Distinct Driver Pathway Enrichments and a High Prevalence of TSC2 Mutations in Right Colon Cancer in Chile: A Preliminary Comparative Analysis.

Colorectal cancer (CRC) is the second leading cause of cancer deaths globally. While ethnic differences in driver gene mutations have been documented, the South American population remains understudied at the genomic level, despite facing a rising burden of CRC. We analyzed tumors of 40 Chilean CRC patients (Chp) using next-generation sequencing and compared them to data from mainly Caucasian cohorts (TCGA and MSK-IMPACT). We identified 388 mutations in 96 out of 135 genes, with TP53 (45%), KRAS (30%), PIK3CA (22.5%), ATM (20%), and POLE (20%) being the most frequently mutated. TSC2 mutations were associated with right colon cancer (44.44% in RCRC vs. 6.45% in LCRC, p-value = 0.016), and overall frequency was higher compared to TCGA (p-value = 1.847 × 10-5) and MSK-IMPACT cohorts (p-value = 3.062 × 10-2). Limited sample size restricts definitive conclusions, but our data suggest potential differences in driver mutations for Chilean patients, being that the RTK-RAS oncogenic pathway is less affected and the PI3K pathway is more altered in Chp compared to TCGA (45% vs. 25.56%, respectively). The prevalence of actionable pathways and driver mutations can guide therapeutic choices, but can also impact treatment effectiveness. Thus, these findings warrant further investigation in larger Chilean cohorts to confirm these initial observations. Understanding population-specific driver mutations can guide the development of precision medicine programs for CRC patients.

Classification of patients with metastatic colorectal cancer into consensus molecular subtypes into real-world: A pilot study.

BACKGROUND: Colorectal cancer is a complex disease with high mortality rates. Over time, the treatment of metastatic colorectal cancer (mCRC) has gradually improved due to the development of modern chemotherapy and targeted therapy regimens. However, due to the inherent heterogeneity of this condition, identifying reliable predictive biomarkers for targeted therapies remains challenging. A recent promising classification system-the consensus molecular subtype (CMS) system-offers the potential to categorize mCRC patients based on their unique biological and molecular characteristics. Four distinct CMS categories have been defined: immune (CMS1), canonical (CMS2), metabolic (CMS3), and mesenchymal (CMS4). Nevertheless, there is currently no standardized protocol for accurately classifying patients into CMS categories. To address this challenge, reverse transcription polymerase chain reaction (RT-qPCR) and next-generation genomic sequencing (NGS) techniques may hold promise for precisely classifying mCRC patients into their CMSs. AIM: To investigate if mCRC patients can be classified into CMS categories using a standardized molecular biology workflow. METHODS: This observational study was conducted at the University of Chile Clinical Hospital and included patients with unresectable mCRC who were undergoing systemic treatment with chemotherapy and/or targeted therapy. Molecular biology techniques were employed to analyse primary tumour samples from these patients. RT-qPCR was utilized to assess the expression of genes associated with fibrosis (TGF-ß and ß-catenin) and cell growth pathways (c-MYC). NGS using a 25-gene panel (TumorSec) was performed to identify specific genomic mutations. The patients were then classified into one of the four CMS categories according to the clinical consensus of a Tumour Board. Informed consent was obtained from all the patients prior to their participation in this study. All techniques were conducted at University of Chile. RESULTS: Twenty-six patients were studied with the techniques and then evaluated by the Tumour Board to determine the specific CMS. Among them, 23% (n = 6), 19% (n = 5), 31% (n = 8), and 19% (n = 5) were classified as CMS1, CMS2, CMS3, and CMS4, respectively. Additionally, 8% of patients (n = 2) could not be classified into any of the four CMS categories. The median overall survival of the total sample was 28 mo, and for CMS1, CMS2, CMS3 and CMS4 it was 11, 20, 30 and 45 mo respectively, with no statistically significant differences between groups. CONCLUSION: A molecular biology workflow and clinical consensus analysis can be used to accurately classify mCRC patients. This classification process, which divides patients into the four CMS categories, holds significant potential for improving research strategies and targeted therapies tailored to the specific characteristics of mCRC.

Patient Pain and Satisfaction With 10, 30, and 70 mL Transcervical Foley Balloons for Cervical Ripening During Induction of Labor.

Objective To assess patient pain and satisfaction and time to delivery following transcervical Foley catheter balloon inflation to 10, 30, or 70 mL with simultaneous administration of oxytocin. Methods We performed a randomized prospective study with 30 or 70 mL transcervical Foley balloon catheters in combination with oxytocin during labor induction at term. A 10 mL group was included as a sham control group. Time to delivery was measured, and a patient questionnaire was administered at the time the catheter was expelled to determine patient pain and satisfaction. Results In 120 enrolled patients, there was a non-significant trend toward reduced time to delivery in the large Foley balloon group (10 mL: 30:45 ± 38:53, 30 mL: 26:41 ± 20:53, and 70 mL 22:40 ± 15:35, hh:mm, P = 0.412). The pain score at the time the balloon was expelled was significantly higher in the 70 ml group compared to the 10 ml and 30 ml groups (P = 0.004 and P = 0.034, respectively). We found no other differences in patient satisfaction or pain scores at the time of placement of the Foley catheter for the three groups. Conclusion Small gains in time to delivery should be balanced against patient experiences, and expectations of pain during the ripening process should be addressed at the time of Foley insertion.

Uterine Dehiscence in the Early Third Trimester: A Report of Two Cases.

As the incidence of cesarean deliveries increases, so do its accompanying complications. Although the incidence of uterine dehiscence in the late second trimester to the early third trimester is rare, it may be a potentially catastrophic complication if uterine rupture occurs. Here, we present two cases of uterine dehiscence at 28 and 29 weeks, which were diagnosed on prenatal ultrasound and confirmed intraoperatively at the time of cesarean delivery. We recommend consideration of earlier screening for preoperative detection of uterine dehiscence to help prevent maternal and neonatal morbidity and mortality.

Efficacy and Safety of Transdermal Abaloparatide in Postmenopausal Women with Osteoporosis: A Randomized Study.

Anabolic therapies, recommended for patients at very high fracture risk, are administered subcutaneously (SC). The objective of this study was to evaluate the efficacy and safety of the abaloparatide microstructured transdermal system (abaloparatide-sMTS) as an alternative to the SC formulation. This phase 3, noninferiority study (NCT04064411) randomly assigned postmenopausal women with osteoporosis (N = 511) 1:1 to open-label abaloparatide administered daily via abaloparatide-sMTS or SC injection for 12 months. The primary comparison between treatment groups was the percentage change in lumbar spine bone mineral density (BMD) at 12 months, with a noninferiority margin of 2.0%. Secondary endpoints included percentage change in total hip and femoral neck BMD, bone turnover markers, dermatologic safety, and new clinical fracture incidence. At 12 months, percentage increase from baseline in lumbar spine BMD was 7.14% (SE: 0.46%) for abaloparatide-sMTS and 10.86% (SE: 0.48%) for abaloparatide-SC (treatment difference: -3.72% [95% confidence interval: -5.01%, -2.43%]). Percentage change in total hip BMD was 1.97% for abaloparatide-sMTS and 3.70% for abaloparatide-SC. Median changes from baseline at 12 months in serum procollagen type I N-terminal propeptide (s-PINP) were 52.6% for abaloparatide-sMTS and 74.5% for abaloparatide-SC. Administration site reactions were the most frequently reported adverse events (abaloparatide-sMTS, 94.4%; abaloparatide-SC, 70.5%). Incidence of serious adverse events was similar between groups. Mild or moderate skin reactions occurred with abaloparatide-sMTS with no identifiable risk factors for sensitization reactions. Few new clinical fractures occurred in either group. Noninferiority of abaloparatide-sMTS to abaloparatide-SC for percentage change in spine BMD at 12 months was not demonstrated; however, clinically meaningful increases from baseline in lumbar spine and total hip BMD were observed in both treatment groups. © 2023 Radius Health, Inc and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Interest in and Barriers to Telehealth Uptake in an Obstetric and Pediatric Medicaid Population.

Telehealth has been shown to be generally well accepted by patients and physicians with an increasing desire and utilization of this practice since the COVID-19 pandemic. However, studies looking specifically at the United States' low socioeconomic populations' interest in and barriers to accessing Telehealth care are limited. In this study, we performed a survey to determine the interest of pediatric and obstetric patients on and the reasons they may or may not choose Telehealth visits in a practice that serves solely California Medicaid (Medi-Cal) patients. A total of 636 patients completed the questionnaire, 383 (60%) from an obstetric practice and 253 (40%) from a pediatric practice. The majority expressed that they were not interested in Telehealth (N=407, 64%), and 228 (36%) stated interest. Interest in Telehealth was related to domains of cost, access, and attitude (P<0.005 for each) for the entire sample. The highest scores (preference toward Telehealth) were noted in the domain of enjoyment; this suggests that both pediatric and obstetric patients may decline Telehealth in favor of in-person meetings simply because they like meeting with their provider. Despite readily available technology/access for Telehealth visits in low socioeconomic patients, in-person healthcare may be preferred by this patient population. In the world of changing healthcare delivery and epidemics, in-person visits are an important option for disadvantaged patients.

Trial of Intravenous Immune Globulin in Dermatomyositis.

BACKGROUND: Intravenous immune globulin (IVIG) for the treatment of dermatomyositis has not been extensively evaluated. METHODS: We conducted a randomized, placebo-controlled trial involving patients with active dermatomyositis. The patients were assigned in a 1:1 ratio to receive IVIG at a dose of 2.0 g per kilogram of body weight or placebo every 4 weeks for 16 weeks. The patients who received placebo and those without confirmed clinical deterioration while receiving IVIG could enter an open-label extension phase for another 24 weeks. The primary end point was a response, defined as a Total Improvement Score (TIS) of at least 20 (indicating at least minimal improvement) at week 16 and no confirmed deterioration up to week 16. The TIS is a weighted composite score reflecting the change in a core set of six measures of myositis activity over time; scores range from 0 to 100, with higher scores indicating greater improvement. Key secondary end points included at least moderate improvement (TIS ≥40) and major improvement (TIS ≥60), and change in score on the Cutaneous Dermatomyositis Disease Area and Severity Index. RESULTS: A total of 95 patients underwent randomization: 47 patients were assigned to the IVIG group, and 48 to the placebo group. At 16 weeks, 79% of the patients in the IVIG group (37 of 47) and 44% of those in the placebo group (21 of 48) had a TIS of at least 20 (difference, 35 percentage points; 95% confidence interval, 17 to 53; P<0.001). The results with respect to the secondary end points, including at least moderate improvement and major improvement, were generally in the same direction as the results of the primary end-point analysis, except for the change in creatine kinase level (an individual core measure of the TIS), which did not differ meaningfully between the two groups. Over 40 weeks, 282 treatment-related adverse events occurred in the IVIG group, including headache (in 42% of patients), pyrexia (in 19%), and nausea (in 16%). A total of 9 serious adverse events that were considered to be related to IVIG occurred, including 6 thromboembolic events. CONCLUSIONS: In this 16-week trial involving adults with dermatomyositis, the percentage of patients with a response of at least minimal improvement based on a composite score of disease activity was significantly greater among those who received IVIG than among those who received placebo. IVIG was associated with adverse events, including thromboembolism. (Funded by Octapharma Pharmazeutika; ProDERM ClinicalTrials.gov number, NCT02728752.).

Liquid biopsy to detect resistance mutations against anti-epidermal growth factor receptor therapy in metastatic colorectal cancer.

Colorectal cancer (CRC) is a major cause of mortality worldwide, associated with a steadily growing prevalence. Notably, the identification of KRAS, NRAS, and BRAF mutations has markedly improved targeted CRC therapy by affording treatments directed against the epidermal growth factor receptor (EGFR) and other anti-angiogenic therapies. However, the survival benefit conferred by these therapies remains variable and difficult to predict, owing to the high level of molecular heterogeneity among patients with CRC. Although classification into consensus molecular subtypes could optimize response prediction to targeted therapies, the acquisition of resistance mutations to targeted therapy is, in part, responsible for the lack of response in some patients. However, the acquisition of such mutations can induce challenges in clinical practice. The utility of liquid biopsy to detect resistance mutations against anti-EGFR therapy has recently been described. This approach may constitute a new standard in the decision algorithm for targeted CRC therapy.

Cinaciguat (BAY-582667) Modifies Cardiopulmonary and Systemic Circulation in Chronically Hypoxic and Pulmonary Hypertensive Neonatal Lambs in the Alto Andino.

Neonatal pulmonary hypertension (NPHT) is produced by sustained pulmonary vasoconstriction and increased vascular remodeling. Soluble guanylyl cyclase (sGC) participates in signaling pathways that induce vascular vasodilation and reduce vascular remodeling. However, when sGC is oxidized and/or loses its heme group, it does not respond to nitric oxide (NO), losing its vasodilating effects. sGC protein expression and function is reduced in hypertensive neonatal lambs. Currently, NPHT is treated with NO inhalation therapy; however, new treatments are needed for improved outcomes. We used Cinaciguat (BAY-582667), which activates oxidized and/or without heme group sGC in pulmonary hypertensive lambs studied at 3,600 m. Our study included 6 Cinaciguat-treated (35 ug kg-1 day-1 x 7 days) and 6 Control neonates. We measured acute and chronic basal cardiovascular variables in pulmonary and systemic circulation, cardiovascular variables during a superimposed episode of acute hypoxia, remodeling of pulmonary arteries and changes in the right ventricle weight, vasoactive functions in small pulmonary arteries, and expression of NO-sGC-cGMP signaling pathway proteins involved in vasodilation. We observed a decrease in pulmonary arterial pressure and vascular resistance during the acute treatment. In contrast, the pulmonary pressure did not change in the chronic study due to increased cardiac output, resulting in lower pulmonary vascular resistance in the last 2 days of chronic study. The latter may have had a role in decreasing right ventricular hypertrophy, although the direct effect of Cinaciguat on the heart should also be considered. During acute hypoxia, the pulmonary vascular resistance remained low compared to the Control lambs. We observed a higher lung artery density, accompanied by reduced smooth muscle and adventitia layers in the pulmonary arteries. Additionally, vasodilator function was increased, and vasoconstrictor function was decreased, with modifications in the expression of proteins linked to pulmonary vasodilation, consistent with low pulmonary vascular resistance. In summary, Cinaciguat, an activator of sGC, induces cardiopulmonary modifications in chronically hypoxic and pulmonary hypertensive newborn lambs. Therefore, Cinaciguat is a potential therapeutic tool for reducing pulmonary vascular remodeling and/or right ventricular hypertrophy in pulmonary arterial hypertension syndrome.

Secukinumab in United States Biologic-Naïve Patients With Psoriatic Arthritis: Results From the Randomized, Placebo-Controlled CHOICE Study.

OBJECTIVE: To evaluate secukinumab (SEC) 300 mg and 150 mg vs placebo in a United States-only population of biologic-naïve patients with psoriatic arthritis (PsA). METHODS: CHOICE was a double-blind, randomized controlled trial conducted in the US. Biologic-naïve patients with PsA and psoriasis (PsO) were randomized 2:2:1 to SEC 300 mg (n = 103), SEC 150 mg (n = 103), or placebo (n = 52). The primary objective was to show superiority of SEC 300 mg vs placebo in American College of Rheumatology 20% (ACR20) response at week 16. Additional objectives included the effect of SEC on dactylitis, enthesitis, PsO, and safety. RESULTS: ACR20 response rates at week 16 were higher with SEC 300 mg than with placebo (51.5% vs 23.1%; odds ratio 3.51 [95% CI 1.65-7.45]; P = 0.001). SEC 300 mg also led to greater ACR50/70 responses and improvements in other variables vs placebo. Responses were generally sustained over time. Patients with inadequate response to SEC 150 mg at weeks 16, 28, or 40 who received dose escalation to 300 mg experienced improved clinical response after uptitration. The most common adverse events were upper respiratory tract infections and diarrhea. No inflammatory bowel disease was reported or new safety signals observed. CONCLUSION: SEC 300 mg led to rapid and significant improvements over placebo in symptoms of PsA in this heavier population of US-only, biologic-naïve patients. Findings were consistent with previous studies and suggest that SEC 300 mg is a safe and efficacious first-line biologic treatment for patients with PsA. [ClinicalTrials.gov: NCT02798211].

Prevalence of the number of pre-gestational diagnoses and trends in the United States in 2006 and 2016.

INTRODUCTION: There is a trend in reproductive-aged women to live with more chronic conditions, likely resulting in pregnancies complicated by one or more pre-gestational diagnoses. The objective of this study is to determine the prevalence of women with pre-gestational diagnoses and pregnancy-related complications, and assess the trends of pre-gestational diagnoses between two time-points, ten-years apart from 2006 to 2016. MATERIALS AND METHODS: We abstracted pregnant patients from the Healthcare Cost and Utilization Project's National Inpatient Sample by the Agency for Healthcare Research and Quality in 2006 and 2016. We classified diagnosis codes, ICD 9 for 2006 and ICD 10 for 2016, as pre-gestational diagnoses or as pregnancy-related complications. Descriptive statistics were presented as frequencies and proportions for categorical variables. Chi-square analysis was performed. All statistical analyses were two-sided and p-value < .05 was considered to be statistically significant. RESULTS: Between 2006 and 2016, the percentage of patients with at least one pre-gestational diagnoses increased from 35.3% in 2006 to 53.8% in 2016 (p < .0001) and the percentage of patients with at least one pregnancy-related complication increased from 62.6% to 69.1% (p < .0001). We found a trend of increasing pregnancy-related complications with an increasing number of pre-gestational diagnoses. The prevalence of asthma and obesity, either alone or in combination were found to rise over the ten-year time span. CONCLUSION: The percent of patients entering pregnancy with any pre-gestational diagnosis has increased, along with the number of pregnancy-related complications. Future research is needed to understand the effects of these diagnoses in combination and the possible impact on pregnancy outcomes.

Outpatient Cervical Ripening With Misoprostol in Low-Risk Pregnancies.

Objective To determine if outpatient cervical ripening with daily misoprostol can reduce admission to delivery time in women with low-risk pregnancies at 39 or more weeks of gestation. Study design This is a retrospective cohort study of a convenience sample of low-risk pregnancies that underwent elective outpatient cervical ripening compared to matched controls for parity (nulliparous vs. parous) and gestational age. Time from admission to delivery, induction agents, presence of tachysystole, mode of delivery, length of hospitalization, neonatal intensive care unit (NICU) admission, and low Apgar scores were compared. Results Fifty-six patients who underwent outpatient cervical ripening with daily dosing of misoprostol were compared to 56 patients matched for parity and gestational weeks who underwent inpatient cervical ripening/induction of labor with misoprostol. We found the time from admission to delivery in the outpatient cervical ripening cohort was significantly lesser than the inpatient cohort (17.5 ± 11.5 hours outpatient vs. 26.6 ± 15.6 hours inpatient, P=0.001). More patients (N=18, 32%) were able to deliver within 12 hours of admission in the outpatient induction group compared to the inpatient group (N=8, 11%, P=0.010). There were no differences in frequency of cesarean delivery, uterine tachysystole with or without fetal heart rate changes, NICU admission, low Apgar scores, or low umbilical artery pH values between the two groups. Conclusion Outpatient cervical ripening with misoprostol may be a feasible alternative to inpatient cervical ripening in low-risk pregnancies, may help improve patient experience, and reduce the operational burden that elective induction confers upon labor and delivery units.

Consensus molecular subtypes of colorectal cancer in clinical practice: A translational approach.

The identification of several genetic mutations in colorectal cancer (CRC) has allowed a better comprehension of the prognosis and response to different antineoplastic treatments. Recently, through a systematic process, consensus molecular subtypes (CMS) have been described to characterize genetic and molecular mutations in CRC patients. Through CMS, CRC patients can be categorized into four molecular subtypes of CRC by wide transcriptional genome analysis. CMS1 has microsatellite instability and mutations in CIMP and BRAF pathways. CMS2, distinguished by mutations in specific pathways linked to cellular metabolism, also has a better prognosis. CMS3 has a KRAS mutation as a hallmark. CMS4 presents mutations in fibrogenesis pathways and mesenchymal-epithelial transition, associated with a worse prognosis. CMS classification can be a meaningful step in providing possible answers to important issues in CRC, such as the use of adjuvant chemotherapy in stage II, personalized first-line chemotherapy for metastasic CRC, and possible new target treatments that address specific pathways in each molecular subtype. Understanding CMS is a crucial step in personalized medicine, although prospective clinical trials selecting patients by CMS are required to pass proof-of-concept before becoming a routine clinical tool in oncology routine care.

Common Combinations of Pregestational Diagnosis and Pregnancy Complications.

Objective Single pregestational diagnoses have been demonstrated to be associated with pregnancy-related complications. But, the effect of multiple diagnoses is understudied. The objective of this study is to determine the most common combinations of pregestational diagnoses and to determine if specific combinations increase the risk of pregnancy-related complications. Study design We performed a cross-sectional study of the 2016 Healthcare Cost and Utilization Project's National Inpatient Sample (HCUP NIS) database. Inclusion criteria were: Diagnosis-related groups assumed to be associated with delivery, and three or fewer International Classification of Diseases, Tenth Revision (ICD-10), clinical modification codes with a prevalence greater than or equal to 0.5%, or clinically important risk factors in Bateman's co-morbidity index. Chi-squared analysis of combinations of pregestational diagnoses was performed to assess the relative risk of pregnancy-related complications. Results The 2016 database included 255,233 delivered pregnancies. The most common combinations of pregestational diagnoses involved advanced maternal age, prior cesarean delivery, obesity, and tobacco use. Most combinations did not demonstrate an increased risk for complications greater than the risk with a single diagnosis. In those with statistically significant risk, all were 3-fold or less except we noted a 4.4-fold higher risk (95% CI: 3.16-6.15) of preeclampsia in obese patients of advanced maternal age compared to patients who were only of advanced maternal age. Conclusion Our results revealed that common combinations of pregestational diagnoses, in general, do not increase the risk for common pregnancy-related complications greater than the risk with a single diagnosis. This is reassuring, given that women entering pregnancy with multiple co-morbidities are becoming more common.

Efficacy of Long-Term Treatment with Once-Daily Baricitinib 2 mg in Patients with Active Rheumatoid Arthritis: Post Hoc Analysis of Two 24-Week, Phase III, Randomized, Controlled Studies and One Long-Term Extension Study.

INTRODUCTION: To evaluate long-term efficacy of once-daily baricitinib 2 mg in patients with active rheumatoid arthritis who had an inadequate response (IR) to conventional synthetic disease-modifying antirheumatic drugs (csDMARD) or biologic DMARDs (bDMARD). METHODS: Data from patients treated with baricitinib 2 mg daily in two 24-week, phase III studies, RA-BUILD (csDMARD-IR; NCT01721057) and RA-BEACON (bDMARD-IR; NCT01721044), and one long-term extension study (RA-BEYOND; NCT01885078), were analyzed (120 weeks). The main outcomes were achievement of low-disease activity (LDA; Simple Disease Activity Index [SDAI] ≤ 11), clinical remission (SDAI ≤ 3.3), Health Assessment Questionnaire Disability Index (HAQ-DI) ≤ 0.5 and improvement from baseline of ≥ 0.22, and safety. Analysis populations included (1) all patients and (2) never-rescued patients. Completer and non-responder imputation (NRI) analyses were conducted on each population. RESULTS: In RA-BUILD, 684 were randomized (229 to baricitinib 2 mg, 180 of whom completed RA-BUILD and entered RA-BEYOND). In RA-BEACON, 527 were randomized (174 to baricitinib 2 mg, 117 of whom completed RA-BEACON and entered RA-BEYOND). In RA-BUILD-BEYOND, 85.1% (63/74, completer) and 27.5% (63/229, NRI) of csDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 40.5% (30/74, completer) and 13.1% (30/229, NRI) were in SDAI remission; 62.2% (46/74, completer) and 20.1% (46/229, NRI) had HAQ-DI ≤ 0.5 and 81.1% (60/74, completer); and 26.2% (60/229, NRI) achieved ≥ 0.22 change from baseline at week 120. In RA-BEACON-BEYOND, 86.5% (32/37, completer) and 18.4% (32/174, NRI) of bDMARD-IR patients treated with baricitinib 2 mg achieved SDAI LDA; 24.3% (9/37, completer) and 5.2% (9/174, NRI) were in SDAI remission; 50.0% (19/38, completer) and 10.9% (19/174, NRI) had HAQ-DI ≤ 0.5; and 73.7% (28/38, completer) and 16.1% (28/174, NRI) achieved ≥ 0.22 change from baseline at week 120. Rates of adverse events of special interest were consistent with previous reports. CONCLUSIONS: Long-term treatment with baricitinib 2 mg demonstrated efficacy for up to 120 weeks and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01721057, NCT01721044, and NCT01885078.

Hydrogen production automatic control in continuous microbial electrolysis cells reactors used in wastewater treatment.

In this paper, two control laws are proposed and applied in a model for a continuous Microbial Electrochemical Cells system. The used model is based on mass balances describing the behavior of substrate consumption, microbial growth, competition between anodophilic and methanogenic microorganisms for the carbon source in the anode, hydrogen generation, and electrical current production. The main control objective is to improve the electrical current generated and thus the production of bio-hydrogen gas in the reactor, using the dilution rate and the applied potential as individual control input variables. The control laws implemented are nonlinear adaptive type. In order to demonstrate its usefulness, numerical simulation runs involving multiple set-point changes and input perturbations were conducted for each control variable. The results of these simulations show that both control laws were able to respond adequately and efficiently to the disturbances and reach the reference value to which they were subjected. Moreover, it is possible to control both the electrical current produced and the hydrogen produced. Finally, these simulations also show that the highest rate of hydrogen production can be obtained using the applied potential as a control input, but such productivity is only attainable for a short period of time.

Extracorporeal Cardiopulmonary Resuscitation in Acute Fulminant Myocarditis: A Case Report and Review of the Literature.

Fulminant myocarditis is a life-threatening fast progressive condition. We present a 7-year-old female patient admitted with a diagnosis of acute myocarditis with a rapidly progressive cardiac dysfunction despite conventional vasoactive and inotropic treatment. The patient presented with ventricular fibrillation and subsequent cardiac arrest. Cardiopulmonary resuscitation (CPR) was performed during 105 minutes before extracorporeal membrane oxygenation (ECMO) cannulation was performed. Effective hemodynamic function was obtained, and ECMO was weaned after 7 days, without neurological complications. There are not established extracorporeal cardiopulmonary resuscitation (eCPR) treatment criteria, and some international guidelines consider up to 100 minutes of "low flow" phase as a time limit to start the support. Some mortality risk factors for ECMO treatment mortality are female gender, renal failure, and arrhythmias. Pre-ECMO good prognostic factors are high levels of pH and blood lactate.

Management of cancer patients during COVID-19 pandemic at developing countries.

Cancer patient care requires a multi-disciplinary approach and multiple medical and ethical considerations. Clinical care during a pandemic health crisis requires prioritising the use of resources for patients with a greater chance of survival, especially in developing countries. The coronavirus disease 2019 crisis has generated new challenges given that cancer patients are normally not prioritised for admission in critical care units. Nevertheless, the development of new cancer drugs and novel adjuvant/neoadjuvant protocols has dramatically improved the prognosis of cancer patients, resulting in a more complex decision-making when prioritising intensive care in pandemic times. In this context, it is essential to establish an effective and transparent communication between the oncology team, critical care, and emergency units to make the best decisions, considering the principles of justice and charity. Concurrently, cancer treatment protocols must be adapted to prioritise according to oncologic response and prognosis. Communication technologies are powerful tools to optimise cancer care during pandemics, and we must adapt quickly to this new scenario of clinical care and teaching. In this new challenging pandemic scenario, multi-disciplinary work and effective communication between clinics, technology, science, and ethics is the key to optimising clinical care of cancer patients.

Colorectal Cancer Diagnosed During Pregnancy With Delayed Treatment.

Colorectal cancer during pregnancy is rare. Because of a pattern of delay in childbearing and because colorectal cancer is now diagnosed more often in young adults, the incidence is expected to rise. Diagnosis during pregnancy is challenging as many of the symptoms mimic common pregnancy symptoms. Colonoscopy is the gold standard for diagnosis, but pregnancy is a relative contraindication to colonoscopy. Once diagnosed, pregnant women often have more advanced disease. Due to its rarity, treatment is often based on case reports and limited studies. A multidisciplinary team is important in the optimization of treatment. We present a case of a 29-year-old African-American primigravid with chronic gastrointestinal symptoms diagnosed with colorectal adenocarcinoma at 17 weeks of gestation. She delayed surgical intervention for several weeks due to fear of miscarriage, and ultimately underwent exploratory laparotomy with hemicolectomy and colostomy placement at 20 weeks. Abdominal ultrasound and magnetic resonance imaging revealed non-specific hepatic lesions concerning for metastatic disease, but the patient refused biopsy due to concern for radiation harm to the fetus. Chemotherapy was considered, but postponed until the postpartum period, for fear of fetal harm. Computed tomography imaging after delivery noted an increased number of hepatic lesions, representing progression of her disease. She received two rounds of chemotherapy in the postpartum period, but remained non-compliant with treatment recommendations and ultimately was lost to follow-up.  This case presents a delayed diagnosis of colorectal cancer in pregnancy, as well as delayed treatment due to concerns for fetal harm with current therapies. It emphasizes the diagnostic challenges and the complexity and ethical issues involved when a pregnant patient faces a life-threatening terminal illness. This case adds to the growing body of literature on colorectal cancer in pregnancy and highlights the importance of clinical suspicion, informed patient centered decision making, and tailored treatment goals.

The Proteasomal Deubiquitinating Enzyme PSMD14 Regulates Macroautophagy by Controlling Golgi-to-ER Retrograde Transport.

Ubiquitination regulates several biological processes, however the role of specific members of the ubiquitinome on intracellular membrane trafficking is not yet fully understood. Here, we search for ubiquitin-related genes implicated in protein membrane trafficking performing a High-Content siRNA Screening including 1187 genes of the human "ubiquitinome" using amyloid precursor protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a novel regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing or pharmacological inhibition of PSMD14 with Capzimin (CZM) caused a robust increase in APP levels at the Golgi apparatus and the swelling of this organelle. We showed that this phenotype is the result of rapid inhibition of Golgi-to-ER retrograde transport, a pathway implicated in the early steps of the autophagosomal formation. Indeed, we observed that inhibition of PSMD14 with CZM acts as a potent blocker of macroautophagy by a mechanism related to the retention of Atg9A and Rab1A at the Golgi apparatus. As pharmacological inhibition of the proteolytic core of the 20S proteasome did not recapitulate these effects, we concluded that PSMD14, and the K63-Ub chains, act as a crucial regulatory factor for macroautophagy by controlling Golgi-to-ER retrograde transport.