Severe cerebral edema related to oral methadone: A case report and literature review.

Introduction: Opioids are widely used for pain management, and increased intracranial pressure (ICP) has been evidenced in some cases. We reported a patient with severe cerebral edema after initiating methadone and its complete resolution upon discontinuing the medication. Additionally, a review of the literature is made. Case report: A 53-year-old woman patient with a history of systemic lupus erythematosus developed mechanic chronic lower back pain, refractory to conventional treatments. She presented improvement with oxycodone. She withdrew this medication due to a lack of supplies in her country (Colombia) and showed withdrawal symptoms. She consulted the emergency department, where oral methadone was started and symptom control was achieved. Three days after admission, she presented intense headaches and emesis. A brain CT scan was performed in which severe cerebral edema was appreciated. Methadone was discontinued, and neurological symptoms quickly disappeared. A follow-up brain CT scan was performed later, finding full resolution of the edema. Conclusion: A case of severe cerebral edema associated with the initiation of oral methadone and its rapid resolution without neurological sequelae after its withdrawal is presented, clinicians must be attentive to this adverse event.

Clinical outcomes and mortality in patients with atrial fibrillation and recently diagnosed lung cancer in oncology outpatient settings.

INTRODUCTION: Our aim was to investigate the prevalence of atrial fibrillation (AF) and recently diagnosed lung cancer in the outpatient oncology clinic and to describe the clinical profile, management and outcomes of this population. METHODS: Among 6984 patients visited at the outpatient oncology clinics attending lung cancer patients in five university hospitals from 2017 to 2019, all consecutive subjects with recently diagnosed (<1 year) disease and AF were retrospectively selected and events in follow up were registered. RESULTS: A total of 269 patients (3.9 % of all attended, 71 ± 8 years, 91 % male) were included. Charlson, CHA2DS2-VASc and HAS-BLED indexes were 6.7 ± 2.9, 2.9 ± 1.5 y 2.5 ± 1.2, respectively. Tumour stage was I, II, III and IV in 11 %, 11 %, 33 % and 45 % of them, respectively. Anticoagulants were prescribed to 226 patients (84 %): direct anticoagulants (n = 99;44 %), low molecular weight heparins (n = 69;30 %) and vitamin K antagonists (n = 58;26 %). After 46 months of maximum follow-up, 186 patients died (69 %). Cumulative incidences of events at 3 years were 3.3 ± 1.3 % for stroke/systemic embolism (n = 7); 8.9 ± 2.2 % for thrombotic events (n = 18); 9.9 ± 2.6 % for major bleeding (n = 16), and 15.9 ± 3,0 % for cardiovascular events (n = 33). In patients with early stages of cancer (I-II), 2-year mortality was significantly higher in those with cardiovascular events or major bleeding (85 % vs 25 %, p = 0.01). CONCLUSION: Nearly 4 % or all outpatients in the oncology clinic attending lung cancer present recently diagnosed disease and AF. Major bleeding and cardiovascular event rates are high in this population, with an impact on mortality in early stages of cancer.

Dostarlimab or pembrolizumab plus chemotherapy in previously untreated metastatic non-squamous non-small cell lung cancer: the randomized PERLA phase II trial.

PERLA is a global, double-blind, parallel phase II trial (NCT04581824) comparing efficacy and safety of anti-PD-1 antibodies dostarlimab and pembrolizumab, plus chemotherapy (DCT and PCT, respectively) as first-line treatment in patients with metastatic non-squamous NSCLC without known targetable genomic aberrations. Patients stratified by PD-L1 tumor proportion score and smoking status were randomized 1:1, receiving ≤35 cycles 500 mg dostarlimab or 200 mg pembrolizumab, ≤35 cycles 500 mg/m2 pemetrexed and ≤4 cycles cisplatin (75 mg/m2) or carboplatin (AUC 5 mg/ml/min) Q3W. Primary endpoint was overall response rate (ORR) (blinded independent central review). Secondary endpoints include progression-free survival (PFS) based on investigator assessment, overall survival (OS) and safety. Exploratory endpoints include ORR by PD-L1 subgroup and duration of response. PERLA met its pre-specified endpoint. ORR (n/N; 95% CI) is 45% (55/121; 36.4-54.8) for DCT and 39% (48/122; 30.6-48.6) for PCT (data cut-off: 07 July 23), numerically favoring dostarlimab in PD-L1-positive subgroups. Median PFS (months [95% CI]) is 8.8 (6.7-10.4) for DCT and 6.7 (4.9-7.1) for PCT (HR 0.70 [95% CI: 0.50-0.98]; data cut-off: 04 August 22). Median OS (months [95% CI]) is 19.4 (14.5-NR) for DCT and 15.9 (11.6-19.3) for PCT (HR 0.75 [95% CI: 0.53-1.05]) (data cut-off: 07 July 23). Safety profiles are similar between groups. In this study, DCT shows similar efficacy to PCT and demonstrates clinical efficacy as first-line treatment for patients with metastatic non-squamous NSCLC.

Eosinophilic enteritis presenting as intestinal obstruction: case report and review of the literature.

Eosinophilic enteritis (EE) is characterized by intense eosinophilic infiltrate of the gastrointestinal tract. Clinical manifestations depend on the affected segment and intestinal layer. First-line treatment is systemic corticosteroids; surgery is reserved for complications. 84-year-old male patient with a history of right hemicolectomy and two episodes of intestinal obstruction presented to the ED with abdominal pain, distension, nausea, and vomiting. CBC showed leukocytosis and no eosinophilia. Contrast-enhanced CT revealed stenosis with thickening of the distal intestinal wall and partial intestinal obstruction. Colonoscopy found aphthous ulcers. Histopathology reported EE. The patient received budesonide and metronidazole, with resolution within 24 h.

La enteritis eosinofílica (EE) se caracteriza por infiltrado eosinofilico del tracto GI. Las manifestaciones clínicas dependen de la capa intestinal afectada. Se recomiendan esteroides sistémicos como primera línea de tratamiento, reservando la cirugía para complicaciones. Masculino de 84 años con antecedente de hemicolectomía derecha y dos episodios de oclusión intestinal acude al servicio de urgencias con dolor abdominal, distensión, náusea y vómito. Laboratorio reportó leucocitosis, sin eosinofilia. Tomografía con contraste evidenció estenosis, con engrosamiento de la pared del intestino delgado e imagen compatible con oclusión intestinal. La colonoscopía demostró ulceras en íleon terminal la cual reporto EE. Se inició tratamiento con budesonide y metronidazol, con adecuada respuesta y resolución a las 24 h.

Spanish cohort of VEXAS syndrome: clinical manifestations, outcome of treatments and novel evidences about UBA1 mosaicism.

BACKGROUND: The vacuoles, E1-enzyme, X linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease (AID) due to postzygotic UBA1 variants. OBJECTIVES: To investigate the presence of VEXAS syndrome among patients with adult-onset undiagnosed AID. Additional studies evaluated the mosaicism distribution and the circulating cytokines. METHODS: Gene analyses were performed by both Sanger and amplicon-based deep sequencing. Patients' data were collected from their medical charts. Cytokines were quantified by Luminex. RESULTS: Genetic analyses of enrolled patients (n=42) identified 30 patients carrying UBA1 pathogenic variants, with frequencies compatible for postzygotic variants. All patients were male individuals who presented with a late-onset disease (mean 67.5 years; median 67.0 years) characterised by cutaneous lesions (90%), fever (66.7%), pulmonary manifestations (66.7%) and arthritis (53.3%). Macrocytic anaemia and increased erythrocyte sedimentation rate and ferritin were the most relevant analytical abnormalities. Glucocorticoids ameliorated the inflammatory manifestations, but most patients became glucocorticoid-dependent. Positive responses were obtained when targeting the haematopoietic component of the disease with either decitabine or allogeneic haematopoietic stem cell transplantation. Additional analyses detected the UBA1 variants in both haematopoietic and non-haematopoietic tissues. Finally, analysis of circulating cytokines did not identify inflammatory mediators of the disease. CONCLUSION: Thirty patients with adult-onset AID were definitively diagnosed with VEXAS syndrome through genetic analyses. Despite minor interindividual differences, their main characteristics were in concordance with previous reports. We detected for the first time the UBA1 mosaicism in non-haematopoietic tissue, which questions the previous concept of myeloid-restricted mosaicism and may have conceptual consequences for the disease mechanisms.

Characterization of a Potent and Orally Bioavailable Lys-Covalent Inhibitor of Apoptosis Protein (IAP) Antagonist.

We have recently reported on the use of aryl-fluorosulfates in designing water- and plasma-stable agents that covalently target Lys, Tyr, or His residues in the BIR3 domain of the inhibitor of the apoptosis protein (IAP) family. Here, we report further structural, cellular, and pharmacological characterizations of this agent, including the high-resolution structure of the complex between the Lys-covalent agent and its target, the BIR3 domain of X-linked IAP (XIAP). We also compared the cellular efficacy of the agent in two-dimensional (2D) and three-dimensional (3D) cell cultures, side by side with the clinical candidate reversible IAP inhibitor LCL161. Finally, in vivo pharmacokinetic studies indicated that the agent was long-lived and orally bioavailable. Collectively our data further corroborate that aryl-fluorosulfates, when incorporated correctly in a ligand, can result in Lys-covalent agents with pharmacodynamic and pharmacokinetic properties that warrant their use in the design of pharmacological probes or even therapeutics.

Smooth pursuit eye movements contribute to anticipatory force control during mechanical stopping of moving objects.

When stopping a closing door or catching an object, humans process the motion of inertial objects and apply reactive limb force over short period to interact with them. One way in which the visual system processes motion is through extraretinal signals associated with smooth pursuit eye movements (SPEMs). We conducted three experiments to investigate how SPEMs contribute to anticipatory and reactive hand force modulation when interacting with a virtual object moving in the horizontal plane. We hypothesized that SPEM signals are critical for timing motor responses, anticipatory control of hand force, and task performance. Participants held a robotic manipulandum and attempted to stop an approaching simulated object by applying a force impulse (area under force-time curve) that matched the object's virtual momentum upon contact. We manipulated the object's momentum by varying either its virtual mass or its speed under free gaze or constrained gaze conditions. We examined gaze variables, the timing of hand motor responses, anticipatory force control, and overall task performance. Our results show that when participants were fixated at a designated location instead of following objects with SPEM, anticipatory modulation of hand force before contact decreased. However, constraining gaze by asking participants to fixate did not seem to affect the timing of the motor response or the task performance. Together, these results suggest that SPEMs may be important for anticipatory control of hand force before contact and may also play a critical role in anticipatory stabilization of limb posture when humans interact with moving objects.NEW & NOTEWORTHY We show for the first time that smooth pursuit eye movements (SPEMs) play a role in the modulation of anticipatory control of hand force to stabilize posture against contact forces. SPEMs are critical for tracking moving objects, facilitate processing motion of moving objects, and are impacted during aging and in many neurological disorders, such as Alzheimer's disease and multiple sclerosis. These results provide a novel basis to probe how changes in SPEMs could contribute to deficient limb motor control in older adults and patients with neurological disorders.

Object motion influences feedforward motor responses during mechanical stopping of virtual projectiles: a preliminary study.

An important window into sensorimotor function is how humans interact and stop moving projectiles, such as stopping a door from closing shut or catching a ball. Previous studies have suggested that humans time the initiation and modulate the amplitude of their muscle activity based on the momentum of the approaching object. However, real-world experiments are constrained by laws of mechanics, which cannot be manipulated experimentally to probe the mechanisms of sensorimotor control and learning. An augmented-reality variant of such tasks allows for experimental manipulation of the relationship between motion and force to obtain novel insights into how the nervous system prepares motor responses to interact with moving stimuli. Existing paradigms for studying interactions with moving projectiles use massless objects and are primarily focused on quantifying gaze and hand kinematics. Here, we developed a novel collision paradigm using a robotic manipulandum where participants mechanically stopped a virtual object moving in the horizontal plane. On each block of trials, we varied the virtual object's momentum by increasing either its velocity or mass. Participants stopped the object by applying a force impulse that matched the object momentum. We observed that hand force increased as a function of object momentum linked to changes in virtual mass or velocity, similar to results from studies involving catching free-falling objects. In addition, increasing object velocity resulted in later onset of hand force relative to the impending time-to-contact. These findings show that the present paradigm can be used to determine how humans process projectile motion for hand motor control.

Identification of ALK-positive patients with advanced NSCLC and real-world clinical experience with crizotinib in Spain (IDEALK study).

OBJECTIVES: To determine the incidence of ALK translocations in patients with advanced/metastatic NSCLC in Spain, to describe the clinical characteristics of these patients, and to evaluate the effectiveness and safety of treatment with crizotinib in a real-world setting. METHODS: This is an observational prospective and retrospective cohort study to determine the incidence of ALK translocations and to analyze the effectiveness and safety of crizotinib in a real-world setting. Patient characteristics, treatment patterns, time to best overall response, duration of treatment, objective response rates (ORR), rates of adverse events (AE), progression free survival (PFS) and overall survival (OS) were evaluated in the ALK study cohort of patients treated with crizotinib (prospective and retrospective). ALK incidence and quality of life (QoL) questionnaires were measured from patients included in the prospective cohort. RESULTS: The incidence of ALK translocations was 5.5 % (31 of 559 patients). Compared with ALK-negative patients, ALK-positive patients were significantly younger, predominantly female, and non-smokers. In the crizotinib effectiveness and safety study, 91 patients (42 prospective, 49 retrospective) with ALK-positive NSCLC (43.9 % in first-line, 56.1 % in second or more lines) were included. The ORR was 59.3 % and the median duration of response was 13.5 months (IQR, 5.3-26.2). The median PFS was 15.8 months (95 % CI, 11.8-22.3) and the median OS was 46.5 months, with 53 patients (58.2 %) still alive at data cut-off date. Frequently reported AEs included elevated transaminases, gastrointestinal disorders, and asthenia. Most patients (76.5 %) reported improved or stable scores for global QoL during treatment. CONCLUSIONS: The observed incidence of ALK translocations in NSCLC patients is aligned with published reports. This analysis of the real-world clinical experience in Spain confirms the therapeutic benefit and safety of crizotinib in advanced/metastatic ALK-positive NSCLC. CLINICALTRIALS: gov: NCT02679170.

Predicting dynamic response to neoadjuvant chemotherapy in breast cancer: a novel metabolomics approach.

Neoadjuvant chemotherapy (NACT) outcomes vary according to breast cancer (BC) subtype. Since pathologic complete response is one of the most important target endpoints of NACT, further investigation of NACT outcomes in BC is crucial. Thus, identifying sensitive and specific predictors of treatment response for each phenotype would enable early detection of chemoresistance and residual disease, decreasing exposures to ineffective therapies and enhancing overall survival rates. We used liquid chromatography-high-resolution mass spectrometry (LC-HRMS)-based untargeted metabolomics to detect molecular changes in plasma of three different BC subtypes following the same NACT regimen, with the aim of searching for potential predictors of response. The metabolomics data set was analyzed by combining univariate and multivariate statistical strategies. By using ANOVA-simultaneous component analysis (ASCA), we were able to determine the prognostic value of potential biomarker candidates of response to NACT in the triple-negative (TN) subtype. Higher concentrations of docosahexaenoic acid and secondary bile acids were found at basal and presurgery samples, respectively, in the responders group. In addition, the glycohyocholic and glycodeoxycholic acids were able to classify TN patients according to response to treatment and overall survival with an area under the curve model > 0.77. In relation to luminal B (LB) and HER2+ subjects, it should be noted that significant differences were related to time and individual factors. Specifically, tryptophan was identified to be decreased over time in HER2+ patients, whereas LysoPE (22:6) appeared to be increased, but could not be associated with response to NACT. Therefore, the combination of untargeted-based metabolomics along with longitudinal statistical approaches may represent a very useful tool for the improvement of treatment and in administering a more personalized BC follow-up in the clinical practice.

Synchronous volvulus of the cecum and sigmoid colon: a rare cause of intestinal obstruction.

A 102-year-old female with a past medical history of sigmoid volvulus resolved by colonoscopy a year ago presents to the emergency department with sigmoid volvulus, which is resolved by colonoscopy and rectal tube placement. Three days later, she presented abdominal distention and recurrence of the volvulus, for which a surgical resolution was decided. Laparotomy was performed, where sigmoid and cecal volvulus was found. A cecal detorsion and a cecopexy were performed, and an extended left hemicolectomy with a terminal colostomy to treat the sigmoid volvulus. The patient presents an adequate postoperative period and is discharged. Three months later, the patient was in good clinical condition, eating normally without complications. Volvulus refers to the torsion of a segment of the gastrointestinal tract. The most common sites for colonic volvulus are sigmoid and cecum; however, it is infrequent for these to occur together. We only found six cases reported in the literature of synchronous volvulus of the cecum and sigmoid colon. None of the cases was the diagnosis made preoperatively, suggesting a difficult diagnosis. Treatment depends on the patient's condition; in most reported cases, a subtotal colectomy was performed. The prognosis depends on prompt surgical intervention.

Se reporta un caso de una femenina de 102 años de edad, con antecedente de vólvulo sigmoideo resuelto por medio de colonoscopia hace un año. Se presenta al servicio de urgencias con vólvulo sigmoideo, el cual se resuelve por medio de colonoscopia y se coloca un tubo rectal. Tres días después, presenta nuevamente distensión y recurrencia del vólvulo, por lo cual se decide resolución quirúrgica. Durante la cirugía se encuentra un vólvulo sigmoideo, así como cecal. Se realiza una detorsión con cecopexia y hemicolectomía izquierda con colostomía terminal. La paciente presenta adecuada evolución. Sin complicaciones tres meses después. Vólvulo se refiere a la torsión de un segmento del tracto gastrointestinal. Los sitios más comunes de vólvulos colónicos son sigmoides y ciego, sin embargo, es extremadamente raro que estos se presenten juntos. Únicamente encontramos seis casos reportados en la literatura de vólvulo sincronico sigmoideo y cecal. En ninguno de los casos, se hizo el diagnóstico preoperatoriamente, lo que sugiere un diagnóstico complicado. El tratamiento depende del estado del paciente; en la mayoría de los casos reportados, se realizó una colectomía subtotal. El pronóstico depende de la intervención quirúrgica oportuna.

Age-related deficits in rapid visuomotor decision-making.

Many goal-directed actions that require rapid visuomotor planning and perceptual decision-making are affected in older adults, causing difficulties in execution of many functional activities of daily living. Visuomotor planning and perceptual identification are mediated by the dorsal and ventral visual streams, respectively, but it is unclear how age-induced changes in sensory processing in these streams contribute to declines in visuomotor decision-making performance. Previously, we showed that in young adults, task demands influenced movement strategies during visuomotor decision-making, reflecting differential integration of sensory information between the two streams. Here, we asked the question if older adults would exhibit deficits in interactions between the two streams during demanding motor tasks. Older adults (n = 15) and young controls (n = 26) performed reaching or interception movements toward virtual objects. In some blocks of trials, participants also had to select an appropriate movement goal based on the shape of the object. Our results showed that older adults corrected fewer initial decision errors during both reaching and interception movements. During the interception decision task, older adults made more decision- and execution-related errors than young adults, which were related to early initiation of their movements. Together, these results suggest that older adults have a reduced ability to integrate new perceptual information to guide online action, which may reflect impaired ventral-dorsal stream interactions.NEW & NOTEWORTHY Older adults show declines in vision, decision-making, and motor control, which can lead to functional limitations. We used a rapid visuomotor decision task to examine how these deficits may interact to affect task performance. Compared with healthy young adults, older adults made more errors in both decision-making and motor execution, especially when the task required intercepting moving targets. This suggests that age-related declines in integrating perceptual and motor information may contribute to functional deficits.

Early use of tocilizumab in patients with severe pneumonia secondary to severe acute respiratory syndrome coronavirus 2 infection and poor prognostic criteria: Impact on mortality rate and intensive care unit admission.

ABSTRACT: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, keeps spreading globally. Evidence suggests that a subgroup of patients with severe symptomatology might have cytokine storms, which increases mortality. The use of interleukin-6 (IL-6) inhibitors may help in controlling the pathological immune response to the virus. Tocilizumab, a monoclonal antibody against IL-6, stands as an optional treatment for COVID-19 patients presenting this inflammatory hyper-response.We conducted a retrospective, observational, cohort study including 50 patients affected by COVID-19 with severe pneumonia and poor prognosis criteria, who have also undergone standard treatment; 36 of these patients additionally received tocilizumab in an early stage. The need for intensive care unit (ICU) admission, mortality, recovery of respiratory function, and improvement of biochemical and hematological parameters were compared between cohorts.Most patients were men, non-smokers and the most frequently reported comorbidities were hypertension and diabetes. Recurrent symptoms were fever, cough, and dyspnoea. 54.8% of patients from the tocilizumab group needed intubation, while in the control group 85.7% needed it. Treatment with tocilizumab significatively increased IL-6 levels, (554.45; CI 95% 186.69, 1032.93; P < .05) while C-reactive protein mean levels were reduced (-108.19; CI 95% -140.15, -75.33; P < .05), but no significant difference was found between cohorts. In comparison with the controls, tocilizumab reduced mortality (25.0% vs 42.9%, P = .021) and the number of ICU admissions (63.9% vs 100.0%, P = .021). 44.1% of patients treated with tocilizumab showed favorable radiological evolution, when compared with 15.4% of patients from the control group.Tocilizumab may improve clinical symptoms and mitigate deterioration observed in severe COVID-19 patients, and could be considered as an effective therapeutic option in subjects experiencing a significant inflammatory response to the disease.

"High Tumor Burden" in Metastatic Non-Small Cell Lung Cancer: Defining the Concept.

PURPOSE: Identifying patient characteristics that define a worse disease prognosis or "high tumor burden" (HTB) status is essential for clinical decision-making and treatment selection in metastatic non-small cell lung cancer (mNSCLC). We aimed to define this concept based on the experience of oncologists in clinical practice. PATIENTS AND METHODS: A representative sample of Spanish experts was selected and asked to complete an online survey regarding the definition of HTB according to their personal experience. RESULTS: HTB was identified by the oncologists (N = 81) as one of the principle factors influencing first-line treatment decision-making. According to the experts, HTB is mainly defined by the number of metastatic lesions (n = 45, 56%), location (n = 34, 42%), tumor size (sum of diameters of target lesions; n = 26, 32%) and liver involvement (n = 24, 30). High lactate dehydrogenase (LDH) levels were also associated with HTB. Almost half of respondents (n = 33, 41%) believed that one metastatic lesion was sufficient to consider a patient as presenting HTB, 72% (n = 58) considered that two were necessary and 99% (n = 80) three. Liver (n = 76, 100%) followed by brain (n = 65, 86%) were the main metastatic sites associated with HTB. Tumor size ranging from 6 cm to 10 cm as well as high LDH levels (three times the upper limit) defined the concept for 82% (n = 62) and 100% (n = 76) of oncologists, respectively. CONCLUSION: In the real-world setting, according to experts, HTB is defined by the number of metastatic lesions, location of metastases, tumor size and by high LDH levels. Given the relevance of this concept, efforts should be made to unify its definition and to further explore its potential as a prognostic factor for mNSCLC patients.

A Possible Association Between Zika Virus Infection and CDK5RAP2 Mutation.

INTRODUCTION: Flaviviridae family belongs to the Spondweni serocomplex, which is mainly transmitted by vectors from the Aedes genus. Zika virus (ZIKV) is part of this genus. It was initially reported in Brazil in December 2014 as an unknown acute generalized exanthematous disease and was subsequently identified as ZIKV infection. ZIKV became widespread all over Brazil and was linked with potential cases of microcephaly. CASE REPORT: We report a case of a 28-year-old Colombian woman, who came to the Obstetric Department with an assumed conglomerate of fetal abnormalities detected via ultrasonography, which was performed at 29.5 weeks of gestation. The patient presented with multiple abnormalities, which range from a suggested Arnold-Chiari malformation, compromising the lateral and third ventricles, liver calcifications, bilateral pyelocalic dilatations, other brain anomalies, and microcephaly. At 12 weeks of gestation, the vertical transmission of ZIKV was suspected. At 38.6 weeks of gestation, the newborn was delivered, with the weight in the 10th percentile (3,180 g), height in the 10th percentile (48 cm), and cephalic circumference under the 2nd percentile (31 cm). Due to the physical findings, brain magnetic resonance imaging (MRI) was performed, revealing a small and deviated brain stem, narrowing of the posterior fossa, a giant posterior fossa cyst with ventricular dilatation, a severe cortical and white matter thinning, cerebellar vermis with hypoplasia, and superior and lateral displacement of the cerebellum. In addition, hydrocephalus was displayed by the axial sequence, and the cerebral cortex was also compromised with lissencephaly. Schizencephaly was found with left frontal open-lip, and no intracranial calcifications were found. Two novel heterozygous nonsense mutations were identified using whole-exome sequencing, and both are located in exon 8 under the affection of ZIKV congenital syndrome (CZS) that produced a premature stop codon resulting in the truncation of the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 (CDK5RAP2) protein. CONCLUSION: We used molecular and microbiological assessments to report the initial case of vertically transmitted ZIKV infection with congenital syndrome associated with a neurological syndrome, where a mutation in the CDK5RAP2 gene was also identified. The CDK5RAP2 gene encodes a pericentriolar protein that intervenes in microtubule nucleation and centriole attachment. Diallelic mutation has previously been associated with primary microcephaly.

High-dose corticosteroid pulse therapy increases the survival rate in COVID-19 patients at risk of hyper-inflammatory response.

OBJECTIVE: Test whether high dose corticosteroid pulse therapy (HDCPT) with either methylprednisolone or dexamethasone is associated with increased survival in COVID-19 patients at risk of hyper-inflammatory response. Provide some initial diagnostic criteria using laboratory markers to stratify these patients. METHODS: This is a prospective observational study, 318 met the inclusion criteria. 64 patients (20.1%) were treated with HDCPT by using at least 1.5mg/kg/24h of methylprednisolone or dexamethasone equivalent. A multivariate Cox regression (controlling for co-morbidities and other therapies) was carried out to determine whether HDCPT (among other interventions) was associated with decreased mortality. We also carried out a 30-day time course analysis of laboratory markers between survivors and non-survivors, to identify potential markers for patient stratification. RESULTS: HDCPT showed a statistically significant decrease in mortality (HR = 0.087 [95% CI 0.021-0.36]; P < 0.001). 30-day time course analysis of laboratory marker tests showed marked differences in pro-inflammatory markers between survivors and non-survivors. As diagnostic criteria to define the patients at risk of developing a COVID-19 hyper-inflammatory response, we propose the following parameters (IL-6 > = 40 pg/ml, and/or two of the following: C-reactive protein > = 100 mg/L, D-dimer > = 1000 ng/ml, ferritin > = 500 ng/ml and lactate dehydrogenase > = 300 U/L). CONCLUSIONS: HDCPT can be an effective intervention to increase COVID-19 survival rates in patients at risk of developing a COVID-19 hyper-inflammatory response, laboratory marker tests can be used to stratify these patients who should be given HDCPT. This study is not a randomized clinical trial (RCT). Future RCTs should be carried out to confirm the efficacy of HDCPT to increase the survival rates of COVID-19.

Human Plasma Metabolomics for Biomarker Discovery: Targeting the Molecular Subtypes in Breast Cancer.

PURPOSE: The aim of this study is to identify differential metabolomic signatures in plasma samples of distinct subtypes of breast cancer patients that could be used in clinical practice as diagnostic biomarkers for these molecular phenotypes and to provide a more individualized and accurate therapeutic procedure. METHODS: Untargeted LC-HRMS metabolomics approach in positive and negative electrospray ionization mode was used to analyze plasma samples from LA, LB, HER2+ and TN breast cancer patients and healthy controls in order to determine specific metabolomic profiles through univariate and multivariate statistical data analysis. RESULTS: We tentatively identified altered metabolites displaying concentration variations among the four breast cancer molecular subtypes. We found a biomarker panel of 5 candidates in LA, 7 in LB, 5 in HER2 and 3 in TN that were able to discriminate each breast cancer subtype with a false discovery range corrected p-value < 0.05 and a fold-change cutoff value > 1.3. The model clinical value was evaluated with the AUROC, providing diagnostic capacities above 0.85. CONCLUSION: Our study identifies metabolic profiling differences in molecular phenotypes of breast cancer. This may represent a key step towards therapy improvement in personalized medicine and prioritization of tailored therapeutic intervention strategies.

Effect of bariatric surgery on cardiac structure and function in obese patients: Role of the renin-angiotensin system.

Echocardiographic alterations have been described in obesity, but their modifications after bariatric surgery (BS) and mechanisms are little known, mostly in normotensive patients. We aimed to analyze cardiac changes 1 year post-BS and to explore possible mechanisms. A cohort of patients with severe obesity (58% normotensives) were prospectively recruited and examined before surgery and after 12 months. Clinical and echocardiographic data, 24 h BP, renin-angiotensin-aldosterone system (RAAS) components, cytokines, and inflammatory markers were analyzed at these two time points. Overall reduction in body weight was mean (IQR) = 30.0% (25.9-33.8). There were statistically significant decreases in left ventricle mass index2.7 (LVMI)2.7 , septum thickness (ST), posterior wall thickness (PWT), relative wall thickness (RWT), and E/e', both in the whole cohort and in patients without RAAS blockers (p ≤ .04 for all). Plasma renin activity (PRA) decreased from (median, IQR) = 0.8 (0.3;1.35) to 0.4 (0.2;0.93) ng/ml/h, plasma aldosterone from 92 (58.6;126) to 68.1 (56.2;83.4) ng/dl, and angiotensin-converting enzyme (ACE)-2 activity from 7.7 (5.7;11.8) to 6.8 (5.3;11.2) RFU/µl/h, p < .05. The body weight loss correlated with a decrease in both 24 h SBP and 24 h DBP (Pearson's coefficient 0.353, p = .022 and 0.384, p = .012, respectively). Variation (Δ) of body weight correlated with ΔE/e' (Pearson's coeff. 0.414, p = .008) and with Δ lateral e' (Pearson's coeff. = -0.363, p = .018). Generalized linear models showed that ΔPRA was an independent variable for the final (12-months post-BS) LVMI2.7 (p = .028). No other changes in cardiac parameters correlated with ΔBP. In addition to the respective baseline value, final values of PWT and RWT were dependent on 12-month Δ of PRA, ACE, and ACE/ACE2 (p < .03 for all). We conclude that there are cardiac changes post-BS in patients with severe obesity, normotensives included. Structural changes appear to be related to modifications in the renin-angiotensin axis.