Development and internal validation of a clinical score to predict neonatal hypoglycaemia in women with gestational diabetes.

INTRODUCTION: Gestational diabetes (GD) is a risk factor for neonatal hypoglycaemia (NH), but other factors can increase this risk. OBJECTIVES: To create a score to predict NH in women with GD. METHODS: Retrospective study of women with GD with a live singleton birth between 2012 and 2017 from the Portuguese GD registry. Pregnancies with and without NH were compared. A logistic regression was used to study NH predictors. Variables independently associated with NH were used to score derivation. The model's internal validation was performed by a bootstrapping. The association between the score and NH was assessed by logistic regression. RESULTS: We studied 10216 pregnancies, 410 (4.0%) with NH. The model's AUC was 0.628 (95%CI: 0.599-0.657). Optimism-corrected c-index: 0.626. Points were assigned to variables associated with NH in proportion to the model's lowest regression coefficient: insulin-treatment 1, preeclampsia 3, preterm delivery 2, male sex 1, and small-for-gestational-age 2, or large-for-gestational-age 3. NH prevalence by score category 0-1, 2, 3, 4, and ≥5 was 2.3%, 3.0%, 4.5%, 6.0%, 7.4%, and 11.5%, respectively. Per point, the OR for NH was 1.35 (95% CI: 1.27-1.42). A score of 2, 3, 4, 5 or ≥6 (versus ≤1) had a OR for NH of 1.67 (1.29-2.15), 2.24 (1.65-3.04), 2.83 (2.02-3.98), 3.08 (1.83-5.16), and 6.84 (4.34-10.77), respectively. CONCLUSION: Per each score point, women with GD had 35% higher risk of NH. Those with ≥6 points had 6.8-fold higher risk of NH compared to a score ≤1. Our score may be useful for identifying women at a higher risk of NH.

Infectious Sacroiliitis as a Rare Postpartum Complication: A Case Report.

Infectious sacroiliitis is a rare and challenging diagnosis. Sacroiliac joint changes related to pregnancy and puerperium can predispose to this condition. However, its clinical presentation can often mimic common causes of lower back pain and delay the diagnosis. We report the case of a 31-year-old pregnant woman with twins who presented at 29 weeks of gestation with lower back and right buttock pain that radiated down to the thigh. Although initially interpreted as sciatica pain, the diagnosis of psoas hematoma complicated with infectious sacroiliitis was made. With this case, we aim to bring awareness to this condition in order to raise suspicion among clinicians for an earlier diagnosis.

Apolipoprotein E-ε2 and Resistance to Atherosclerosis in Midlife: The PESA Observational Study.

BACKGROUND: APOE is a known genetic contributor to cardiovascular disease, but the differential role APOE alleles play in subclinical atherosclerosis remains unclear. METHODS: The PESA (Progression of Early Subclinical Atherosclerosis) is an observational cohort study that recruited 4184 middle-aged asymptomatic individuals to be screened for cardiovascular risk and multiterritorial subclinical atherosclerosis. Participants were APOE-genotyped, and omics data were additionally evaluated. RESULTS: In the PESA study, the frequencies for APOE -ε2, -ε3, and -ε4 alleles were 0.060, 0.844, and 0.096, respectively. This study included a subcohort of 3887 participants (45.8±4.3 years of age; 62% males). As expected, APOE-ε4 carriers were at the highest risk for cardiovascular disease and had significantly greater odds of having subclinical atherosclerosis compared with ε3/ε3 carriers, which was mainly explained by their higher levels of low-density lipoprotein (LDL)-cholesterol. In turn, APOE-ε2 carriers were at the lowest risk for cardiovascular disease and had significantly lower odds of having subclinical atherosclerosis in several vascular territories (carotids: 0.62 [95% CI, 0.47-0.81]; P=0.00043; femorals: 0.60 [0.47-0.78]; P=9.96×10-5; coronaries: 0.53 [0.39-0.74]; P=0.00013; and increased PESA score: 0.58 [0.48-0.71]; P=3.16×10-8). This APOE-ε2 atheroprotective effect was mostly independent of the associated lower LDL-cholesterol levels and other cardiovascular risk factors. The protection conferred by the ε2 allele was greater with age (50-54 years: 0.49 [95% CI, 0.32-0.73]; P=0.00045), and normal (<150 mg/dL) levels of triglycerides (0.54 [0.44-0.66]; P=4.70×10-9 versus 0.90 [0.57-1.43]; P=0.67 if ≥150 mg/dL). Omics analysis revealed an enrichment of several canonical pathways associated with anti-inflammatory mechanisms together with the modulation of erythrocyte homeostasis, coagulation, and complement activation in ε2 carriers that might play a relevant role in the ε2's atheroprotective effect. CONCLUSIONS: This work sheds light on the role of APOE in cardiovascular disease development with important therapeutic and prevention implications on cardiovascular health, especially in early midlife. REGISTRATION: URL: https://www.clinicaltrials.gov: NCT01410318.

Walking the talk for dementia: A unique immersive, embodied, and multi-experiential initiative.

Coping with dementia requires an integrated approach encompassing personal, health, research, and community domains. Here we describe "Walking the Talk for Dementia," an immersive initiative aimed at empowering people with dementia, enhancing dementia understanding, and inspiring collaborations. This initiative involved 300 participants from 25 nationalities, including people with dementia, care partners, clinicians, policymakers, researchers, and advocates for a 4-day, 40 km walk through the Camino de Santiago de Compostela, Spain. A 2-day symposium after the journey provided novel transdisciplinary and horizontal structures, deconstructing traditional hierarchies. The innovation of this initiative lies in its ability to merge a physical experience with knowledge exchange for diversifying individuals' understanding of dementia. It showcases the transformative potential of an immersive, embodied, and multi-experiential approach to address the complexities of dementia collaboratively. The initiative offers a scalable model to enhance understanding, decrease stigma, and promote more comprehensive and empathetic dementia care and research.

The clinical and genetic landscape of developmental and epileptic encephalopathies in Egyptian children.

Developmental and epileptic encephalopathies (DEEs) are a heterogeneous group of epilepsies characterized by early-onset, refractory seizures associated with developmental regression or impairment, with a heterogeneous genetic landscape including genes implicated in various pathways and mechanisms. We retrospectively studied the clinical and genetic data of patients with genetic DEE who presented at two tertiary centers in Egypt over a 10-year period. Exome sequencing was used for genetic testing. We report 74 patients from 63 unrelated Egyptian families, with a high rate of consanguinity (58%). The most common seizure type was generalized tonic-clonic (58%) and multiple seizure types were common (55%). The most common epilepsy syndrome was early infantile DEE (50%). All patients showed variable degrees of developmental impairment. Microcephaly, hypotonia, ophthalmological involvement and neuroimaging abnormalities were common. Eighteen novel variants were identified and the phenotypes of five DEE genes were expanded with novel phenotype-genotype associations. Obtaining a genetic diagnosis had implications on epilepsy management in 17 patients with variants in 12 genes. In this study, we expand the phenotype and genotype spectrum of DEE in a large single ethnic cohort of patients. Reaching a genetic diagnosis guided precision management of epilepsy in a significant proportion of patients.

Seasonal and Geographic Dynamics in Bioproperties and Phytochemical Profile of Limonium algarvense Erben.

This study delved into the influence of ecological and seasonal dynamics on the synthesis of secondary metabolites in the medicinal halophyte Limonium algarvense Erben, commonly known as sea lavender, and examined their antioxidant and anti-inflammatory properties. Aerial parts of sea lavender were systematically collected across winter, spring, summer, and autumn seasons from distinct geographic locations in southern Portugal, specifically "Ria de Alvor" in Portimão and "Ria Formosa" in Tavira. The investigation involved determining the total polyphenolic profile through spectrophotometric methods, establishing the chemical profile via liquid chromatography electrospray ionization quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS/MS), and evaluating in vitro antioxidant properties using radical and metal-based methods, along with assessing anti-inflammatory capacity through a cell model. Results unveiled varying polyphenol levels and profiles across seasons, with spring and autumn samples exhibiting the highest content, accompanied by the most notable antioxidant and anti-inflammatory capacities. Geographic location emerged as an influential factor, particularly distinguishing plants from "Ria de Alvor". Seasonal fluctuations were associated with environmental factors, including temperature, which, when excessively high, can impair plant metabolism, but also with the presence of flowers and seeds in spring and autumn samples, which also seems to contribute to elevated polyphenol levels and enhanced bioproperties of these samples. Additionally, genetic factors may be related to differences observed between ecotypes (geographical location). This study underscores sea lavender's potential as a natural source of antioxidant and anti-inflammatory agents, emphasizing the significance of considering both geographic location and seasonal dynamics in the assessment of phenolic composition and bioactive properties in medicinal plant species.

Trends in 3D models of inflammatory bowel disease.

Inflammatory bowel disease (IBD) encompasses a set of chronic inflammatory conditions, namely Crohn's disease and ulcerative colitis. Despite all advances in the management of IBD, a definitive cure is not available, largely due to a lack of a holistic understanding of its etiology and pathophysiology. Several in vitro, in vivo, and ex vivo models have been developed over the past few decades in order to abbreviate remaining gaps. The establishment of reliable and predictable in vitro intestinal inflammation models may indeed provide valuable tools to expedite and validate the development of therapies for IBD. Three-dimensional (3D) models provide a more accurate representation of the different layers of the intestine, contributing to a stronger impact on drug screening and research on intestinal inflammation, and bridging the gap between in vitro and in vivo research. This work provides a critical overview on the state-of-the-art on existing 3D models of intestinal inflammation and discusses the remaining challenges, providing insights on possible pathways towards achieving IBD mimetic models. We also address some of the main challenges faced by implementing cell culture models in IBD research while bearing in mind clinical translational aspects.

Oral anticoagulants: A plausible new treatment for Alzheimer's disease?

Alzheimer's disease (AD) and cardiovascular disease (CVD) are strongly associated. Both are multifactorial disorders with long asymptomatic phases and similar risk factors. Indeed, CVD signatures such as cerebral microbleeds, micro-infarcts, atherosclerosis, cerebral amyloid angiopathy and a procoagulant state are highly associated with AD. However, AD and CVD co-development and the molecular mechanisms underlying such associations are not understood. Here, we review the evidence regarding the vascular component of AD and clinical studies using anticoagulants that specifically evaluated the development of AD and other dementias. Most studies reported a markedly decreased incidence of composite dementia in anticoagulated patients with atrial fibrillation, with the highest benefit for direct oral anticoagulants. However, sub-analyses by differential dementia diagnosis were scarce and inconclusive. We finally discuss whether anticoagulation could be a plausible preventive/therapeutic approach for AD and, if so, which would be the best drug and strategy to maximize clinical benefit and minimize potential risks. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.

Long-term care facilities' response to the COVID-19 pandemic: An international, cross-sectional survey.

AIMS: To (i) assess the adherence of long-term care (LTC) facilities to the COVID-19 prevention and control recommendations, (ii) identify predictors of this adherence and (iii) examine the association between the adherence level and the impact of the pandemic on selected unfavourable conditions. DESIGN: Cross-sectional survey. METHODS: Managers (n = 212) and staff (n = 2143) of LTC facilities (n = 223) in 13 countries/regions (Brazil, Egypt, England, Hong Kong, Indonesia, Japan, Norway, Portugal, Saudi Arabia, South Korea, Spain, Thailand and Turkey) evaluated the adherence of LTC facilities to COVID-19 prevention and control recommendations and the impact of the pandemic on unfavourable conditions related to staff, residents and residents' families. The characteristics of participants and LTC facilities were also gathered. Data were collected from April to October 2021. The study was reported following the STROBE guidelines. RESULTS: The adherence was significantly higher among facilities with more pre-pandemic in-service education on infection control and easier access to information early in the pandemic. Residents' feelings of loneliness and feeling down were the most affected conditions by the pandemic. More psychological support to residents was associated with fewer residents' aggressive behaviours, and more psychological support to staff was associated with less work-life imbalance. CONCLUSIONS: Pre-pandemic preparedness significantly shaped LTC facilities' response to the pandemic. Adequate psychological support to residents and staff might help mitigate the negative impacts of infection outbreaks. IMPACT: This is the first study to comprehensively examine the adherence of LTC facilities to COVID-19 prevention and control recommendations. The results demonstrated that the adherence level was significantly related to pre-pandemic preparedness and that adequate psychological support to staff and residents was significantly associated with less negative impacts of the pandemic on LTC facilities' staff and residents. The results would help LTC facilities prepare for and respond to future infection outbreaks. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

Biomarkers for intervertebral disc and associated back pain: From diagnosis to disease prognosis and personalized treatment.

Biomarkers are commonly recognized as objective indicators of a medical state or clinical outcome and have been widely used as clinical and diagnostic tools and surrogate endpoints in many pathological conditions. In the context of intervertebral disc (IVD) and associated back pain, also known as degenerative disc disease (DDD), the use of biomarkers has been poorly explored. DDD is currently diagnosed using imaging techniques and subjective pain scales, limiting an objective association between DDD and pain levels, as well as an evaluation of disease progression. There is a need for objective and reliable measurements for DDD, pain and pathology progression. DDD predictors could also help clinicians in deciding on the optimal treatment for distinct patient groups. This review addresses the current candidate biomarkers in DDD, including imaging, genetic, metabolite and protein-based parameters, both at the tissue and systemic levels, that may become a major advance in the diagnosis and prognosis of the disease, as well as in the management of therapeutic approaches to DDD.

Application of a dried blood spot based proteomic and genetic assay for diagnosing hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is a rare disease caused by low level (type I) or dysfunction (type II) of the C1-inhibitor protein with subsequent reduction of certain complement protein levels. METHODS: To develop and test the reliability of a two-tier method based on C1-INH and C4 quantitation followed by genetic analysis from dried blood spot (DBS) for establishing the diagnosis of C1-INH-HAE. C1-INH and C4 proteins have been quantified in human plasma using a classical immuno-assay and in DBS using a newly developed proteolytic liquid chromatography-mass spectrometry method. Genetic analysis was carried out as reported previously (PMID: 35386643) and by a targeted next-generation sequencing panel, multiplex ligation-dependent probe amplification and in some cases whole genome sequencing. RESULTS: DBS quantification of C1-INH and C4 showed the same pattern as plasma, offering the possibility of screening patients with AE symptoms either locally or remotely. Genetic analysis from DBS verified each of the previously identified SERPING1 mutations of the tested C1-INH-HAE patients and revealed the presence of other rare variations in genes that may be involved in the pathogenesis of AE episodes. CONCLUSIONS: C1-INH/C4 quantification in DBS can be used for screening of hereditary AE and DNA extracted from dried blood spots is suitable for identifying various types of mutations of the SERPING1 gene.

Harnessing the Bioactive Potential of Limonium spathulatum (Desf.) Kuntze: Insights into Enzyme Inhibition and Phytochemical Profile.

This study assessed the halophyte species Limonium spathulatum (Desf.) as a possible source of natural ingredients with the capacity to inhibit enzymes related to relevant human health disorders and food browning. Extracts using food-grade solvents such as water and ethanol were prepared by maceration from dried L. spathulatum leaves. They were evaluated for in vitro inhibition activity of enzymes such as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), α-glucosidase, tyrosinase and lipase, related to Alzheimer's disease, type-2-diabetes mellitus, skin hyperpigmentation, and obesity, respectively. These extracts were also appraised for in vitro acute toxicity on tumoral and non-tumoral cell lines and their chemical composition by high-performance liquid chromatography coupled with electrospray ionization mass spectrometry (HPLC-ESI-MS/MS). The extracts were more effective towards BChE than AChE. The best results were obtained with the hydroethanolic and water extracts, with IC50 values of 0.03 mg/mL and 0.06 mg/mL, respectively. The hydroethanolic extract had the highest capacity to inhibit α-glucosidase (IC50: 0.04 mg/mL), higher than the positive control used (acarbose, IC50 = 3.14 mg/mL). The ethanol extract displayed the best inhibitory activity against tyrosinase (IC50 = 0.34 mg/mL). The tested samples did not inhibit lipase and exhibited low to moderate cytotoxic activity against the tested cell lines. The hydroethanolic extract had a higher diversity of compounds, followed by the ethanol and water samples. Similar molecules were identified in all the extracts and were mainly hydroxybenzoic acids, hydroxycinnamic acids, and flavonoids. Taken together, these results suggest that L. spathulatum should be further explored as a source of bioactive ingredients for the food, cosmetic, and pharmaceutical industries.

Longitudinal interplay between subclinical atherosclerosis, cardiovascular risk factors, and cerebral glucose metabolism in midlife: results from the PESA prospective cohort study.

BACKGROUND: Cardiovascular disease and dementia often coexist at advanced stages. Yet, longitudinal studies examining the interplay between atherosclerosis and its risk factors on brain health in midlife are scarce. We aimed to characterise the longitudinal associations between cerebral glucose metabolism, subclinical atherosclerosis, and cardiovascular risk factors in middle-aged asymptomatic individuals. METHODS: The Progression of Early Subclinical Atherosclerosis (PESA) study is a Spanish longitudinal observational cohort study of 4184 asymptomatic individuals aged 40-54 years (NCT01410318). Participants with subclinical atherosclerosis underwent longitudinal cerebral [18F]fluorodeoxyglucose ([18F]FDG)-PET, and annual percentage change in [18F]FDG uptake was assessed (primary outcome). Cardiovascular risk was quantified with SCORE2 and subclinical atherosclerosis with three-dimensional vascular ultrasound (exposures). Multivariate regression and linear mixed effects models were used to assess associations between outcomes and exposures. Additionally, blood-based biomarkers of neuropathology were quantified and mediation analyses were performed. Secondary analyses were corrected for multiple comparisons using the false discovery rate (FDR) approach. FINDINGS: This longitudinal study included a PESA subcohort of 370 participants (median age at baseline 49·8 years [IQR 46·1-52·2]; 309 [84%] men, 61 [16%] women; median follow-up 4·7 years [IQR 4·2-5·2]). Baseline scans took place between March 6, 2013, and Jan 21, 2015, and follow-up scans between Nov 24, 2017, and Aug 7, 2019. Persistent high risk of cardiovascular disease was associated with an accelerated decline of cortical [18F]FDG uptake compared with low risk (ß=-0·008 [95% CI -0·013 to -0·002]; pFDR=0·040), with plasma neurofilament light chain, a marker of neurodegeneration, mediating this association by 20% (ß=0·198 [0·008 to 0·740]; pFDR=0·050). Moreover, progression of subclinical carotid atherosclerosis was associated with an additional decline in [18F]FDG uptake in Alzheimer's disease brain regions, not explained by cardiovascular risk (ß=-0·269 [95% CI -0·509 to -0·027]; p=0·029). INTERPRETATION: Middle-aged asymptomatic individuals with persistent high risk of cardiovascular disease and subclinical carotid atherosclerosis already present brain metabolic decline, suggesting that maintenance of cardiovascular health during midlife could contribute to reductions in neurodegenerative disease burden later in life. FUNDING: Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III, Santander Bank, Pro-CNIC Foundation, BrightFocus Foundation, BBVA Foundation, "la Caixa" Foundation.

Standardized approach for extubation during extracorporeal membrane oxygenation in severe acute respiratory distress syndrome: a prospective observational study.

BACKGROUND: Extubation during extracorporeal oxygenation (ECMO) in severe acute respiratory distress syndrome (ARDS) has not been well studied. Despite the potential benefits of this strategy, weaning from ECMO before liberation from invasive mechanical ventilation remains the most frequent approach. Our aim was to evaluate the safety and feasibility of a standardized approach for extubation during ECMO in patients with severe ARDS. RESULTS: We conducted a prospective observational study to assess the safety and feasibility of a standardized approach for extubation during ECMO in severe ARDS among 254 adult patients across 4 intensive care units (ICU) from 2 tertiary ECMO centers over 6 years. This consisted of a daily assessment of clinical and gas exchange criteria based on an Extracorporeal Life Support Organization guideline, with extubation during ECMO after validation by a dedicated intensive care medicine specialist. Fifty-four (21%) patients were extubated during ECMO, 167 (66%) did not reach the clinical criteria, and in 33 (13%) patients, gas exchange precluded extubation during ECMO. At ECMO initiation, there were fewer extrapulmonary organ dysfunctions (lower SOFA score [OR, 0.88; 95% CI, 0.79-0.98; P = .02] with similar PaO2/FiO2) when compared with patients not extubated during ECMO. Extubation during ECMO associated with shorter duration of invasive mechanical ventilation (7 (4-18) vs. 32 (18-54) days; P < .01) and of ECMO (12 (7-25) vs. 19 (10-41) days; P = .01). This was accompanied by a lower incidence of hemorrhagic shock (2 vs. 11%; P = .05), but more cannula-associated deep vein thrombosis (49 vs. 31%; P = .02) and failed extubation (20 vs. 6%; P < .01). There were no increased major adverse events. Extubation during ECMO is associated with a lower risk of all-cause death, independently of measured confounding (adjusted logistic regression OR 0.23; 95% confidence interval 0.08-0.69, P = .008). CONCLUSIONS: A standardized approach was safe and feasible allowing extubation during ECMO in 21% of patients with severe ARDS, selecting patients who will have a shorter duration of invasive mechanical ventilation, ECMO course, and ICU stay, as well as fewer infectious complications, and high hospital survival.

From Threat to Opportunity: Harnessing the Invasive Carpobrotus edulis (L.) N.E.Br for Nutritional and Phytotherapeutic Valorization Amid Seasonal and Spatial Variability.

Carpobrotus edulis (L.) N.E.Br. (Hottentot-fig) is a problematic invasive species found in coastal areas worldwide. Mechanical removal is a common control method, leaving the removed biomass available as a possible source of natural phytochemicals with prospective commercial applications. While the Hottentot-fig's vegetative organs have been studied previously, this work establishes for the first time a seasonal and spatial comparative analysis of its nutritional, chemical, and bioactivity profiles (in three locations over four seasons). Proximate and mineral contents were assessed, along with its phenolic composition and in vitro antioxidant and anti-inflammatory properties. Hottentot-fig's biomass offered a good supply of nutrients, mainly carbohydrates, proteins, and minerals, with a tendency for higher concentrations of the most relevant minerals and proteins in autumn and winter, and in plants from sites A (Ria de Alvor lagoon) and B (Ancão beach). The extracts were rich in polyphenolics, with higher levels in spring and summer, especially for luteolin-7-O-glucoside and salicylic and coumaric acids. The extracts were also effective antioxidants, with stronger radical scavenging activities in spring and summer, along with anti-inflammatory properties. Our results suggest that the usually discarded plant material of this invasive halophyte could be valuable as a source of natural products with potential biotechnological applications in the food and nutraceutical industries.

Mimicking 3D breast tumor-stromal interactions to screen novel cancer therapeutics.

Most of the 3D breast tumor models used in drug screening studies only comprise tumor cells, keeping out other essential cell players of the tumor microenvironment. Tumor-associated macrophages and fibroblasts are frequently correlated with tumor progression and therapy resistance, and targeting these cells at the tumor site has been appointed as a promising therapeutic strategy. However, the translation of new therapies to the clinic has been hampered by the absence of cellular models that more closely mimic the features of in vivo breast tumor microenvironment. Therefore, the development of innovative 3D models able to provide consistent and predictive responses about the in vivo efficacy of novel therapeutics is still an unmet preclinical need. Herein, we have established an in vitro 3D heterotypic spheroid model including MCF-7 breast tumor cells, human mammary fibroblasts and human macrophages. To establish this model, different cell densities have been combined and characterized through the evaluation of the spheroid size and metabolic activity, as well as histological and immunohistochemistry analysis of the 3D multicellular structures. The final optimized 3D model consisted in a multicellular spheroid seeded at the initial density of 5000 cells and cell ratio of 1:2:1 (MCF-7:monocytes:fibroblasts). Our model recapitulates several features of the breast tumor microenvironment, including the formation of a necrotic core, spatial organization, and extracellular matrix production. Further, it was validated as a platform for drug screening studies, using paclitaxel, a currently approved drug for breast cancer treatment, and Gefitinib, a chemotherapeutic approved for lung cancer and in preclinical evaluation for breast cancer. Generally, the impact on the cell viability of the 3D model was less evident than in 2D model, reinforcing the relevance of such complex 3D models in addressing novel treatment approaches. Overall, the use of a 3D heterotypic spheroid of breast cancer could be a valuable tool to predict the therapeutic effect of new treatments for breast cancer patients, by recapitulating key features of the breast cancer microenvironment.

At a glance: the largest Niemann-Pick type C1 cohort with 602 patients diagnosed over 15 years.

Niemann-Pick type C1 disease (NPC1 [OMIM 257220]) is a rare and severe autosomal recessive disorder, characterized by a multitude of neurovisceral clinical manifestations and a fatal outcome with no effective treatment to date. Aiming to gain insights into the genetic aspects of the disease, clinical, genetic, and biomarker PPCS data from 602 patients referred from 47 countries and diagnosed with NPC1 in our laboratory were analyzed. Patients' clinical data were dissected using Human Phenotype Ontology (HPO) terms, and genotype-phenotype analysis was performed. The median age at diagnosis was 10.6 years (range 0-64.5 years), with 287 unique pathogenic/likely pathogenic (P/LP) variants identified, expanding NPC1 allelic heterogeneity. Importantly, 73 P/LP variants were previously unpublished. The most frequent variants detected were: c.3019C > G, p.(P1007A), c.3104C > T, p.(A1035V), and c.2861C > T, p.(S954L). Loss of function (LoF) variants were significantly associated with earlier age at diagnosis, highly increased biomarker levels, and a visceral phenotype (abnormal abdomen and liver morphology). On the other hand, the variants p.(P1007A) and p.(S954L) were significantly associated with later age at diagnosis (p < 0.001) and mildly elevated biomarker levels (p ≤ 0.002), consistent with the juvenile/adult form of NPC1. In addition, p.(I1061T), p.(S954L), and p.(A1035V) were associated with abnormality of eye movements (vertical supranuclear gaze palsy, p ≤ 0.05). We describe the largest and most heterogenous cohort of NPC1 patients published to date. Our results suggest that besides its utility in variant classification, the biomarker PPCS might serve to indicate disease severity/progression. In addition, we establish new genotype-phenotype relationships for "frequent" NPC1 variants.

Abdominal wall hernia repair: from prosthetic meshes to smart materials.

Hernia reconstruction is one of the most frequently practiced surgical procedures worldwide. Plastic surgery plays a pivotal role in reestablishing desired abdominal wall structure and function without the drawbacks traditionally associated with general surgery as excessive tension, postoperative pain, poor repair outcomes, and frequent recurrence. Surgical meshes have been the preferential choice for abdominal wall hernia repair to achieve the physical integrity and equivalent components of musculofascial layers. Despite the relevant progress in recent years, there are still unsolved challenges in surgical mesh design and complication settlement. This review provides a systemic summary of the hernia surgical mesh development deeply related to abdominal wall hernia pathology and classification. Commercial meshes, the first-generation prosthetic materials, and the most commonly used repair materials in the clinic are described in detail, addressing constrain side effects and rational strategies to establish characteristics of ideal hernia repair meshes. The engineered prosthetics are defined as a transit to the biomimetic smart hernia repair scaffolds with specific advantages and disadvantages, including hydrogel scaffolds, electrospinning membranes, and three-dimensional patches. Lastly, this review critically outlines the future research direction for successful hernia repair solutions by combing state-of-the-art techniques and materials.

A Systematic Literature Review of Gaps and Challenges in Value Assessment of Biosimilars: An ISPOR Special Interest Group Report.

OBJECTIVES: This study aims to provide an overview of the gaps and challenges in the value assessment of biosimilars and to identify potential approaches to address them. METHODS: A multidisciplinary, international team of biosimilar experts identified gaps and challenges. A systematic review was conducted of the peer-reviewed literature in PubMed, EMBASE, Web of Science Core Collection, EBSCOhost Business Source Complete; and of the gray literature. Preliminary results were presented at ISPOR conferences and this article benefited from 2 review rounds among ISPOR Biosimilar Special Interest Group members. RESULTS: Given that a biosimilar is highly similar to its reference biologic, health technology assessment agencies should accept the comparability exercise approved by regulatory authorities and, thus, conduct a price comparison when biosimilar reimbursement is requested for the same indication as the reference biologic. If the reference biologic is not reimbursed or is not the standard of care, a full economic evaluation of the biosimilar versus a relevant comparator needs to be conducted. To date, little consideration has been given to specific challenges, such as how biosimilar value assessment can account for the nocebo effect, potential differences between biologic-naive and biologic-experienced patients, the availability of intravenous and subcutaneous administration forms or different administration devices for the same active compound, value-added services, and the contribution of biosimilars for generating health gain at the population level. CONCLUSIONS: There is a need to gather further insights in the methodology of value assessment for biosimilars, and health technology assessment agencies need to develop more elaborate guidance on biosimilar value assessment in specific circumstances.