sunitinib improves disease-free survival, however with considerable toxicity.•Adjuvant systemic treatment with immune checkpoint inhibitors (ICI) is associated with lower risk of toxicity, however with conflicting clinical benefit.•This meta-analysis, with the available high-level data of adjuvant systemic treatment with ICI for RCC patients, was not able to demonstrate survival benefit in the overall population.

Synthetic lethality (SL) is an innovative strategy in targeted anticancer therapy that exploits tumor genetic vulnerabilities. This topic has come to the forefront in recent years, as witnessed by the increased number of publications since 2007. The first proof of concept for the effectiveness of SL was provided by the approval of poly(ADP-ribose)polymerase inhibitors, which exploit a SL interaction in BRCA-deficient cells, although their use is limited by resistance. Searching for additional SL interactions involving BRCA mutations, the DNA polymerase theta (POLθ) emerged as an exciting target. This review summarizes, for the first time, the POLθ polymerase and helicase inhibitors reported to date. Compounds are described focusing on chemical structure and biological activity. With the aim to enable further drug discovery efforts in interrogating POLθ as a target, we propose a plausible pharmacophore model for POLθ-pol inhibitors and provide a structural analysis of the known POLθ ligand binding sites.

ABSTRACTIntroductionSignificant advances have been made in the first-line therapy of metastatic renal cell carcinoma (mRCC) since the approval of immune-based combinations, including nivolumab plus ipilimumab or cabozantinib, and pembrolizumab plus axitinib or lenvatinib.Areas coveredThe aim of this review is to compare the different safety profiles of first-line immune-based combinations versus sunitinib across the four respective pivotal trials (CheckMate 214, CheckMate 9ER, KEYNOTE-426, and CLEAR), with a particular attention to patients’ health-related quality of life (HRQoL) assessment.Expert opinionThe concurrent use of an immune-checkpoint inhibitor (ICI) with a tyrosine kinase inhibitor (TKI) as a first-line treatment strategy for mRCC has highlighted the unmet clinical need for prompt detection and consequently proper management of adverse events (AEs), both immune-related and TKI-induced. Overlapping AEs, such as hypertransaminasemia, are most challenging to manage, and evidence is still outlined from clinical practice. The specific patterns of toxicities of the approved first-line immune-based combinations, along with the impact of these interventions on patients’ HRQoL, demand a deeper consideration by physicians while choosing the appropriate treatment for each individual mRCC patient. Both safety profile and HRQoL evaluation could be exploited to guide the first-line treatment selection in this setting.

The treatment of castration-sensitive prostate cancer (CSPC) has been revolutionized by the advent of apalutamide and enzalutamide in this setting; however, a direct comparison between these agents is still missing. In the current paper, we performed both Number Needed to Treat (NNT) and Number Needed to Harm (NNH) analyses aimed to compare clinical outcomes in CSPC patients treated with apalutamide or enzalutamide; data from 3323 CSPC patients enrolled in the ARCHES, ENZAMET and TITAN phase III studies were included. According to our results, apalutamide showed better results in terms of overall survival (OS) and safety in patients with CSPC, while better outcomes were observed with enzalutamide in the low-volume subgroup.

Due to climate changes, resources availability and evolving markets, the food system is developing towards an articulated and complex ecology, with fast transformations occurring in food production, preparation, delivery and disposal. In this context, innovation is needed not just to ideate solutions to deal with a fast-changing system but also to accompany the change adopting a systemic long-term approach. We reflect on the transformational potential of design in the food sector enabled by digital technologies, one of the current major drivers of change. We define two levels of changes implying digital technologies, those that radically change the food system and those enabling changes within a given system. These levels are exemplified with case studies documented in literature and with students’ projects showing how transformational design can help grasp the complexity of current problems, and question the current status quo by facilitating a dialogue among stakeholders to stimulate behaviour change without prescribing it. In this article we encourage a paradigm shift of design from craft activity to a holistic approach of systemic thinking where the designer assumes the role of promoter and facilitator of change. Reflections on challenges at cultural, social and technological levels are provided in the conclusion section.

This Special Issue focuses on exploring the latest trends in the use of information technology to cope with emerging societal transformations on the food system and its interrelations. It aims to be a starting point, especially to show what a key role designers play today in the ongoing transformation process and transition of food systems. It shows that the great challenge of digital innovation in the food sector is to re-design not only the products, but also the services and processes imposed by the ongoing digital transformation.

We report [1,2,4]triazolo[3,4-b]benzothiazole (TBT) as a new inhibitor scaffold, which competes with nicotinamide in the binding pocket of human poly- and mono-ADP-ribosylating enzymes. The binding mode was studied through analogues and cocrystal structures with TNKS2, PARP2, PARP14, and PARP15. Based on the substitution pattern, we were able to identify 3-amino derivatives 21(OUL243) and 27(OUL232) as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14, and PARP15 at nM potencies, with 27being the most potent PARP10 inhibitor described to date (IC50of 7.8 nM) and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative 16(OUL245) inhibits poly-ARTs with a selectivity toward PARP2. The scaffold does not possess inherent cell toxicity, and the inhibitors can enter cells and engage with the target protein. This, together with favorable ADME properties, demonstrates the potential of TBT scaffold for future drug development efforts toward selective inhibitors against specific enzymes.

BackgroundSuper large-bore aspiration (SLBA) has shown high rates of complete clot ingestion.ObjectiveTo report the initial clinical feasibility, safety, and efficacy of this novel SLBA insert combination—super large-bore ingestion of clot (SLIC) technique for stroke.MethodsWe performed a retrospective review of three comprehensive stroke center databases. The SLIC technique entails a triaxial assembly of an 8 Fr 0.106″ Base Camp catheter, 0.088″ catheter extender (HiPoint), and an insert catheter (Tenzing 8) that completely consumes the inner diameter of the 0.088″ SLBA catheter. The HiPoint catheter is delivered over the Tenzing 8 to the face of the embolus, which is withdrawn, while aspirating through the Base Camp and HiPoint catheters as a single assembly.ResultsThirty-three consecutive patients with large vessel occlusion were treated with SLIC. The median age was 70 years (30–91) and 17 were male (51.5%). The median presenting National Institutes of Health Stroke Scale score and Alberta Stroke Program Early CT score was 21 (1–34) and 8 (5–10), respectively. There was 100% success in delivering the 0.088″ catheter to the site of the occlusion. The successful revascularization rate (modified Thrombolysis in Cerebral Infarction (mTICI) score ≥2B) was 100% within a single pass in most cases (82%). Final mTICI ≥2C was achieved in 94.1% of occlusions, with 73.5% mTICI 3 recanalization. The rate of first pass effect in achieving excellent reperfusion (mTICI ≥2C) was 70.5%. There were no adverse events or postprocedural symptomatic hemorrhages.ConclusionsOur initial experience with the SLIC technique resulted in achieving a first pass effect (mTICI ≥2C) in 70.5%. Navigation of the SLBA catheter extender over the Tenzing insert was successful and safe in this early experience.

ObjectiveExhausted hepatitis B virus (HBV)-specific CD8 T cells in chronic HBV infection are broadly heterogeneous. Characterisation of their functional impairment may allow to distinguish patients with different capacity to control infection and reconstitute antiviral function.DesignHBV dextramer+CD8 T cells were analysed ex vivo for coexpression of checkpoint/differentiation markers, transcription factors and cytokines in 35 patients with HLA-A2+chronic hepatitis B (CHB) and in 29 control HBsAg negative CHB patients who seroconverted after NUC treatment or spontaneously. Cytokine production was also evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of antioxidant, polyphenolic, PD-1/PD-L1 inhibitor and TLR-8 agonist compounds and the effect on HBV-specific responses was further validated on additional 24 HLA-A2 negative CHB patients.ResultsSeverely exhausted HBV-specific CD8 T cell subsets with high expression of inhibitory receptors, such as PD-1, TOX and CD39, were detected only in a subgroup of chronic viraemic patients. Conversely, a large predominance of functionally more efficient HBV-specific CD8 T cell subsets with lower expression of coinhibitory molecules and better response to in vitro immune modulation, typically detected after resolution of infection, was also observed in a proportion of chronic viraemic HBV patients. Importantly, the same subset of patients who responded more efficiently to in vitro immune modulation identified by HBV-specific CD8 T cell analysis were also identified by staining total CD8 T cells with PD-1, TOX, CD127 and Bcl-2.ConclusionsThe possibility to distinguish patient cohorts with different capacity to respond to immune modulatory compounds in vitro by a simple analysis of the phenotypic CD8 T cell exhaustion profile deserves evaluation of its clinical applicability.

NADPH oxidases (NOXs) are transmembrane enzymes that are devoted to the production of reactive oxygen species (ROS). In cancers, dysregulation of NOX enzymes affects ROS production, leading to redox unbalance and tumor progression. Consequently, NOXs are a drug target for cancer therapeutics, although current therapies have off-target effects: there is a need for isoenzyme-selective inhibitors. Here, we describe fully validated human NOX inhibitors, obtained from an in silico screen, targeting the active site of Cylindrospermum stagnaleNOX5 (csNOX5). The hits are validated by in vitro and in cellulo enzymatic and binding assays, and their binding modes to the dehydrogenase domain of csNOX5 studied via high-resolution crystal structures. A high-throughput screen in a panel of cancer cells shows activity in selected cancer cell lines and synergistic effects with KRAS modulators. Our work lays the foundation for the development of inhibitor-based methods for controlling the tightly regulated and highly localized ROS sources.

Purpose: Hypoparathyroidism is a rare endocrine disorder characterized by low or absent secretion of parathyroid hormone (PTH), which leads to decreased calcium and increased phosphorus levels in the serum. The diagnosis of hypoparathyroidism is based on the identification of the aforementioned biochemical abnormalities, which may be accompanied by clinical manifestations. Symptoms of hypoparathyroidism, primarily attributed to hypocalcemia, include muscle cramps or spasms, facial, leg, and foot pain, seizures, and tingling in the lips or fingers. The treatment of hypoparathyroidism depends on the severity of symptoms and the underlying pathology. Over the long term, calcium supplements, active vitamin D analogs, and thiazide diuretics may be needed. In fact, in patient cohorts in which optimal disease control still remains elusive, replacement therapy with recombinant parathyroid hormone analogs may be contemplated. Despite the predominantly neuromuscular symptoms of hypoparathyroidism, further effects of parathyroid hormone deficiency at the muscle cell level remain poorly understood. Thus, the aim of our study was to evaluate the effects of hypocalcemia in combination with hyperphosphatemia on muscle cells differentiation in vitro. Methods: C2C12 cells, an in vitro model of muscle cells, were differentiated for 2 or 6 days in the presence of hypocalcemia (CaCl20.9 mmol/l) and moderate (PO4 1.4 mmol/l) or severe (PO4 2.9 mmol/l) hyperphosphatemia, or combinations of both conditions. Cell differentiation and expression of genes linked to muscle differentiation were evaluated. Results: The combination of hypocalcemia with hyperphosphatemia induced a significant reduction (50%) in differentiation marker levels, such as MyoD (protein 1 for myoblast determination) and myogenin on the 1st day of differentiation, and MHC (myosin heavy chains) after 6 days of differentiation compared to control. Furthermore, this condition induced a statistically significant reduction of insulin-like growth factor-1 (IGF-1) mRNA expression and inhibition of IGF signaling and decrease in ERK phosphorylation compared to control cells. Conclusions: Our results showed that a condition of hypocalcemia with hyperphosphatemia induced an alteration of muscle cell differentiation in vitro. In particular, we observed the reduction of myogenic differentiation markers, IGF-1 signaling pathway, and ERK phosphorylation in differentiated skeletal myoblasts. These data suggest that this altered extracellular condition might contribute to the mechanisms causing persistence of symptoms in patients affected by hypoparathyroidism.

Circular Supply Chains (CSCs) are self-regenerative ecosystems adopting the principles of Circular Economy to extract new value from end-of-life resources, extend product life, and increase resource efficiency toward zero-wasteoperating conditions. CSCs extend the boundaries of closed loop SCs by involving multiple stakeholders, with both firms belonging to the linear supply chain stages and organizations from the external industrial networks, carrying out the circular activities. Both of them are required to collaborate on managing multiple resource flows i.e., by-products and wastes other than raw materials and main products. A higher level of complexity thus characterizes the transition to CSCs. However, despite the interest on the topic, a robust framework exploring the main dimensions regarding the complexity of CSCs is yet to be developed. We address this research gap by developing a conceptual model using the theory of the Complex Adaptive Systems (CASs). A novel agent-based model is developed to simulate the dynamics of circular supply chains characterized by different levels of internal and external interdependence, and inter-firm coordination mechanisms.

IntroductionExposure to asbestos increases the risk of lung cancer and mesothelioma. Few studies quantified the premature occurrence of these diseases in asbestos-exposed workers. Focus on premature disease onset (rate advancement or acceleration) can be useful in risk communication and for the evaluation of exposure impact. We estimated rate advancement for total mortality, lung cancer and pleural mesothelioma deaths, by classes of cumulative asbestos exposure in a pooled cohort of asbestos cement (AC) workers in Italy.MethodThe cohort study included 12 578 workers from 21 cohorts, with 6626 deaths in total, 858 deaths from lung cancer and 394 from pleural malignant neoplasm (MN). Rate advancement was estimated by fitting a competitive mortality Weibull model to the hazard of death over time since first exposure (TSFE).ResultAcceleration time (AT) was estimated at different TSFE values. The highest level of cumulative exposure compared with the lowest, for pleural MN AT was 16.9 (95% CI 14.9 to 19.2) and 33.8 (95% CI 29.8 to 38.4) years at TSFE of 20 and 40 years, respectively. For lung cancer, it was 13.3 (95% CI 12.0 to 14.7) and 26.6 (95% CI 23.9 to 29.4) years, respectively. As for total mortality, AT was 3.35 (95% CI 2.98 to 3.71) years at 20 years TSFE, and 6.70 (95% CI 5.95 to 7.41) at 40 years TSFE.ConclusionThe current study observed marked rate advancement after asbestos exposure for lung cancer and pleural mesothelioma, as well as for total mortality.

The article offers information about the human body is a complex phenomenon that operates based on the principles of quantum bio-physics. It is a combination of frequencies and molecules that work together to maintain the state of homeostasis and health. Certain frequencies may have the ability to repel diseases, and there is a possible link between frequency and health.