Overnight stay in Spanish emergency departments and mortality in older patients.

To assess whether older adults who spend a night in emergency departments (ED) awaiting admission are at increased risk of mortality. This was a retrospective review of a multipurpose cohort that recruited all patients ≥ 75 years who visited ED and were admitted to hospital on April 1 to 7, 2019, at 52 EDs across Spain. Study groups were: patients staying in ED from midnight until 8:00 a.m. (ED group) and patients admitted to a ward before midnight (ward group). The primary endpoint was in-hospital mortality, truncated at 30 days, and secondary outcomes assessed length of stay for the index episode. The sample comprised 3,243 patients (median [IQR] age, 85 [81-90] years; 53% women), with 1,096 (34%) in the ED group and 2,147 (66%) in the ward group. In-hospital mortality for patients spending the night in the ED the ED group was 10.7% and 9.5% for patients transferred to a ward bed before midnight the ward group (adjusted OR: 1.12, 95%CI: 0.80-1.58). Sensitivity analyses rendered similar results (ORs ranged 1.06-1.13). Interaction was only detected for academic/non-academic hospitals (p < 0.001), with increased mortality risk for the latter (1.01, 0.33-3.09 vs 2.86, 1.30-6.28). There were no differences in prolonged hospitalization (> 7 days), with adjusted OR of 1.16 (0.94-1.43) and 1.15 (0.94-1.42) depending on whether time spent in the ED was or was not taken into consideration. No increased risk of in-hospital mortality or prolonged hospitalization was found in older patients waiting overnight in the ED for admission. Nonetheless, all estimations suggest a potential harmful effect of staying overnight, especially if a proper bedroom and hospitalist ward bed and hospitalized care are not provided.

Antiviral treatment for SARS-CoV-2 infection in the current situation: a position paper of the Spanish Society of Emergency Medicine (SEMES). / Posicionamiento de la Sociedad Española de Medicina de Urgencias y Emergencias (SEMES) ante el tratamiento antiviral frente al SARS-CoV-2 en la situación epidemiológica actual.

SUMMARY: COVID-19 continues to pose a significant threat: mortality stands at nearly twice that of influenza, and the incidence rate is growing as the population's vaccination rate decreases, particularly in Spain and other areas of Europe. Given this situation, it is vitally important know whether medical protocols are consistent and appropriately implemented by health care staff in the interest of preventing possible inefficiency or inequity. Physicians from hospital emergency departments met to study their hospitals' usual clinical practices for managing SARS-CoV-2 infection and to determine their expert opinions on the use of antiviral agents. The participating physicians then reached consensus on evidencebased recommendations for strategies that would optimize emergency treatment.

RESUMEN: Actualmente, la COVID-19 sigue representando una amenaza significativa, con una mortalidad cercana al doble de la ocasionada por la gripe y con una incidencia variable debido a una disminución en la tasa de vacunación de la población, especialmente en el contexto europeo y español. Ante este panorama, es de vital importancia comprobar que los protocolos médicos están consolidados y son debidamente implementados por los profesionales sanitarios, con la finalidad de evitar posibles ineficiencias o inequidades. A través de reuniones con profesionales de urgencias se han observado las prácticas clínicas habituales en los servicios de urgencias hospitalarios para pacientes con infección por SARS-CoV-2, con la finalidad de comprender la perspectiva de estos profesionales acerca del uso de antivirales y, tras un consenso de expertos basados en la evidencia actual, se han generado estas de recomendaciones para poder enfocar estrategias que optimicen el tratamiento de los pacientes en estos servicios.

Epidemiological and clinical management aspects of pneumonias diagnosed in the emergency department in elderly patients in Spain: Results of the EDEN-29 study.

OBJECTIVES: To estimate the incidence of pneumonia diagnosis in elderly patients in Spanish emergency departments (ED), need for hospitalization, adverse events and predictive capacity of biomarkers commonly used in the ED. METHODS: Patients ≥65 years with pneumonia seen in 52 Spanish EDs were included. We recorded in-hospitaland 30-day mortality as adverse events, as well as intensive care unit (ICU) admission among hospitalizedpatients. Association of 10 predefined variables with adverse events was calculated and expressed as odds ratio (OR) with 95% confidence interval (CI), as well as predictive capacity of 5 commonly used biomarkers in the ED (leukocytes, hemoglobin, C-reactive protein, glucose, creatinine) was investigated using area under the receiver operating characteristic curve (AUC-ROC). RESULTS: 591 patients with pneumonia attended in the ED were included (annual incidence of 18,4 per 1000 inhabitants). A total of 78.0% were hospitalized. Overall, 30-day mortality was 14.2% and in-hospital mortality was 12.9%. Functional dependency was associated with both events (OR=4.453, 95%CI=2.361-8.400; and OR=3.497, 95%CI=1.578-7.750, respectively) as well as severe comorbidity (2.344, 1.363-4.030, and 2.463, 1.252-4.846, respectively). Admission to the ICU during hospitalization occurred in 3.5%, with no associated factors. The predictive capacity of biomarkers was only moderate for creatinine for ICU admission (AUC-ROC=0.702, 95% CI=0.536-0.869) and for leukocytes for post-discharge adverse event (0.669, 0.540-0.798). CONCLUSIONS: Pneumonia is a frequent diagnosis in elderly patients consulting in the ED. Their functional dependence and comorbidity is the factor most associated with adverse events. The biomarkers analyzed do not have a good predictive capacity for adverse events.

Gene expression profiling of cultured mouse testis fragments treated with ethinylestradiol.

The assessment of xenobiotic-induced testicular toxicity is important in drug development. Nonetheless, in vitro models to test drugs and chemicals that may cause testicular toxicity are lacking, requiring the continued use of animal models for those studies. We previously evaluated an in vitro mouse testis organ culture system using ethinylestradiol (EE), a well-studied testicular toxicant, and demonstrated a dose-dependent relationship between adverse effects to germ cell differentiation and increasing EE concentrations. However, we terminated that study after 20 days of culture due to oxygen deficiency during germ cell differentiation. Therefore, in the current study, we aimed to identify gene(s) with potential for supporting the histopathological evaluations of testicular toxicity using in vitro testis organ culture system. We cultured testis fragments obtained from mice at postnatal day (PND) 5 in α-Minimal Essential Medium containing 40 mg/mL AlbuMAX™ I and treated them with 0.01 or 1 nM EE on day 1 of culture. On day 20, we collected testis fragments for RNA sequencing analysis and quantitative polymerase chain reaction (qPCR). We found that phospholipase C, zeta 1 and testis-specific serine kinase 4 genes, that are involved in spermatogenesis and predominantly expressed in the testis, were significantly reduced in testis fragments treated with the highest concentration of EE. Also, cytochrome P450, family 26, subfamily b, polypeptide 1 (Cyp26b1) and interleukin 16 (Il16) were up-regulated in the highest EE-treated groups. Further studies are needed to confirm the variations of these gene expression using other testicular toxicants.

FDA Approval Summary: Glasdegib for Newly Diagnosed Acute Myeloid Leukemia.

On November 21, 2018, the FDA approved glasdegib (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, in combination with low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy. Evidence of clinical benefit came from Study BRIGHT AML 1003, a randomized trial comparing glasdegib+LDAC with LDAC alone for treatment of newly diagnosed AML in 115 patients either ≥ 75 years old or ≥ 55 years old with preexisting comorbidities. Efficacy was established by improved overall survival (OS) with the combination compared with LDAC alone (HR, 0.46; 95% confidence interval, 0.30-0.71; one-sided stratified log-rank P = 0.0002). Median OS was 8.3 months with the combination and 4.3 months with LDAC alone. Common adverse reactions included cytopenias, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. The label includes a boxed warning for embryo-fetal toxicity and a warning for QT interval prolongation. There is a limitation of use for patients with moderate-to-severe hepatic and severe renal impairment; trials studying glasdegib in these patient populations are required as a condition of this approval.See related commentary by Fathi, p. 6015.

Testicular function in cultured postnatal mouse testis fragments is similar to that of animals during the first wave of spermatogenesis.

BACKGROUND: Previously, we evaluated optimal organ culture conditions to produce elongated spermatids in an in vitro mouse testis culture system. However, differences in testicular function between the cultured testis fragments and animal testis have not been determined. METHODS: To examine how closely cultured testis fragments in vitro approximates what typically occurs during the first wave of spermatogenesis in vivo, C57BL/6J mouse testis fragments obtained on postnatal day (PND) 5 were cultured in AlbuMAX™ I/ α-Minimal Essential Medium for 15, 23, 30, 35, 42, and 49 days, and compared to mouse testes obtained at PND 5, 14, 20, 24, 28, 30, 35, and 40. At the specified days of culture or PND of mice, the following analyses were conducted: histology, flow cytometry for haploid cell detection, qPCR for spermatid markers, and liquid chromatography/mass spectrometry for testosterone levels. RESULTS: Round spermatids were initially observed at 23 days, and their percentage of the total number of cells continued to increase with culture time, as did gene expression of the spermatid markers and haploid cell percentage in the cultured testis fragments. These results were similar in temporal sequence to those in animals. Testosterone levels in the testis fragments reached a maximum at Day 49. CONCLUSION: These findings show this in vitro mouse testis organ culture model may be a useful and convenient tool for mechanistic studies. However, because germ cell differentiation in all seminiferous tubules was not observed, improvements in the system/methods are needed to more closely replicate spermatogenesis as observed in animals.

Evaluation of an in vitro mouse testis organ culture system for assessing male reproductive toxicity.

BACKGROUND: Development of an in vitro system capable of producing mature sperm remains a challenging goal, with only few successes reported. Such a system, could be used to test agents for potential toxicity to the male reproductive system; to explore this, we exposed immature mouse testis fragments in culture to ethinylestradiol (EE), a well-known testicular toxicant in vivo. METHODS: Testis fragments from postnatal day 5 mice were cultured in Albumax I medium. After 24 hr of culture, fragments were treated with 0.01, 0.1 or 1 nM EE, then harvested after 20 days in culture and examined for histology or gene expression measures by quantitative PCR. RESULTS: There was substantial variability between fragments in the degree of spermatogenesis observed. The percentage of seminiferous tubules containing any dead germ cells increased as a result of EE exposure in a dose dependent fashion. This was accompanied with a decreased percentage of tubules with round spermatids. Expression of estrogen receptor 1, cytochrome P450, family 11, subfamily a, and polypeptide 1 also was reduced, depending on the dose. CONCLUSION: These gene expression changes in the testis fragments are similar to those seen after animals have been exposed to EE. Gene expression changes in testis fragments are encouraging, but the variability across samples will need to be reduced for this in vitro system to become a generally applicable method for assessing testicular toxicants.

FDA Approval: Gemtuzumab Ozogamicin for the Treatment of Adults with Newly Diagnosed CD33-Positive Acute Myeloid Leukemia.

On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51-0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53-0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242-6. ©2018 AACR.

An FDA oncology analysis of CD3 bispecific constructs and first-in-human dose selection.

We retrospectively examined the nonclinical studies conducted with 17 CD3 bispecific constructs in support of first-in-human (FIH) trials in oncology. We also collected information on the design of dose-finding clinical trials. Sponsors have used different MABEL approaches for FIH dose selection. To better assess acceptable approaches, FIH doses were computed from nonclinical studies and compared to the maximum tolerated doses (MTDs) in patients, to the highest human doses (HHDs) when an MTD was not identified, or to the recommended human dose (RHD) for blinatumomab. We concluded that approaches based on receptor occupancy, highest non-severely toxic dose, or no-observed adverse effect level are not acceptable for selecting the FIH dose as they resulted in doses close to or above the MTDs, HHDs, or the RHD. A FIH dose corresponding to 10%-30% pharmacologic activity (PA) was an acceptable approach. A FIH dose corresponding to 50% PA was acceptable for all except one construct, potentially due to its biological or structural properties. The most common toxicities in animals and patients were those related to cytokine release. Doses were better tolerated when intra-animal or intra-patient dose escalation was used. Exposing naïve patients to an MTD achieved with intra-patient dose escalation design may be unsafe.

Evaluation of Culture Time and Media in an In Vitro Testis Organ Culture System.

BACKGROUND: The complexity of spermatogenesis makes development of appropriate in vitro testis models challenging. A novel in vitro mouse testis culture system has been reported but not yet evaluated as an alternative model for male reproductive toxicity testing. We assessed the effects of media composition on sperm differentiation and testis morphology of cultured mouse testis fragments. METHODS: Testes from postnatal day 5 B6:CBA-Tg(Acrv1-EGFP)2727Redd/J male mice were cultured in knockout serum replacement (KSR) or Albumax I (Albumax) medium. Enhanced green fluorescent protein (EGFP) expression was examined on days 35, 42, 45, and 49 of culture. Histology and flow cytometry were performed for testis morphology and spermatid differentiation. RESULTS: EGFP signals were first observed in round spermatids on day 22 of culture (corresponding to postnatal day 27) and were observed until the end of culture, indicating testis-specific protein expression. A-kinase anchor protein 4 expression, a marker of elongated spermatid (step 15-16) occurred earlier in explants cultured in KSR than Albumax medium (typically day 35 and after day 42 of culture, respectively). The percentage of seminiferous tubules with elongated spermatid was higher in Albumax than KSR medium from days 45 to 49 of culture. CONCLUSION: Albumax medium may facilitate or support better morphology and spermatid production than KSR medium. Further studies need to improve spermatid production and refinement of this in vitro testis culture system that may be useful as a supplement to current male reproductive toxicity testing or an alternative model in cases where in vivo testing may be unfeasible. Birth Defects Research 109:465-474, 2017. © 2017 Wiley Periodicals, Inc.

FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma.

On July 3, 2014, the FDA granted accelerated approval for belinostat (Beleodaq; Spectrum Pharmaceuticals, Inc.), a histone deacetylase inhibitor, for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). A single-arm, open-label, multicenter, international trial in the indicated patient population was submitted in support of the application. Belinostat was administered intravenously at a dose of 1000 mg/m(2) over 30 minutes once daily on days 1 to 5 of a 21-day cycle. The primary efficacy endpoint was overall response rate (ORR) based on central radiology readings by an independent review committee. The ORR was 25.8% [95% confidence interval (CI), 18.3-34.6] in 120 patients that had confirmed diagnoses of PTCL by the Central Pathology Review Group. The complete and partial response rates were 10.8% (95% CI, 5.9-17.8) and 15.0% (95% CI, 9.1-22.7), respectively. The median duration of response, the key secondary efficacy endpoint, was 8.4 months (95% CI, 4.5-29.4). The most common adverse reactions (>25%) were nausea, fatigue, pyrexia, anemia, and vomiting. Grade 3/4 toxicities (≥5.0%) included anemia, thrombocytopenia, dyspnea, neutropenia, fatigue, and pneumonia. Belinostat is the third drug to receive accelerated approval for the treatment of relapsed or refractory PTCL.

FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease.

On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. The approval was primarily based on the results of a randomized, double-blind trial in which 79 symptomatic patients with MCD were allocated (2:1) to siltuximab plus best supportive care (BSC) or to placebo plus BSC. The primary efficacy endpoint was the proportion of patients in each arm achieving a durable tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. Tumor response was based on independent review of CT scans using the revised Response Criteria for Malignant Lymphoma, and symptomatic response was defined as complete resolution or stabilization of 34 MCD-related signs and symptoms as reported by the investigator. Thirty-four percent of patients in the siltuximab arm and no patients in the placebo arm met the primary endpoint (P = 0.0012). The most common adverse reactions (>10% compared with placebo) during treatment with siltuximab were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection.

Reparación mediante prótesis de una perforación tras dilatación endoscópica en un paciente con acalasia / Prosthetic repair of perforation after endoscopic dilation in a patient with achalasia

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Characterization of glucose transport by cultured rabbit kidney proximal convoluted and proximal straight tubule cells.

Rabbit kidney proximal convoluted tubule (RPCT) and proximal straight tubule (RPST) cells were independently isolated and cultured. The kinetics of the sodium-dependent glucose transport was characterized by determining the uptake of the glucose analog alpha-methylglucopyranoside. Cell culture and assay conditions used in these experiments were based on previous experiments conducted on the renal cell line derived from the whole kidney of the Yorkshire pig (LLC-PK1). Results indicated the presence of two distinct sodium-dependent glucose transporters in rabbit renal cells: a relatively high-capacity, low-affinity transporter (V(max) = 2.28 +/- 0.099 nmoles/mg protein min, Km = 4.1 +/- 0.27 mM) in RPCT cells and a low-capacity, high-affinity transporter (V(max) = 0.45 +/- 0.076 nmoles/mg protein min, K(m) = 1.7 +/- 0.43 mM) in RPST cells. A relatively high-capacity, low-affinity transporter (V(max) = 1.68 +/- 0.215 nmoles/mg protein min, Km = 4.9 +/- 0.23 mM) was characterized in LLC-PK1 cells. Phlorizin inhibited the uptake of alpha-methylglucopyranoside in proximal convoluted, proximal straight, and LLC-PK1 cells by 90, 50, and 90%, respectively. Sodium-dependent glucose transport in all three cell types was specific for hexoses. These data are consistent with the kinetic heterogeneity of sodium-dependent glucose transport in the S1-S2 and S3 segments of the mammalian renal proximal tubule. The RPCT-RPST cultured cell model is novel, and this is the first report of sodium-dependent glucose transport characterization in primary cultures of proximal straight tubule cells. Our results support the use of cultured monolayers of RPCT and RPST cells as a model system to evaluate segment-specific differences in these renal cell types.