The Increased Burden of Rare Variants in Four Matrix Metalloproteinase-Related Genes in Childhood Glaucoma Suggests a Complex Genetic Inheritance of the Disease.

Childhood glaucoma encompasses congenital and juvenile primary glaucoma, which are heterogeneous, uncommon, and irreversible optic neuropathies leading to visual impairment with a poorly understood genetic basis. Our goal was to identify gene variants associated with these glaucoma types by assessing the mutational burden in 76 matrix metalloproteinase-related genes. We studied 101 childhood glaucoma patients with no identified monogenic alterations using next-generation sequencing. Gene expression was assessed through immunohistochemistry. Functional analysis of selected gene variants was conducted in cultured cells and in zebrafish. Patients presented a higher proportion of rare variants in four metalloproteinase-related genes, including CPAMD8 and ADAMTSL4, compared to controls. ADAMTSL4 protein expression was observed in the anterior segment of both the adult human and zebrafish larvae's eye, including tissues associated with glaucoma. In HEK-293T cells, expression of four ADAMTSL4 variants identified in this study showed that two variants (p.Arg774Trp and p.Arg98Trp) accumulated intracellularly, inducing endoplasmic reticulum stress. Additionally, overexpressing these ADAMTSL4 variants in zebrafish embryos confirmed partial loss-of-function effects for p.Ser719Leu and p.Arg1083His. Double heterozygous functional suppression of adamtsl4 and cpamd8 zebrafish orthologs resulted in reduced volume of both the anterior eye chamber and lens within the chamber, supporting a genetic interaction between these genes. Our findings suggest that accumulation of partial functional defects in matrix metalloproteinase-related genes may contribute to increased susceptibility to early-onset glaucoma and provide further evidence supporting the notion of a complex genetic inheritance pattern underlying the disease.

Cytomegalovirus seropositivity correlates with both human ß-defensin 1 and IFN-γ downregulation in women with obesity.

Human ß-defensin 1 (hBD-1) is a constitutively expressed antimicrobial peptide with antiviral properties. CMV seropositivity has been associated with obesity. It is unknown if hBD-1 levels of are altered in women with obesity and/or CMV seropositivity. In a pilot project of 31 adult women with CMV seropositivity, we calculated the correlation among hBD-1 serum levels (ELISA) and IgG anti-CMV-Index with anthropometric measurements, lipid profiles and glucose levels. hBD-1 showed negative correlation with triglycerides (TG) (r = -0.617; p = 0.033,) and hip circumference (r = -0.596; p = 0.041,). IgG anti-CMV index was negatively correlated with hBD-1 levels and positively correlated with TG (r = 0.702; p = 0.011,) and HC (r = 0.583; p = 0.047,) in women with obesity. As expected, hBD-1 levels correlates with IFN-γ (an antimicrobial peptide elicitor) in the three analyzed groups.These results shows that CMV seropositivity correlates with both IFN-γ levels and hBD-1 levels which in contrast with non-CMV seropositivity scenario, is commonly found an IFN-γ upregulation in individuals with obesity. Further research is encouraged to test if CMV is causing the observed downregulation of the antiviral immune responses of both hBD-1 and IFN-γ as well as their involved mechanisms.

Glaucoma medical treatment as a predictor of XEN45 subconjunctival gel implant hypotensive efficacy.

PURPOSE: The aim of this study was to determine the preoperative characteristics influencing hypotensive efficacy of the XEN45 gel stent in patients with open-angle glaucoma at one-year follow-up. MATERIALS AND METHODS: This was a retrospective multicentre study. All patients who underwent XEN45 gel stent implantation between January 2017 and January 2021 were included. The main study outcome was the assessment of one-year postoperative intraocular pressure (IOP) and glaucoma medication differences according to the number and type of preoperative topical treatments or glaucoma surgery, glaucoma stage and time since diagnosis. Follow-up period was 1-year post-surgery in all cases. IOP reduction and surgery success (not requiring reoperation or pressure failures [IOP > 18 mmHg and < 20% reduction in IOP]), safety and cost savings in topical glaucoma therapy after surgery were secondarily assessed. Linear regression analysis to determine the preoperative parameters influence on 1-year postoperative results was performed. RESULTS: XEN45 gel stent was implanted in 85 patients. One-year postoperative mean IOP dropped from 20.6 ± 4.1 to 13.7 ± 2.8 mmHg (p < 0.0001). Likewise, mean number of topical treatments decreased from 2.05 ± 0.9 to 0.36 ± 0.65 (p < 0.001). Both were mainly influenced by the number of preoperative glaucoma treatments, such that for each one-glaucoma medication increase, postoperative intraocular pressure increased by 1.18 mmHg (95% CI 0.56-1.79, p < 0.0001) and number of glaucoma medications increased by 0.3 (95% CI 0.16-0.43, p < 0.001). Overall success rates (with and without supplemental glaucoma medication use) were 97.6% (95% CI 94.5-100%), 87.1% (95% CI 80.2-87.1%) and 61.2% (95% CI 51.6-72.5%) at 3, 6 months and 1 year after surgery. No sight-threatening adverse events were reported. Mean annual cost savings on medical treatment since surgery reached EUR 251.19 ± 169. 93 euros. CONCLUSIONS: One year after surgery, XEN45 gel implant significantly reduced IOP and number of topical medications with an adequate safety profile being both mainly influenced by the number of preoperative glaucoma treatments.

Efficacy and safety of the PreserFlo implant with mitomycin C in childhood glaucoma after previous failed glaucoma surgeries.

PURPOSE: This study aims to evaluate the efficacy and safety of the PreserFlo MicroShunt (Santen, Osaka, Japan) in lowering intraocular pressure (IOP) in childhood glaucoma patients with previous failed glaucoma surgeries. METHODS: This is a prospective case review of consecutive PreserFlo procedures performed in childhood glaucoma patients after failed surgeries. Age, sex, diagnosis, and previous glaucoma surgeries, as well as visual acuity, IOP, and treatment in the preoperative visit and all follow-up visits were collected. Outcome measures included IOP reduction from baseline, mean IOP change from baseline at month 6, medication use at 6 months, complications, adverse events, and need for further procedures. RESULTS: Fourteen patients were included, 8 (57%) males and 6 (43%) females; the mean age was 27.5 ± 13.5 years. Nine patients (64%) had at least two trabeculectomies, and 6 patients (43%) had at least one trabeculectomy and a glaucoma drainage implant. The mean IOP change from baseline was 11.3 ± 4.9 mmHg at 12 months. At 12 months, 12 patients (86%) presented ≥ 20% IOP lowering from baseline, and 11 patients (79%) presented ≥ 30%. The mean medication count decreased from 3.9 ± 0.7 (baseline) to 0.7 ± 1.3 (12 months). No intraoperative complications were reported. No adverse events were noted. No secondary filtration surgery was required, although bleb needling was required in one case, 1 month after the surgery. CONCLUSIONS: PreserFlo with MMC can be used successfully to treat uncontrolled IOP in childhood glaucoma cases with previous failed surgeries. Larger studies with longer follow-up are needed to further explore the role of the device in resistant childhood glaucoma cases.

Serum Vitamins A and E at Mid-Pregnancy and Their Relationships with Both Maternal and Cord Blood Antioxidant Status and Perinatal Conditions: The NELA Cohort.

INTRODUCTION: Most of the pregnant women do not achieve the recommended dietary intake of vitamins A and E. These vitamins may counteract oxidative stress involved in some adverse perinatal outcomes. We aimed to assess the associations between maternal vitamin A and E at mid-pregnancy with both maternal and fetal outcomes and to identify possible early biomarkers during pregnancy to predict and prevent oxidative stress in the offspring. METHODS: Data on dietary and serum levels of vitamins A and E were collected from 544 pregnant women from the Nutrition in Early Life and Asthma (NELA) study, a prospective mother-child cohort set up in Spain. RESULTS: There were large discrepancies between low dietary vitamin E intake (78% of the mothers) and low serum vitamin E levels (3%) at 24 weeks of gestation. Maternal serum vitamins A and E at mid-pregnancy were associated with higher antioxidant status not only in the mother at this time point (lower hydroperoxides and higher total antioxidant activity [TAA]) but also with the newborn at birth (higher TAA). Gestational diabetes mellitus (GDM) was negatively associated with maternal serum vitamin A (OR: 0.95 CI: 0.91-0.99, p = 0.009) at mid-pregnancy. Nevertheless, we could not detect any association between GDM and oxidative stress parameters. CONCLUSIONS: In conclusion, maternal vitamin A and E serum levels may be used as an early potential biomarker of antioxidant status of the neonate at birth. Control of these vitamins during pregnancy could help avoid morbid conditions in the newborn caused by oxidative stress in GDM pregnancies.

Real-world analysis of main clinical outcomes in patients with polycythemia vera treated with ruxolitinib or best available therapy after developing resistance/intolerance to hydroxyurea.

BACKGROUND: Ruxolitinib is approved for patients with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea, but its impact on preventing thrombosis or disease-progression is unknown. METHODS: A retrospective, real-world analysis was performed on the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to subsequent treatment with ruxolitinib (n = 105) or the best available therapy (BAT; n = 272). Survival probabilities and rates of thrombosis, hemorrhage, acute myeloid leukemia, myelofibrosis, and second primary cancers were calculated according to treatment. To minimize biases in treatment allocation, all results were adjusted by a propensity score for receiving ruxolitinib or BAT. RESULTS: Patients receiving ruxolitinib had a significantly lower rate of arterial thrombosis than those on BAT (0.4% vs 2.3% per year; P = .03), and this persisted as a trend after adjustment for the propensity to have received the drug (incidence rate ratio, 0.18; 95% confidence interval, 0.02-1.3; P = .09). There were no significant differences in the rates of venous thrombosis (0.8% and 1.1% for ruxolitinib and BAT, respectively; P = .7) and major bleeding (0.8% and 0.9%, respectively; P = .9). Ruxolitinib exposure was not associated with a higher rate of second primary cancers, including all types of neoplasia, noncutaneous cancers, and nonmelanoma skin cancers. After a median follow-up of 3.5 years, there were no differences in survival or progression to acute leukemia or myelofibrosis between the 2 groups. CONCLUSIONS: The results suggest that ruxolitinib treatment for PV patients with resistance/intolerance to hydroxyurea may reduce the incidence of arterial thrombosis. LAY SUMMARY: Ruxolitinib is better than other available therapies in achieving hematocrit control and symptom relief in patients with polycythemia vera who are resistant/intolerant to hydroxyurea, but we still do not know whether ruxolitinib provides an additional benefit in preventing thrombosis or disease progression. We retrospectively studied the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to whether they subsequently received ruxolitinib (n = 105) or the best available therapy (n = 272). Our findings suggest that ruxolitinib could reduce the incidence of arterial thrombosis, but a disease-modifying effect could not be demonstrated for ruxolitinib in this patient population.

Predictors of thrombosis and bleeding in 1613 myelofibrosis patients from the Spanish Registry of Myelofibrosis.

Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient-years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient-years. Prior history of thrombosis, the JAK2 mutation, and the intermediate-2/high-risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk-modifying effect of anti-thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti-thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient-years. Patients in the intermediate-2/high-risk IPSS categories treated with anti-coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision-making in clinical practice.

One-Year Changes in Optic Nerve Head Parameters in Recovered COVID-19 Patients.

BACKGROUND: The main purpose was to evaluate the changes in peripapillary retinal nerve fiber layer (RNFL) thickness and vessel density (VD) in post-COVID-19 patients during 12-month follow-up. METHODS: In this prospective study, patients with COVID-19 who were attended in the Hospital Clinico San Carlos (Madrid, Spain) were included. All patients underwent a complete ophthalmological examination, optic nerve head optical coherence tomography (OCT), and OCT angiography (OCTA) using the Cirrus HD-OCT 5,000 with AngioPlex OCTA 1, 3, and 12 months after laboratory-confirmed diagnosis. Sociodemographic data, medical history, disease severity, and laboratory workup were registered. RESULTS: A total of 180 eyes of 90 patients with SARS-CoV-2 infection were included; the mean age was 55.5 ± 8.9 years, and 46 patients (51%) were females. The mean visual acuity was 0.76 ± 0.16, and no abnormalities attributable to SARS-CoV-2 were detected in the ocular or fundus examination. No differences in the OCT and OCTA data were found between severity groups in each visit (all P > 0.05). Overall, there was a decrease in RNFL global thickness ( P < 0.001) from the first to the last visit, and an increase in VD and flux index was noted in some sectors at the 12-month examination. A significant correlation was detected at 12 months between vascularization parameters and RNFL thickness. CONCLUSIONS: One year after SARS-CoV-2 infection, changes in peripapillary RNFL thickness and vascularization occur, possibly indicating a recovery in such parameters.

Complexing the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T with Cationic Nanoparticles Enhances Viral Infection and Spread in Prostate and Pancreatic Cancer Models.

Oncolytic adenoviruses (OAd) can be employed to efficiently eliminate cancer cells through multiple mechanisms of action including cell lysis and immune activation. Our OAds, AdΔΔ and Ad-3∆-A20T, selectively infect, replicate in, and kill adenocarcinoma cells with the added benefit of re-sensitising drug-resistant cells in preclinical models. Further modifications are required to enable systemic delivery in patients due to the rapid hepatic elimination and neutralisation by blood factors and antibodies. Here, we show data that support the use of coating OAds with gold nanoparticles (AuNPs) as a possible new method of virus modification to help augment tumour uptake. The pre-incubation of cationic AuNPs with AdΔΔ, Ad-3∆-A20T and wild type adenovirus (Ad5wt) was performed prior to infection of prostate/pancreatic cancer cell lines (22Rv, PC3, Panc04.03, PT45) and a pancreatic stellate cell line (PS1). Levels of viral infection, replication and cell viability were quantified 24-72 h post-infection in the presence and absence of AuNPs. Viral spread was assessed in organotypic cultures. The presence of AuNPs significantly increased the uptake of Ad∆∆, Ad-3∆-A20T and Ad5wt in all the cell lines tested (ranging from 1.5-fold to 40-fold), compared to virus alone, with the greatest uptake observed in PS1, a usually adenovirus-resistant cell line. Pre-coating the AdΔΔ and Ad-3∆-A20T with AuNPs also increased viral replication, leading to enhanced cell killing, with maximal effect in the most virus-insensitive cells (from 1.4-fold to 5-fold). To conclude, the electrostatic association of virus with cationic agents provides a new avenue to increase the dose in tumour lesions and potentially protect the virus from detrimental blood factor binding. Such an approach warrants further investigation for clinical translation.

Genetic evidence for the involvement of Dicer-like 2 and 4 as well as Argonaute 2 in the Nicotiana benthamiana response against Pelargonium line pattern virus.

In plants, RNA silencing functions as a potent antiviral mechanism. Virus-derived double-stranded RNAs (dsRNAs) trigger this mechanism, being cleaved by Dicer-like (DCL) enzymes into virus small RNAs (vsRNAs). These vsRNAs guide sequence-specific RNA degradation upon their incorporation into an RNA-induced silencing complex (RISC) that contains a slicer of the Argonaute (AGO) family. Host RNA dependent-RNA polymerases, particularly RDR6, strengthen antiviral silencing by generating more dsRNA templates from RISC-cleavage products that, in turn, are converted into secondary vsRNAs by DCLs. Previous work showed that Pelargonium line pattern virus (PLPV) is a very efficient inducer and target of RNA silencing as PLPV-infected Nicotiana benthamiana plants accumulate extraordinarily high amounts of vsRNAs that, strikingly, are independent of RDR6 activity. Several scenarios may explain these observations including a major contribution of dicing versus slicing for defence against PLPV, as the dicing step would not be affected by the RNA silencing suppressor encoded by the virus, a protein that acts via vsRNA sequestration. Taking advantage of the availability of lines of N. benthamiana with DCL or AGO2 functions impaired, here we have tried to get further insights into the components of the silencing machinery that are involved in anti-PLPV-silencing. Results have shown that DCL4 and, to lesser extent, DCL2 contribute to restrict viral infection. Interestingly, AGO2 apparently makes even a higher contribution in the defence against PLPV, extending the number of viruses that are affected by this particular slicer. The data support that both dicing and slicing activities participate in the host race against PLPV.

Cytoreductive treatment in patients with CALR-mutated essential thrombocythaemia: a study comparing indications and efficacy among genotypes from the Spanish Registry of Essential Thrombocythaemia.

The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which were CALR-mutated. In low risk patients, time from diagnosis to cytoreduction was shorter in CALR-positive than in the other genotypes (2·8, 3·2, 7·4 and 12·5 years for CALR, MPL, JAK2V617F and TN, respectively, P < 0·0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% in CALR and JAK2V617F genotypes, respectively. Median time to CR was 192 days for JAK2V617F, 343 for TN, 433 for MPL, and 705 for CALR genotypes (P < 0·0001). Duration of CR was shorter in CALR-mutated ET than in the remaining patients (P = 0·003). In CALR-positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration. CALR-mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% for JAK2V617F, CALR, MPL and TN, respectively; P < 0·0001). In conclusion, conventional cytoreductive agents are less effective in CALR-mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype.

Prenatal urinary concentrations of phthalate metabolites and behavioral problems in Mexican children: The Programming Research in Obesity, Growth Environment and Social Stress (PROGRESS) study.

BACKGROUND: Phthalate exposure has been associated with increased childhood behavioral problems. Existing studies failed to include phthalate replacements and did not account for high correlations among phthalates. Phthalates' exposure is higher in Mexico than in U.S. locations, making it an ideal target population for this study. AIM: To examine associations between 15 maternal prenatal phthalate metabolite concentrations and children's behavioral problems. METHODS: We quantified phthalate metabolites in maternal urine samples from maternal-child dyads (n = 514) enrolled in the Programming Research in Obesity, Growth Environment and Social Stress (PROGRESS) birth cohort in Mexico City. We performed least absolute shrinkage and selection operator (LASSO) regressions to identify associations between specific-gravity adjusted log2-transformed phthalate metabolites and parent-reported 4-6 year old behavior on the Behavior Assessment System for Children (BASC-2), accounting for metabolite correlations. We adjusted for socio-demographic and birth-related factors, and examined associations stratified by sex. RESULTS: Higher prenatal mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) urinary concentrations were associated with increased hyperactivity scores in the overall sample (ß = 0.57, 95% CI = 0.17, 1.13) and in girls (ß = 0.54, 95% CI = 0.16, 1.08), overall behavioral problems in boys (ß = 0.58, 95% CI = 0.20, 1.15), and depression scores in boys (ß = 0.44, 95% CI = 0.06, 0.88). Higher prenatal monobenzyl phthalate (MBzP) concentrations were associated with reduced hyperactivity scores in girls (ß = -0.54, 95% CI = -1.08, -0.21). DISCUSSION: Our findings suggested that prenatal concentrations of phthalates and their replacements altered child neurodevelopment and those associations may be influenced sex.

First-in-Human, First-in-Child Trial of Autologous MSCs Carrying the Oncolytic Virus Icovir-5 in Patients with Advanced Tumors.

We present here the results of a first-in-human, first-in-child trial for patients with relapsed/refractory solid tumors using Celyvir, an advanced therapy medicine that combines autologous mesenchymal stem cells (MSCs) carrying an oncolytic adenovirus. Celyvir was manufactured from a bone marrow aspirate and then given intravenously. Patients received weekly infusions for 6 weeks at a dose of 2 × 106 cells/kg (children) or 0.5-1 × 106 cells/kg (adults), 2 × 104 viral particles per cell. Fifteen pediatric and 19 adult patients were recruited, but 18 were screen failures, mainly because rapid disease progression before Celyvir was available. No grade 2-5 toxicities were reported. Adenoviral replication detected by PCR was found in all but 2 pediatric patient and in none of the adult ones. Absolute numbers of circulating leukocytes suffered minor changes along therapy, but some subsets showed differences comparing the pediatric versus the adult cohorts. Two patients with neuroblastoma showed disease stabilization, and one of them continued on treatment for up to 6 additional weeks. Celyvir, the combination of MSCs and oncolytic adenovirus, is safe and warrants further evaluation in a phase 2 setting. The use of MSCs may be a strategy to increase the amount of oncolytic virus administered to patients, minimizing toxicities and avoiding direct tumor injections.

Unmet Needs Among Breast Cancer Patients in a Developing Country and Supportive Care Needs Survey Validation.

BACKGROUND: Identifying and addressing breast cancer (BC) patients' unmet needs (UN) are crucial due to their possible contribution to higher levels of morbidity, particularly in vulnerable underserved populations, such as Latinas with BC. OBJECTIVE: This study aimed to (1) identify and describe the most frequently reported items of moderate-high UN among Mexican women with BC covered by public healthcare insurance; (2) analyze the differences in UN domains according to participants' sociodemographic and clinical characteristics; and (3) validate the Supportive Care Needs Survey-Short Form-34 (SCNS-SF34). METHODS: A cross-sectional study was conducted with 396 consecutive BC patients. A linguistically translated and culturally adapted version of the SCNS-SF34 for Mexican women with BC was completed by the participants. RESULTS: The validation yielded a 32-item version of the SCNS with adequate psychometric properties. The Health System and Providers Information was the highest UN domain, followed by the psychological domain. "Fears about cancer spreading" (37.4%) and "Concerns about the worries of those close to you" (37.3%) were the most prevalent moderate-high UN. Sexuality was the only domain associated with clinical and sociodemographic characteristics. CONCLUSION: By defining the most urgent needs of this group of patients, our results will enable the development of targeted support services and patient-centered care.

Long-term outcomes of distal locking in extracapsular fractures treated with trochanteric Gamma3 nails.

BACKGROUND: Few publications have assessed long-term results of distal locking of short endomedullary nails for extracapsular hip fracture. Virtually all of them focus on immediate differences. Criteria for the use of static or dynamic locking are unclear in most nailing systems, and use is advised in unstable fracture patterns or with risk of bell-clapper effect, but often influenced by the "orthopaedic school". MATERIALS AND METHODS: This is a historical cohort study on patients diagnosed and operated in 2014 and followed up until endpoint, considered as consolidation or major complication, plus evaluation of overall long-term survival. They were categorised as static distal locking (ST) or dynamic distal locking (DN). Both are comparable, except for all stable pre-operative classifications, Fracture Mobility Score (FMS) at discharge, and immediate post-operative loading, all of which were in favour of DN. RESULTS: Consolidation took place in > 95% of patients, with a non-statistically significant delay trend in ST. Less than 6% in both ST and DN had major complications, with no differences. Most cases suffered early cut-out. Significant fracture collapse was the most frequent minor complication. There were more statistically significant minor and total complications in ST. Infection, without differences, can precede cut-out. Lateral thigh pain was similar and could be related to back-out. In DN, 21.1% of cases were truly dynamised. We did not find differences in mobility or in long-term survival. CONCLUSIONS: Any type of distal locking seems to be safe for consolidation, despite a slightly longer consolidation time in static locking. Early cut-out was the main complication, while others were very infrequent, which is an advantage over helical blade devices. There was a higher rate of minor and overall mechanical complications in ST, but infection and lateral thigh pain were similar. Most non-traumatic mechanical complications occurred around 5-6 weeks. About one in five of the DN truly dynamised, with all cases occurring before 8 weeks. Mobility until endpoint and overall long-term survival were not influenced by the locking mode used. LEVEL OF EVIDENCE: Therapeutic study, level 2b.

CPAMD8 loss-of-function underlies non-dominant congenital glaucoma with variable anterior segment dysgenesis and abnormal extracellular matrix.

Abnormal development of the ocular anterior segment may lead to a spectrum of clinical phenotypes ranging from primary congenital glaucoma (PCG) to variable anterior segment dysgenesis (ASD). The main objective of this study was to identify the genetic alterations underlying recessive congenital glaucoma with ASD (CG-ASD). Next-generation DNA sequencing identified rare biallelic CPAMD8 variants in four patients with CG-ASD and in one case with PCG. CPAMD8 is a gene of unknown function and recently associated with ASD. Bioinformatic and in vitro functional evaluation of the variants using quantitative reverse transcription PCR and minigene analysis supported a loss-of-function pathogenic mechanism. Optical and electron microscopy of the trabeculectomy specimen from one of the CG-ASD cases revealed an abnormal anterior chamber angle, with altered extracellular matrix, and apoptotic trabecular meshwork cells. The CPAMD8 protein was immunodetected in adult human ocular fluids and anterior segment tissues involved in glaucoma and ASD (i.e., aqueous humor, non-pigmented ciliary epithelium, and iris muscles), as well as in periocular mesenchyme-like cells of zebrafish embryos. CRISPR/Cas9 disruption of this gene in F0 zebrafish embryos (96 hpf) resulted in varying degrees of gross developmental abnormalities, including microphthalmia, pharyngeal maldevelopment, and pericardial and periocular edemas. Optical and electron microscopy examination of these embryos showed iridocorneal angle hypoplasia (characterized by altered iris stroma cells, reduced anterior chamber, and collagen disorganized corneal stroma extracellular matrix), recapitulating some patients' features. Our data support the notion that CPAMD8 loss-of-function underlies a spectrum of recessive CG-ASD phenotypes associated with extracellular matrix disorganization and provide new insights into the normal and disease roles of this gene.

Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts.

Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF). Ruxolitinib was assessed in JUMP, a large (N = 2233), phase 3b, expanded-access study in MF in countries without access to ruxolitinib outside a clinical trial, which included patients with low platelet counts (<100 × 109 /l) and patients without splenomegaly - populations that have not been extensively studied. The most common adverse events (AEs) were anaemia and thrombocytopenia, but they rarely led to discontinuation (overall, 5·4%; low-platelet cohort, 12·3%). As expected, rates of worsening thrombocytopenia were higher in the low-platelet cohort (all grades, 73·2% vs. 53·5% overall); rates of anaemia were similar (all grades, 52·9% vs. 59·5%). Non-haematologic AEs, including infections, were mainly grade 1/2. Overall, ruxolitinib led to meaningful reductions in spleen length and symptoms, including in patients with low platelet counts, and symptom improvements in patients without splenomegaly. In this trial, the largest study of ruxolitinib in patients with MF to date, the safety profile was consistent with previous reports, with no new safety concerns identified. This study confirms findings from the COMFORT studies and supports the use of ruxolitinib in patients with platelet counts of 50-100 × 109 /l. (ClinicalTrials.gov identifier NCT01493414).

Genetic, Immunological, and Clinical Features of the First Mexican Cohort of Patients with Chronic Granulomatous Disease.

PURPOSE: Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by an inability of phagocytes to produce reactive oxygen species, impairing their killing of various bacteria and fungi. We summarize here the 93 cases of CGD diagnosed in Mexico from 2011 to 2019. METHODS: Thirteen Mexican hospitals participated in this study. We describe the genetic, immunological, and clinical features of the 93 CGD patients from 78 unrelated kindreds. RESULTS: Eighty-two of the patients (88%) were male. All patients developed bacterial infections and 30% suffered from some kind of fungal infection. Fifty-four BCG-vaccinated patients (58%) presented infectious complications of BCG vaccine. Tuberculosis occurred in 29%. Granulomas were found in 56% of the patients. Autoimmune and inflammatory diseases were present in 15% of patients. A biological diagnosis of CGD was made in 89/93 patients, on the basis of NBT assay (n = 6), DHR (n = 27), and NBT plus DHR (n = 56). The deficiency was complete in all patients. The median age of biological diagnosis was 17 months (range, 0-186 months). A genetic diagnosis was made in 83/93 patients (when material was available), corresponding to CYBB (n = 64), NCF1 (n = 7), NCF2 (n = 7), and CYBA (n = 5) mutations. CONCLUSIONS: The clinical manifestations in these Mexican CGD patients were similar to those in patients elsewhere. This cohort is the largest in Latin America. Mycobacterial infections are an important cause of morbidity in Mexico, as in other countries in which tuberculosis is endemic and infants are vaccinated with BCG. X-linked CGD accounted for most of the cases in Mexico, as in other Latin American countries. However, a significant number of CYBA and NCF2 mutations were identified, expanding the spectrum of known causal mutations.

Patients' satisfaction with a supportive care program for young breast cancer patients in Mexico: Joven & Fuerte supports patients' needs and eases their illness process.

OBJECTIVE: The aim of this study was to evaluate patients' outlook and satisfaction with "Joven & Fuerte: Program for Young Women with Breast Cancer (YWBC) in Mexico" (J&F) and to determine its strengths and areas of improvement to better fulfill patients' information and supportive care needs. METHODS: Patients enrolled in J&F for ≥ 6 months at three cancer referral centers were invited via a messaging application to anonymously complete an online survey exploring their perspectives of the program's information delivery, support services, and research component. Descriptive statistics, chi2 test, Student t, and ANOVA were used for analysis. RESULTS: Of 484 eligible patients, 28% completed the survey. The program overall was useful/very useful according to 97% and aided 82% to better cope with their illness. The timing, clarity, and usefulness of the information provided were each described as good/very good by ≥ 83% for the written format and ≥ 98% for the verbal one. Eighty-four percent of patients were very satisfied (≥ 9/10) with psychological support and genetic assessment. The number of support services used was significantly associated with patients' perception of J&F's usefulness. Regarding fertility issues, 45% recalled being informed about preservation strategies and J&F financially supported 27/39 of interested patients. Fifty-eight percent were unaware of J&F's ongoing research component. CONCLUSIONS: Patients' satisfaction with J&F is very high, reflecting that the program is meeting Mexican YWBC's needs by providing useful information means and support services in a limited-resource setting. Efforts must keep up to guarantee the program's continuity and advocate for its extension to other oncologic centers.

Oldest old hip fracture patients: centenarians as the lowest complexity patients.

BACKGROUND: Hip fracture leads to an increase in mortality and deterioration in the quality of life. The increase in life expectancy results in an increase in the number of oldest old patients. AIMS: To analyze the characteristics of centenarian hip fracture patients and compare them with younger hip fracture patients. METHODS: Retrospective study, including 176 patients (48 centenarians, 65 nonagenarians and 63 octogenarians) undergoing surgery after hip from 2009 to 2018 and followed for 1-year survival. Qualitative variables were compared by Chi-square test and quantitative variables, by Kruskal-Wallis test. Survival analysis was performed by Kaplan-Meier test and statistical differences were assessed by log-rank test. p value < 0.05 was considered statistically significant. RESULTS: Centenarians showed the lowest Charlson index (p = 0.001), cognitive impairment (p < 0.001), and daily drug intake (p = 0.034). The in-hospital, 30-day and 1-year mortality rates did not show statistical significant differences. The 1-year survival analysis showed that patients died in order of age (p = 0.045). No differences were found regarding readmissions. DISCUSSION: Hip fracture incidence in centenarians is increasing. Our study states the lowest complexity for centenarians. Hip fracture mortality rates have been linked to patients' age. In-hospital mortality rate has been reduced, and for the 30-day and 1-year mortality rates, we noted that mortality follows a pattern clearly related to age. CONCLUSIONS: Centenarians showed the lowest comorbidity and complexity. Readmissions before 1 year, mortality rates at discharge, 30-day and 1-year follow-up were not significantly different, but 1-year survival analysis showed that patients are dying as they are ageing.