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Los modelos de programación lineal se han constituido en una herramienta eficaz en el campo de la administración y la economía, su aporte es fundamental en uno de las campos más complejos de la administración, contribuyendo de forma sistemática en la toma de decisiones, en este trabajo no fue la excepción, ya que con la implementación de un modelo de programación entera, fue posible reducir la fuerza laboral de la empresa en un 65 %, permitiendo una reducción, en los costos de operación y mantenimiento de 36 %, además fue capaz de programar el horario de las actividades que los obreros debían cumplir a diario en el campo, permitiendo que estas fueran desarrolladas por cada obrero designado en un lapso de cinco días por semana.

In the last years, guaranteeing the security in Internet of things communications has become an essential task. In this article, the bias of a wide set of oscillators has been studied to determine their suitability as both true random number generators (TRNGs) and physically unclonable functions (PUFs). For this purpose, a generic configurable structure has been proposed and implemented in an field programmable gate array (FPGA). With this implementation, by introducing some external signals it is possible to configure the system in different oscillator topologies. This way, we have managed to analyze 2730 oscillators composed by seven lookup tables (LUTs) without having to resynthesize the code each time. The performed analysis has included conventional ring oscillators, Galois ring oscillators, and newly proposed oscillator topologies. From this analysis, we have concluded that none of these oscillators behave as an ideal TRNG but ring oscillators present the closest to an ideal behavior. Regarding their suitability as PUFs, some of the newly proposed oscillators in this article present a high reproducibility, higher than that of conventional ring oscillator PUF (RO-PUF) and a high uniqueness. Furthermore, we have noticed that both their reproducibility and their uniqueness tend to improve when increasing the length of the oscillators, which opens the possibility of finding new oscillators with even better properties by studying oscillators of bigger lengths. Finally, by studying the spatial correlation of the bias of these oscillators, we have observed that they present a much lower spatial correlation compared to the ring oscillators, which opens the possibility of using these oscillators in PUF architectures that use more comparisons than typical RO-PUFs.

OBJECTIVES This real-world analysis describes treatment patterns, sequencing and clinical effectiveness, toxicities, and health utility outcomes in advanced-stage, incurable ALK-positive NSCLC patients across five different ALK-TKIs. MATERIALS AND METHODS Clinicodemographic, treatment, and toxicity data were collected retrospectively in patients with advanced-stage ALK-positive NSCLC at Princess Margaret Cancer Centre. Patient-reported symptoms, toxicities, and health utilities were collected prospectively. RESULTS Of 148 ALK-positive NSCLC patients seen July 2009-May 2021, median age was 58.9 years; 84 (57%) were female; 112 (76%) never-smokers; 54 (47%) Asian and 40 (35%) white; 139 (94%) received at least one ALK-TKI: crizotinib (n = 74; 54%) and alectinib (n = 61; 44%) were administered mainly as first-line ALK-TKI, ceritinib, brigatinib and lorlatinib were administered primarily after previous ALK-TKI failure. Median overall survival (OS) was 54.0 months; 31 (21%) patients died within two years of advanced-stage diagnosis. Treatment modifications were observed in 35 (47%) patients with crizotinib, 19 (61%) with ceritinib, 41 (39%) with alectinib, 9 (41%) with brigatinib and 8 (30%) with lorlatinib. Prevalence of dose modifications and self-reported toxicities were higher with early versus later generation ALK-TKIs (P

Background Abdominal wall endometriosis (AWE) is a rare manifestation of endometriosis characterized by the infiltration of endometriotic tissue into the abdominal wall. We present a case report of a 37-year-old female patient with a history of three previous cesarean sections and an appendectomy who developed symptoms of intense abdominal pain and distension. Imaging studies revealed a large intercompartmental mass in the left anterior rectus muscle, and subsequent histopathological examination confirmed the presence of endometrial tissue. The patient underwent surgical resection of the mass, which required a complex abdominal wall repair using a mesh. The postoperative period was uneventful, and the patient experienced a significant improvement in symptoms and overall quality of life. This case highlights the challenges posed by AWE and the importance of accurate diagnosis and appropriate management. Wide surgical resection, although the traditional approach, can be associated with additional operative trauma. In this case, a multidisciplinary treatment approach was employed, involving surgical resection and meticulous reconstruction of the abdominal wall. The successful outcome demonstrates the efficacy of this approach in relieving symptoms and improving patient well-being. Further research is needed to enhance our understanding of AWE and to optimize treatment strategies for this complex condition.

The ray-tracing method is commonly used for solar concentrator analysis. The simulation process consists of an initialization phase where all the input parameters are defined, followed by a simulation cycle that runs through all time instants to later move on to the final evaluation phase. The proposed method includes computational simulation, carrying out a study of the impact of two specific variables: (1) the distribution ratio of the heliostats given a fixed area and (2) the position of the target. The first being the ratio m:n that corresponds to the arrangement and distribution of the mirrors throughout the available area, where m represents the distance of the field along the East-West axis and n represents the distance of the field along the North-South axis. On the other hand, the target is placed on the northern edge of the heliostat field and only depends on its position on the East-West axis. The main interest is to determine where more energy is harvest by the heliostat field. It was shown through simulation in TracePro and results from processing in Matlab, that, for a location in Monterrey, NL, Mexico (25° N, 100° W) with an area of 75 m², an average of 100 kWh of energy can be harvest per day throughout the year with 72 mirrors of half a square meter each. This simulation was carried out using real direct radiation data.

Sickle cell disease is an emerging anemia in Europe leading to high morbidity with severe acute complications requiring hospital admission and chronic consequences. The management of these patients is complex and needs interdisciplinary care. The objective is to analyze clinical characteristics and management of patients with sickle cell disease admitted for acute complications.Retrospective descriptive study of admissions for acute complications of patients with sickle cell disease under 16 years of age in a tertiary hospital between 2010 and 2020. Clinical, laboratory and radiological data were reviewed.We included 71 admissions corresponding to 25 patients, 40% diagnosed by neonatal screening. Admissions increased during this period. The most frequent diagnoses were vaso-occlusive crisis (35.2%), febrile syndrome (33.8%) and acute chest syndrome (32.3%). Nine patients required critical care at PICU. Positive microbiological results were confirmed in 20 cases, bacterial in 60%. Antibiotic therapy was administered in 86% of cases and the vaccination schedule of asplenia was adequately fulfilled by 89%. Opioid analgesia was required in 28%. Chronic therapy with hydroxyurea prior to admission was used in 41%.Acute complications requiring hospital admission are frequent in patients with sickle cell disease, being vaso-occlusive crisis and febrile syndrome the most common. These patients need a high use of antibiotics and opioid analgesia. Prior diagnosis facilitates the recognition of life-threatening complications such as acute chest syndrome and splenic sequestration. Despite the prophylactic and therapeutic measures currently provided to these patients, many patients suffer acute complications that require hospital management.

Resumen Introduccion La drepanocitosis es una anemia emergente en Europa que condiciona una elevada morbilidad con complicaciones agudas y cronicas. El manejo de estos pacientes es complejo y requiere atencion interdisciplinar. El objetivo del estudio es analizar las caracteristicas y el manejo de los pacientes con drepanocitosis que ingresan por complicaciones agudas. Metodos Estudio descriptivo retrospectivo de los ingresos por complicaciones agudas de pacientes con drepanocitosis menores de 16 anos en un hospital terciario entre 2010 y 2020. Se revisaron los datos clinicos, analiticos y radiologicos. Resultados Se incluyeron 71 ingresos correspondientes a 25 pacientes, el 40% diagnosticados por cribado neonatal. Los ingresos se incrementaron de forma progresiva durante este periodo. Los diagnosticos mas frecuentes fueron la crisis vasooclusiva (35,2%), el sindrome febril (33,8%) y el sindrome toracico agudo (32,3%). Nueve pacientes precisaron ingreso en cuidados intensivos. En 20 ingresos se obtuvo documentacion microbiologica, 60% bacterias. En el 86% se administro antibioterapia y 28% precisaron analgesia con opioides. El 89% cumplian la pauta de vacunacion adecuada y el 41% recibian hidroxiurea previo al ingreso. Conclusiones Las complicaciones agudas que precisan ingreso hospitalario son frecuentes en los pacientes con drepanocitosis, siendo las mas habituales la crisis vasooclusiva y el sindrome febril. Esto conlleva un uso elevado de antibioterapia y opioides. El diagnostico precoz facilita el reconocimiento de complicaciones de riesgo vital como el sindrome toracico agudo y el secuestro esplenico. A pesar de las medidas preventivas y los tratamientos indicados en la actualidad, estas complicaciones agudas precisan manejo hospitalario.

OBJECTIVE To test whether the use of a flexible endotracheal tube introducer (ETI) facilitates intubation of cats by veterinary students with little or no experience. ANIMALS 125 healthy cats. PROCEDURES Cats were sedated with dexmedetomidine and morphine IM, and anesthesia was induced with propofol. They were randomly assigned to be intubated by supervised veterinary students using an ETI within a tracheal tube or an endotracheal tube alone (3.0, 3.5, or 4.0 internal diameter sizes). Success rate at first attempt, number of attempts to intubate (up to 3), and time to intubate were recorded. Multivariate logistic regression was used to test associations between several factors such as use of an ETI, cat’s weight, endotracheal tube size, administration of ketamine for sedation, and first-attempt success. Significance was considered when P < 0.05. RESULTS Success rate for the first attempt was higher with an ETI (79% [51/64) than without it (46% [28/61]), and attempts to intubate were fewer when an ETI was used (both P < 0.001). Time to intubate did not differ between groups (ETI, 30 seconds [4 to 143 seconds]; endotracheal tube, 28 seconds [5 to 180 seconds]). Use of an ETI was positively associated with improved first-attempt success, and the 3.0-mm internal diameter of the tube was negatively associated (both P ≤ 0.001). CLINICAL RELEVANCE The use of a flexible ETI improved the success of first-attempt intubation of cats by veterinary students. This technique may help minimize the number of attempts during intubation and incidence of complications that could arise from multiple attempts.

Smectites are selected as barriers in deep geological repositories for high-level radioactive waste repository due to their high swelling capacity and contaminant retention ability. Erosion of the clay barrier can affect repository safety and eroded particles may facilitate radionuclide migration within the host rock fractures. These processes depend on the physicochemical characteristics of the clay, on its structural properties and are affected by the chemical equilibrium established with the groundwater from the geological formation.In order to assess the relationship between clay colloidal properties and the erosion and sedimentation behaviour in fractures, this study correlates the erosion behaviour of a compacted bentonite barrier, under repository conditions, simulating expansion and sedimentation in artificial fractures with physicochemical macroscopic properties (viscosity, turbidity,...) of different smectite suspensions. Studies are carried out under different geochemical conditions.Results showed that sodium smectites had the highest viscosities, all showing similar behaviour: at low ionic strengths the viscosity remained constant and around 10 mM increased significantly. In spite of forming smaller particles, their expansion and sedimentation is hindered by their high viscosity. In contrast, clays with dominant bi-trivalent cations in their structure, has lower viscosity values, independent on the water ionic strength. Due to their higher particle size and lower viscosity, higher sedimentation in rock fractures is expected.Turbidity measurements over time were done to assess sedimentation behaviour. It was observed that sodium smectites remained stable over time, even at high ionic strengths, as observed in viscosity studies. With calcium clays, turbidity decreased rapidly, indicating fast sedimentation occurred.The study contributes to predict the erosion behaviour of the clay barrier in the fractures of the geological formation of a deep geological repository, starting from the colloidal properties of each clay.This work was partially supported by the Swedish Nuclear Fuel and Waste Management Co, SKB (Sweden) and by the Spanish Ministry of Innovation and Science (PID2019-106398GB-I00, ARNO Project).

Introduction Viral infections are associated with pulmonary exacerbations in children with Cystic Fibrosis (cwCF), but after 3 years of SARS-CoV-2 pandemic, whether cwCF are at higher risk of developing COVID-19 or its adverse consequences remains controversial. Methods We conducted an observational, multicenter, cross-sectional study of cwCF infected by SARS-CoV-2 between March 2020 and June 2022, (1 to 6 COVID-19 pandemic waves) in Spain. The study aimed to describe patients’ basal characteristics, SARS-CoV-2 clinical manifestations and outcomes, and whether there were differences across the pandemic waves. Results During study time, 351 SARS-CoV2 infections were reported among 341 cwCF. Median age was 8.5 years (range 0-17) and 51% were female. Cases were unevenly distributed across the pandemic, with most cases (82%) clustered between November 2021 and June 2022 (6 wave, also known as Omicron Wave due to the higher prevalence of this strain in that period in Spain). Most cwCF were asymptomatic (24.8%) or presented with mild Covid-19 symptoms (72.9%). Among symptomatic, most prevalent symptoms were fever (62%) and increased cough (53%). No multisystem inflammatory syndrome (MIS-C), persisting symptoms, long-term sequelae or deaths were reported. Conclusions Spanish current data indicate that cwCF do not experience higher risks of SARS-CoV-2 infection nor worse health outcomes or sequelae. Changes in patients’ basal characteristics, clinical courses and outcomes were detected across waves. While the pandemic continues, and new SARS-CoV-2 variants are being identified, a worldwide monitoring of COVID-19 in pediatric CF patients is needed.

Nowadays, the majority of Internet traffic is multimedia content. Video streaming services are in high demand by end users and use HTTP Adaptive Streaming (HAS) as transmission protocol. HAS splits the video into non-overlapping chunks and each video chunk can be encoded independently using different representations. Therefore, these encode tasks can be parallelized and Cloud computing can be used for this. However, in the most extended solutions, the infrastructure must be configured and provisioned in advance. Recently, serverless platforms have made posible to deploy functions that can scale from zero to a configurable maximum. This work presents and analyses the behavior of event-driven serverless functions to encode video chunks and to compute, optionally, the quality of the encoded videos. These functions have been implemented using an adapted version of embedded Tomcat to deal with CloudEvents. We have deployed these event-driven serverless pipelines for video coding and quality metrics on an on-premises serverless platform based on Knative on one master node and eight worker nodes. We have tested the scalability and resource consumption of the proposed solution using two video codecs: x264 and AV1, varying the maximum number of replicas and the resources allocated to them (fat and slim function replicas). We have encoded different 4K videos to generate multiple representations per function call and we show how it is possible to create pipelines of serverless media functions. The results of the different tests carried out show the good performance of the serverless functions proposed. The system scales the replicas and distributes the jobs evenly across all the replicas. The overall encoding time is reduced by 18% using slim replicas but fat replicas are more adequate in live video streaming as the encoding time per chunk is reduced. Finally, the results of the pipeline test show an appropriate distribution and chaining among the available replicas of each function type.

CD40 ligand (CD40L) deficiency is a rare inborn error of immunity presenting with heterogeneous clinical manifestations. While a detailed characterization of patients affected by CD40L deficiency is essential to an accurate diagnosis and management, information about this disorder in Latin American patients is limited. We retrospectively analyzed data from 50 patients collected by the Latin American Society for Immunodeficiencies registry or provided by affiliated physicians to characterize the clinical, laboratory, and molecular features of Latin American patients with CD40L deficiency. The median age at disease onset and diagnosis was 7 months and 17 months, respectively, with a median diagnosis delay of 1 year. Forty-seven patients were genetically characterized revealing 6 novel mutations in the CD40LG gene. Pneumonia was the most common first symptom reported (66%). Initial immunoglobulin levels were variable among patients. Pneumonia (86%), upper respiratory tract infections (70%), neutropenia (70%), and gastrointestinal manifestations (60%) were the most prevalent clinical symptoms throughout life. Thirty-five infectious agents were reported, five of which were not previously described in CD40L deficient patients, representing the largest number of pathogens reported to date in a cohort of CD40L deficient patients. The characterization of the largest cohort of Latin American patients with CD40L deficiency adds novel insights to the recognition of this disorder, helping to fulfill unmet needs and gaps in the diagnosis and management of patients with CD40L deficiency.

It is the objective to provide a mathematical treatment of a nonhomogeneous and non-lipschitz reaction problem with a non-linear diffusion and advection operator, so that it can be applied to a fire extinguishing process in aerospace. The main findings are related with the existence and characterization of a finite propagation support that emerges in virtue of the the non-linear diffusion formulation. It is provided a precise assessment on different times associated to the extinguisher discharge process. Particularly, the time required to activate the discharge, the time required for the extinguisher front to cover the whole domain, the time required to reach a minimum level of concentration so as to extinguish a fire and the time required by the agent to reach some difficult dead zones where the extinguisher propagates only by diffusion and no advection. The equation proposed is firstly discussed from a mathematical perspective to find analytical solutions and propagating profiles. Afterwards, the application exercise is introduced. pre-print 2494 KB

Wastewater-based epidemiology (WBE) emerged during the COVID-19 pandemic as a scalable and broadly applicable method for community-level monitoring of infectious disease burden, though the lack of high-quality, longitudinal fecal shedding data of SARS-CoV-2 and other viruses limits the interpretation and applicability of wastewater measurements. In this study, we present longitudinal, quantitative fecal shedding data for SARS-CoV-2 RNA, as well as the commonly used fecal indicators Pepper Mild Mottle Virus (PMMoV) RNA and crAss-like phage (crAssphage) DNA. The shedding trajectories from 48 SARS-CoV-2 infected individuals suggest a highly individualized, dynamic course of SARS-CoV-2 RNA fecal shedding, with individual measurements varying from below limit of detection to 2.79×106gene copies/mg - dry mass of stool (gc/mg-dw). Of individuals that contributed at least 3 samples covering a range of at least 15 of the first 30 days after initial acute symptom onset, 77.4% had at least one positive SARS-CoV-2 RNA stool sample measurement. We detected PMMoV RNA in at least one sample from all individuals and in 96% (352/367) of samples overall; and measured crAssphage DNA above detection limits in 80% (38/48) of individuals and 48% (179/371) of samples. Median shedding values for PMMoV and crAssphage nucleic acids were 1×105gc/mg-dw and 1.86×103gc/mg-dw, respectively. These results can be used to inform and build mechanistic models to significantly broaden the potential of WBE modeling and to provide more accurate insight into SARS-CoV-2 prevalence estimates.

Criminal behaviour has previously been associated with an increased risk for several mental health problems, but little is known about the association between criminal behaviour and dementia. We aimed to examine how the criminal background (type of crime, number of convictions, length of the sentence) is associated with dementia and mild cognitive impairment (MCI), and how mental and physical health disorders and educational attainment influenced these associations. A nationwide cohort of 3,617,028 individuals born between 1932 and 1962 were linked with criminal and medical records using Swedish national registers. We used Cox regression models to examine the associations. Increased risks for dementia (Hazard ratios (HRs) 1.54, 95% confidence interval (CI) 1.50–1.57) and MCI (1.55, 1.50–1.61) were found in individuals with criminal background, particularly among those who committed violent or several crimes, or with long sentences. After full adjustment of covariates, the associations attenuated but remained statistically significant for dementia (1.25, 1.22–1.28) and MCI (1.27, 1.22–1.32). The attenuation was mostly explained by mental health problems -depression, anxiety, schizophrenia spectrum disorders, substance use disorder (SUD), and bipolar disorder- (dementia: 1.34, 1.31–1.37; MCI: 1.35, 1.30–1.40). SUD contributed the most to attenuate the associations. Our results may provide important insights to health and penal systems by showing the importance of considering the severity of the criminal background and life-course mental health when assessing the risk of neurodegenerative disorders.

From 2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) household transmission studies (enrolling April 2020 to January 2022) with rapid enrollment and specimen collection for 14 days, 61% (43/70) of primary cases had culturable virus detected ≥6 days post-onset. Risk of secondary infection among household contacts tended to be greater when primary cases had culturable virus detected after onset. Regardless of duration of culturable virus, most secondary infections (70%, 28/40) had serial intervals

The existence of sex differences in disease incidence is attributed, in part, to sex differences in metabolism. Uncovering the precise mechanism driving these differences is an extraordinarily complex process influenced by genetics, endogenous hormones, sex-specific lifetime events, individual differences and external environmental/social factors. In fact, such differences may be subtle, but across a life span, increase susceptibility to a pathology. Whilst research persists in the hope of discovering an elegant biological mechanism to underpin sex differences in disease, here, we show, for the first time, that such a mechanism may be subtle in nature but influenced by multiple sex-specific factors. A proteomic dataset was generated from a gonadectomized mouse model treated with Tibolone, a menopausal hormone therapy. Following functional enrichment analysis, we identified that Alzheimer's disease and the electron transport chain-associated pathways were regulated by sex-hormone interactions. Specifically, we identified that the expression of three respirasome proteins, NDUFA2, NDUFA7 and UQCR10, is significantly altered by compounding factors that contribute to sex differences. These proteins function in bioenergetics and produce reactive oxygen species, which are each dysregulated in many diseases with sex differences in incidence. We show sex-specific reprogrammed responses to Tibolone following gonadectomy, which primarily influence the expression of proteins contributing to metabolic pathways. This further infers that metabolic differences may underpin the observed sex differences in disease, but also that hormone therapy research now has potential in exploring sex-specific interventions to produce an effective method of prevention or treatment., This work was partly supported by funding from Science Foundation Ireland under the Frontiers for the Future Programme (Grant #20/FFP-P/8649) to GEB. This work was also supported by grant PID2020-115019RB-I00, awarded to M.A.A., from Agencia Estatal de Investigación (AEI), co-funded by Fondo Europeo de Desarrollo Regional (FEDER) and by Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.

Mitochondrial transcription factor A (TFAM) plays a critical role in mitochondrial transcription initiation and mitochondrial DNA (mtDNA) packaging. Both functions require DNA binding, but in one case TFAM must recognize a specific promoter sequence, while packaging requires coating of mtDNA by association with non sequence-specific regions. The mechanisms by which TFAM achieves both sequence-specific and non sequence-specific recognition have not yet been determined. Existing crystal structures of TFAM bound to DNA allowed us to identify two guanine-specific interactions that are established between TFAM and the bound DNA. These interactions are observed when TFAM is bound to both specific promoter sequences and non-sequence specific DNA. These interactions are established with two guanine bases separated by 10 random nucleotides (GN10G). Our biochemical results demonstrate that the GN10G consensus is essential for transcriptional initiation and contributes to facilitating TFAM binding to DNA substrates. Furthermore, we report a crystal structure of TFAM in complex with a non sequence-specific sequence containing a GN10G consensus. The structure reveals a unique arrangement in which TFAM bridges two DNA substrates while maintaining the GN10G interactions. We propose that the GN10G consensus is key to facilitate the interaction of TFAM with DNA.

Meta-analyses suggest an association between autism spectrum disorder (ASD) and obesity, but the factors underlying this association remain unclear. This study investigated the association between ASD and obesity stratified on intellectual disability (ID). In addition, in order to gain insight into possible shared etiological factors, the potential role of shared familial liability was examined.We studied a cohort of 3,141,696 individuals by linking several Swedish nationwide registers. We identified 35,461 individuals with ASD and 61,784 individuals with obesity. Logistic regression models were used to estimate the association between ASD and obesity separately by ID and sex and by adjusting for parental education, psychiatric comorbidity, and psychotropic medication. Potential shared familial etiologic factors were examined by comparing the risk of obesity in full siblings, maternal and paternal half-siblings, and full- and half-cousins of individuals with ASD to the risk of obesity in relatives of individuals without ASD.Individuals with ASD + ID (OR = 3.76 [95% CI, 3.38-4.19]) and ASD-ID (OR = 3.40 [95% CI, 3.23-3.58]) had an increased risk for obesity compared with individuals without ASD. The associations remained statistically significant when adjusting for parental education, psychiatric comorbidity, and medication. Sex-stratified analyses indicated a higher relative risk for males compared with females, with statistically significant interaction effects for ASD-ID, but not for ASD+ID in the fully adjusted model. First-degree relatives of individuals with ASD+ID and ASD-ID had an increased risk of obesity compared with first-degree relatives of individuals without ASD. The obesity risk was similar in second-degree relatives of individuals with ASD+ID but was lower for and ASD-ID. Full cousins of individuals with ASD+ID had a higher risk compared with half-cousins of individuals with ASD+ID). A similar difference in the obesity risk between full cousins and half-cousins was observed for ASD-ID.Individuals with ASD and their relatives are at increased risk for obesity. The risk might be somewhat higher for males than females. This warrants further studies examining potential common pleiotropic genetic factors and shared family-wide environmental factors for ASD and obesity. Such research might aid in identifying specific risks and underlying mechanisms in common between ASD and obesity.

Delivery of adeno-associated viral vectors (AAVs) to cerebrospinal fluid (CSF) has emerged as a promising approach to achieve widespread transduction of the central nervous system (CNS) and peripheral nervous system (PNS), with direct applicability to the treatment of a wide range of neurological diseases, particularly lysosomal storage diseases. Although studies in small animal models have provided proof of concept and experiments in large animals demonstrated feasibility in bigger brains, there is not much information on long-term safety or durability of the effect. Here, we report a 7-year study in healthy beagle dogs after intra-CSF delivery of a single, clinically relevant dose (2 × 1013 vg/dog) of AAV9 vectors carrying the canine sulfamidase, the enzyme deficient in mucopolysaccharidosis type IIIA. Periodic monitoring of CSF and blood, clinical and neurological evaluations, and magnetic resonance and ultrasound imaging of target organs demonstrated no toxicity related to treatment. AAV9-mediated gene transfer resulted in detection of sulfamidase activity in CSF throughout the study. Analysis at tissue level showed widespread sulfamidase expression and activity in the absence of histological findings in any region of encephalon, spinal cord, or dorsal root ganglia. Altogether, these results provide proof of durability of expression and long-term safety for intra-CSF delivery of AAV-based gene transfer vectors encoding therapeutic proteins to the CNS., Graphical abstract, Seven-year follow-up of dogs after intra-CSF administration of AAV9-sulfamidase vectors results in detection of sulfamidase activity in CSF and widespread transgene expression in CNS, PNS, and liver, in the absence of any adverse events. Proof of durability and safety of this gene therapy support its clinical translation to treat CNS diseases.

In recent decades, there has been increased interest in the possible adverse neurological effects of 5α-reductase inhibitors (5-ARIs), which have been used mainly for benign prostatic hyperplasia and androgenic alopecia. Numerous studies and reports have indicated associations of 5-ARIs with depression and suicide. However, most of these studies had methodological shortcomings, and very little is known about the potential association of 5-ARIs with dementia.To investigate the association of 5-ARI use with all-cause dementia, Alzheimer disease, vascular dementia, depression, and suicide.This Swedish register-based cohort study included 2 236 876 men aged 50 to 90 years between July 1, 2005, and December 31, 2018. Statistical analyses were performed from September 15, 2021, to May 25, 2022.A diagnosis of all-cause dementia, Alzheimer disease, vascular dementia, depression, or completed suicide.A recorded prescription in the Swedish national prescription register of finasteride or dutasteride and duration of use.Of 2 236 876 men (median age at the start of follow-up, 55 years [IQR, 50-65 years] and at treatment initiation, 73 years [IQR, 66-80 years]), 70 645 (3.2%) started finasteride treatment, and 8774 (0.4%) started dutasteride treatment. Men taking finasteride or dutasteride were at increased risk of all-cause dementia (finasteride: hazard ratio [HR], 1.22 [95% CI, 1.17-1.28]; dutasteride: HR, 1.10 [95% CI, 1.01-1.20]), Alzheimer disease (finasteride: HR, 1.20 [95% CI, 1.10-1.31]; dutasteride: HR, 1.28 [95% CI, 1.09-1.50]), vascular dementia (finasteride: HR, 1.44 [95% CI, 1.30-1.58]; dutasteride: HR, 1.31 [95% CI, 1.08-1.59]), and depression (finasteride: HR, 1.61 [95% CI, 1.48-1.75]; dutasteride: HR, 1.68 [95% CI, 1.43-1.96]). However, the magnitude of the association decreased over time, and the findings became statistically nonsignificant with continuous exposures over 4 years, except for depression, which showed a constant risk over time, with no differences between finasteride and dutasteride. In contrast, 5-ARIs were not associated with suicide (finasteride: HR, 1.22 [95% CI, 0.99-1.49]; dutasteride: HR, 0.98 [95% CI, 0.62-1.54]).This cohort study found that, while men receiving 5-ARI treatment showed a higher risk for dementia in the initial periods after starting treatment, the decreasing magnitude of the association over time suggested that the risk may be, entirely or in part, due to increased dementia detection among patients with benign prostate enlargement. Both finasteride and dutasteride were similarly associated with depression with a constant risk over time, while neither drug was associated with suicide. Prescribing clinicians and potential users should be aware of the possible risks for depression associated with 5-ARI use.

Background Diabetic Foot Ulcers (DFU) are a major complication in patients with diabetes and affect globally 170 million patients. Approximately 28% of patients with infected DFU require amputation. Diabetic foot infections (DFI) caused by persistent or multidrug resistant organisms are a threat to the outcome of therapy. Infections are mostly polymicrobial, and major pathogens include Staphylococcus aureus and Pseudomonas aeruginosa. A promising new approach using phages may potentially be a novel modality to increase treatment success. TP-102 is an innovative bacteriophage cocktail for treatment of DFI, a diabetes related unmet need. Methods TP-102 comprised of 5 different phages, targeting S. aureus, P. aeruginosa and Acinetobacter baumannii. This study is a Phase I/II clinical trial performed in Israel looking at safety and tolerability. TP-102 bacteriophage cocktail was applied topically at a titer of 109 PFU/mL/cm3 of target ulcer. Two cohorts receive multiple doses of TP-102. In non-infected DFU (cohort 1) for 1 week and for 28 days in DFU with infection grade 2 or 3 (PEDIS classification, cohort 2). Treatment groups were TP-102 with standard of care versus placebo and standard of care. Outcomes include microbiologic data on the 3 target bacteria, ulcer healing characteristics, incidence and severity of TP-102-emergent solicited local and systemic adverse events, and their relationship to the treatment, from the first application of TP-102 until the end of study. Results For the evaluation of safety in patients with non-infected ulcers, eight patients were enrolled to the first cohort. Six were treated with TP-102 and 2 with placebo. TP-102-treated patients had no severe adverse events associated with the treatment. In the second cohort a total of 18 patients are currently being treated with TP-102 or placebo for 28 days, three times a week. Recruitment is ongoing and results of the trial will be presented. Conclusion TP-102 appeared to be safe when applied to patients with uninfected diabetic foot ulcers. The treatment is a potential new non-traditional antimicrobial for topical application. The efficacy of TP-102 in the treatment of infected diabetic ulcers is being assessed in an ongoing randomized clinical trial. Disclosures Ran Nir-Paz, MD, BiomX: Advisor/Consultant|Technophage: Advisor/Consultant Clara Leandro, PhD, Technophage: Employee Raquel Barbosa, PhD, Technophage: Employee Helena Dordio, PhD, Technophage S.A.: Employee Miguel Garcia, n/a, IBV Innovation Bioventures Lda: Board Member|IBV Innovation Bioventures Lda: Ownership Interest|LX Bio Pharmaceuticals SA: Board Member|LX Bio Pharmaceuticals SA: Ownership Interest|TechnoPhage, SA: Board Member|TechnoPhage, SA: Author of several patent applications|TechnoPhage, SA: Ownership Interest.

Background Although not validated, cycle threshold (Ct) values from real-time (r)RT-PCR are sometimes used as a proxy for infectiousness to inform public health decision-making. A better understanding of variant-specific viral dynamics, including RNA and infectious virus relationships, is needed to clarify implications for diagnostics and transmission. Methods Non-hospitalized SARS-CoV-2-infected individuals were recruited ≤ 5 days post-onset and self-collected nasal swabs daily for two weeks. Sequencing was used to determine variant, an in-house quantitative rRT-PCR targeting N gene was used to produce Ct values and determine RNA load, and cytopathic effect was used to assess the presence or absence of infectious virus (binary outcome). We used a Ct threshold of 30 to define high-Ct (Ct > 30) or low-Ct (Ct ≤ 30) specimens and assessed the percentage of RNA-positive specimens that had infectious virus; variant-specific percentages were compared by Χ2 test. Results We included 113 and 200 RNA-positive specimens from 18 and 28 Omicron- and Delta-infected participants, respectively; timing of RNA-positive specimen collection was similar in both groups (median = 8d post-onset). Maximum observed RNA levels occurred at median of 5 days post-onset for both variants but were lower for participants with Omicron vs Delta [mean RNA copies/mL = 105.2 vs 107.9]. Despite lower RNA levels, infectious virus was frequently detected for both variants [Omicron: median duration = 4.5d; Delta: median = 6d; p = 0.13]. Omicron specimens with infectious virus had higher Cts vs Delta specimens [mean Ct = 29.9 vs 23.2, p < 0.001]. In high-Ct specimens (Ct > 30; Table), the percentage of specimens with infectious virus was typically higher for Omicron vs Delta, and was significantly higher in adults [27.3% vs 9.5%]. In low-Ct specimens (Ct ≤ 30), the percentage with infectious virus was similar or higher for Omicron vs Delta, and was significantly higher in children [87.5% vs 53.8%] and in those unvaccinated [94.1% vs 47.4%]. Conclusion CDC does not recommend the use of Ct values as a proxy for infectiousness. These data further highlight that Ct values may not provide a reliable or consistent proxy for infectiousness across variants. Disclosures All Authors: No reported disclosures.

Background Recurrent head and neck squamous cell carcinoma (rHNSCC) represents a significant global health burden with an unmet medical need. In this study we determined the safety and efficacy of RM-1929 photoimmunotherapy in patients with heavily pretreated rHNSCC. Methods RM-1929 (anti-EGFR-IR700 dye conjugate) was infused, followed by tumor illumination. We evaluated safety, tumor response, and pharmacokinetics. Results Nine patients were enrolled in Part 1 (dose-finding) and 30 patients in Part 2 (safety and efficacy). No dose-limiting toxicities were experienced in Part 1; 640 mg/m2 with fixed light dose (50 J/cm2 or 100 J/cm) was recommended for Part 2. Adverse events (AEs) in Part 2 were mostly mild to moderate but 19 (63.3%) patients had AE ≥Grade 3, including 3 (10.0%) with serious AEs leading to death (not treatment related). Efficacy in Part 2: unconfirmed objective response rate (ORR) 43.3% (95% CI 25.46%-62.57%); confirmed ORR 26.7% (95% CI 12.28%-45.89%); median overall survival 9.30 months (95% CI 5.16-16.92 months). Conclusions Treatment was well tolerated. Responses and survival following RM-1929 photoimmunotherapy in heavily pretreated patients with rHNSCC were clinically meaningful and warrant further investigation. Clinical trial information NCT02422979.

Purpose The purpose of this study is to examine the effects of chief financial officer (CFO) gender, board gender diversity and the interaction of both factors on financial reporting quality (FRQ) proxied by restatements. Design/methodology/approach Restatements indicate inaccurate financial reporting. The authors use fixed effects conditional logistic regression models to compare firms with and without restatements matched by size, industry and year. The authors’ unique matched–pair sample consists of 546 listed US firms from the period 2005–2016. Findings The authors’ results provide evidence that restatements are less likely when the CFO is a woman and when a higher proportion of women serve on the board of directors (BOD). Considering the interaction effects, the authors find evidence that women on the BOD are more effective at reducing restatement likelihood when the CFO is also a woman. And that although female CFOs reduce restatement likelihood generally, they have no statistically significant effect on restatement likelihood when the BOD is all-male. Originality/value To the best of the authors’ knowledge, this study is the first that the authors know of to consider how FRQ is affected by the interaction effects of CFO gender and board gender diversity. The findings corroborate upper echelons theory and extend the understanding of the effects of managerial gender diversity at a time when firms face growing pressure to increase gender diversity at the highest levels. The unique sample, methodology and findings provide new insights into the impact of gender on FRQ that has important policy implications.

Food system analysis in arid and semi-arid countries inevitably meets water availability as a major constraining food system driver. Many such countries are net food importers using food subsidy systems, as water resources do not allow national food self-sufficiency. As this leaves countries in a position of dependency on international markets, prices and export bans, it is imperative that every domestic drop of water is used efficiently. In addition, policies can be geared towards ‘water footprints’, where water use efficiency is not just evaluated at the field level but also at the level of trade and import/export. In this paper, Egyptian food systems are described based on production, distribution and consumption statistics, key drivers and food system outcomes, i.e., health, sustainable land and water use, and inclusiveness. This is done for three coarsely defined Egyptian food systems: traditional, transitional and modern. A water footprint analysis then shows that for four MENA countries, differences occur between national green and blue water volumes, and the volumes imported through imported foods. Egypt has by far the largest blue water volume, but on a per capita basis, other countries are even more water limited. Then for Egypt, the approach is applied to the wheat and poultry sectors. They show opportunities but also limitations when it comes to projected increased water and food needs in the future. An intervention strategy is proposed that looks into strategies to get more out of the food system components production, distribution and consumption. On top of that food subsidy policies as well as smart water footprint application may lead to a set of combined policies that may lead to synergies between the three food system outcomes, paving the way to desirable food system transformation pathways.

Use of attention-deficit/hyperactivity disorder (ADHD) medications has increased substantially over the past decades, but there are concerns regarding their cardiovascular safety.To provide an updated synthesis of evidence on whether ADHD medications are associated with the risk of a broad range of cardiovascular diseases (CVDs).PubMed, Embase, PsycINFO, and Web of Science up to May 1, 2022.Observational studies investigating the association between ADHD medications (including stimulants and nonstimulants) and risk of CVD.Independent reviewers extracted data and assessed study quality using the Good Research for Comparative Effectiveness (GRACE) checklist. Data were pooled using random-effects models. This study is reported according to the Meta-analyses of Observational Studies in Epidemiology guideline.The outcome was any type of cardiovascular event, including hypertension, ischemic heart disease, cerebrovascular disease, heart failure, venous thromboembolism, tachyarrhythmias, and cardiac arrest.Nineteen studies (with 3 931 532 participants including children, adolescents, and adults; 60.9% male), of which 14 were cohort studies, from 6 countries or regions were included in the meta-analysis. Median follow-up time ranged from 0.25 to 9.5 years (median, 1.5 years). Pooled adjusted relative risk (RR) did not show a statistically significant association between ADHD medication use and any CVD among children and adolescents (RR, 1.18; 95% CI, 0.91-1.53), young or middle-aged adults (RR, 1.04; 95% CI, 0.43-2.48), or older adults (RR, 1.59; 95% CI, 0.62-4.05). No significant associations for stimulants (RR, 1.24; 95% CI, 0.84-1.83) or nonstimulants (RR, 1.22; 95% CI, 0.25-5.97) were observed. For specific cardiovascular outcomes, no statistically significant association was found in relation to cardiac arrest or arrhythmias (RR, 1.60; 95% CI, 0.94-2.72), cerebrovascular diseases (RR, 0.91; 95% CI, 0.72-1.15), or myocardial infarction (RR, 1.06; 95% CI, 0.68-1.65). There was no associations with any CVD in female patients (RR, 1.88; 95% CI, 0.43-8.24) and in those with preexisting CVD (RR, 1.31; 95% CI, 0.80-2.16). Heterogeneity between studies was high and significant except for the analysis on cerebrovascular diseases.This meta-analysis suggests no statistically significant association between ADHD medications and the risk of CVD across age groups, although a modest risk increase could not be ruled out, especially for the risk of cardiac arrest or tachyarrhythmias. Further investigation is warranted for the cardiovascular risk in female patients and patients with preexisting CVD as well as long-term risks associated with ADHD medication use.

Background SARS-CoV-2 nucleocapsid antigen can be detected in plasma, but little is known about its performance as a diagnostic test for acute SARS-CoV-2 infection or infectious viral shedding among nonhospitalized individuals. Methods We used data generated from anterior nasal and blood samples collected in a longitudinal household cohort of SARS-CoV-2 cases and contacts. Participants were classified as true positives if polymerase chain reaction (PCR) positive for SARS-CoV-2 and as true negatives if PCR negative and seronegative. Infectious viral shedding was determined by the cytopathic effect from viral culture. Stratified by 7 days after symptom onset, we constructed receiver operating characteristic (ROC) curves to describe optimized accuracy (Youden index), optimized sensitivity, and specificity. Results Of 80 participants, 58 (73%) were true positives while 22 (27%) were true negatives. Using the manufacturer's cutoff of 1.25 pg/mL for evaluating infection, sensitivity was higher from 0 to 7 days (77.6% [95% confidence interval {CI}, 64%–88.2%]) than from 8 to 14 days (43.2% [95% CI, 31.1%–54.5%]) after symptom onset; specificity was unchanged at 100% (95% CI, 88.1%–100%). This test had higher sensitivity (100% [95% CI, 88.4%–100%]) and lower specificity (65% [95% CI, 40.8%–84.6%]) for infectious viral shedding as compared with infection, particularly within the first week of symptom onset. Although the presence of N-antigen correlated with infectious viral shedding (r = 0.63; P < .01), sensitivity still declined over time. Additional cutoffs from ROC curves were identified to optimize sensitivity and specificity. Conclusions We found that this SARS-CoV-2 N-antigen test was highly sensitive for detecting early but not late infectious viral shedding, making it a viable screening test for community-dwelling individuals to inform isolation practices.

Spain's rate of new human immunodeficiency virus (HIV) diagnoses exceeds that of the European Economic Area average (8.6 vs 5.6:100,000 in 2018). The country has failed to meet the first of United Nations Programme on HIV/AIDS (UNAIDS) 90-90-90 targets for HIV control by 2020, with 87.0% of people living with HIV knowing their status, and late presentation rates of 47.6% and 51.5% country-wide and in the Valencian autonomous community, respectively. Advancing screening and linkage to care (SLTC) practices is necessary to effectively control the epidemic. The Valencia Viral Screening (CRIVALVIR) project adopted the TEST model for opportunistic and systematic HIV SLTC in individuals aged 18 to 80 who required blood work for any purpose, as of February 2019. SLTC was integrated into routine clinical workflow across primary care centers serving a population of 360,000 people in Valencia, Spain. Our project successfully upscaled total HIV testing by 194% to over 32,000 patients tested in 14 months. We found an overall prevalence of 0.13% (0.08-0.21) among those screened per protocol (n = 13,061), with foreign-born citizens presenting a 12.5 times significantly higher likelihood of acquiring HIV (95% confidence interval 4.63-33.96, P.0001). We improved late presentation by 18.2 percentage points and prevented an estimated 58 to 70 new secondary infections. HIV screening of the general population in primary care is an effective strategy for achieving timely diagnosis and preventing new infections. Opportunistic, systematic, opt-out approaches are essential to control the HIV epidemic.

ObjectiveTo assess the inverse relationship between acute appendicitis and ulcerative colitis (UC) using a sibling comparison design to adjust for unmeasured familial genetic and environmental factors.DesignThe cohort comprised 3.1 million individuals resident in Sweden between 1984 and 2018 with the linkage of several Swedish national registers. Fitting Cox hazards models, we calculated the risk for developing UC in individuals with and without acute appendicitis by the age 20 years adjusting for several potential confounding factors. Further, we performed sibling-stratified analyses to adjust for shared unmeasured familial confounding factors.ResultsDuring 57.7 million person-years of follow-up, 20 848/3 125 232 developed UC among those without appendicitis (3.63 (3.59–3.68) per 10 000 person-years), whereas only 59/35 848 people developed UC among those with appendicitis before age 20 years (1.66 (1.28–2.14) per 10 000 person-years). We found a decreased risk for developing UC in those with acute appendicitis by the age 20 years compared with individuals who did not have appendicitis by this age (HR=0.37 (95% CI 0.29 to 0.48)). When adjusting for shared familial confounders, we observed only a slight attenuation in this association (HR=0.46 (95% CI 0.32 to 0.66)).ConclusionIndividuals who had acute appendicitis by late adolescence showed a decreased risk for developing UC compared with those who did not. Genetic and shared familial environmental factors seem to potentially play only a small role in this relationship. Our results suggest an independent association of acute appendicitis, or its underlying causes, with UC risk.

Accumulating evidence suggests a higher risk for cardiovascular diseases among individuals with mental disorders, but very little is known about the risk for overall and specific groups of cardiovascular diseases in people with attention‐deficit/hyperactivity disorder (ADHD). To fill this knowledge gap, we investigated the prospective associations between ADHD and a wide range of cardiovascular diseases in adults. In a nationwide population‐based cohort study, we identified 5,389,519 adults born between 1941 and 1983, without pre‐existing cardiovascular diseases, from Swedish registers. The study period was from January 1, 2001 to December 31, 2013. Incident cardiovascular disease events were identified according to ICD codes. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox proportional hazards regression model, with ADHD as a time‐varying exposure. After an average 11.80 years of follow‐up, 38.05% of individuals with ADHD versus 23.57% of those without ADHD had at least one diagnosis of cardiovascular disease (p

Before emergence in late 2021 of the highly transmissible B.1.1.529 (Omicron) variant of SARS-CoV-2, the virus that causes COVID-19 (1,2), several studies demonstrated that SARS-CoV-2 was unlikely to be cultured from specimens with high cycle threshold (Ct) values