The TICL reconstruction at the CMS Phase-2 High Granularity Calorimeter Endcap

To sustain the harsher conditions of the high-luminosity LHC, the CMS Collaboration is designing a novel endcap calorimeter system. The new calorimeter will predominantly use silicon sensors to achieve sufficient radiation tolerance and will maintain highly granular information in the readout to help mitigate the effects of the pile up. In regions characterized by lower radiation levels, small scintillator tiles with individual SiPM on-tile readout are employed. A unique reconstruction framework (TICL The Iterative CLustering) is being developed within the CMS Software CMSSW to fully exploit the granularity and other significant detector features, such as particle identification and precision timing, with a view to mitigating pile up in the very dense environment of HL-LHC. The TICL framework has been thought of with heterogeneous computing in mind the algorithms and their data structures are designed to be executed on GPUs. In addition, geometry agnostic data structures have been designed to provide fast navigation and searching capabilities. Seeding capabilities (also exploiting information coming from other detectors), dynamic cluster masking, energy calibration, and particle identification are the main components of the framework. To allow for maximal flexibility, TICL allows the composition of different combinations of modules that can be chained together in an iterative fashion. The presenter will describe the design of TICL pattern recognition algorithms and advanced neural networks under development, as well as future plans

Interaction of Antifungal Drugs with CYP3A- and OATP1B-Mediated Venetoclax Elimination

Venetoclax, a BCL-2 inhibitor used to treat certain hematological cancers, exhibits low oral bioavailability and high interpatient pharmacokinetic variability. Venetoclax is commonly administered with prophylactic antifungal drugs that may result in drug interactions, of which the underlying mechanisms remain poorly understood. We hypothesized that antifungal drugs may increase venetoclax exposure through inhibition of both CYP3A-mediated metabolism and OATP1B-mediated transport. Pharmacokinetic studies were performed in wild-type mice and mice genetically engineered to lack all CYP3A isoforms, or OATP1B2 that received venetoclax alone or in combination with ketoconazole or micafungin. In mice lacking all CYP3A isoforms, venetoclax AUC was increased by 1.8-fold, and pretreatment with the antifungal ketoconazole further increased venetoclax exposure by 1.6-fold, despite the absence of CYP3A. Ensuing experiments demonstrated that the deficiency of OATP1B-type transporters is also associated with increases in venetoclax exposure, and that many antifungal drugs, including micafungin, posaconazole, and isavuconazole, are inhibitors of this transport mechanism both in vitro and in vivo. These studies have identified OATP1B-mediated transport as a previously unrecognized contributor to the elimination of venetoclax that is sensitive to inhibition by various clinically-relevant antifungal drugs. Additional consideration is warranted when venetoclax is administered together with agents that inhibit both CYP3A-mediated metabolism and OATP1B-mediated transport

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708

Non classical risk factors for gestational diabetes mellitus: a systematic review of the literature Fatores de risco não clássicos para diabetes mellitus gestacional: uma revisão sistemática da literatura

Age, obesity and family history of diabetes are well known risk factors for gestational diabetes mellitus. Others are more controversial. The objective of this review is to find evidence in the literature that justifies the inclusion of these other conditions among risk factors. The MEDLINE, Cochrane, LILACS and Pan American Health Organization databases were searched, covering articles dating from between 1992 and 2006. Keywords were used in combination (AND) with gestational diabetes mellitus separately and with each one of the risk factors studied. The methodological quality of the studies included was assessed, resulting in the selection of 41 papers. Most studies investigating maternal history of low birth weight, low stature, and low level of physical activity have found positive associations with gestational diabetes mellitus. Low socioeconomic levels, smoking during pregnancy, high parity, belonging to minority groups, and excessive weight gain during pregnancy presented conflicting results. Publication bias cannot be ruled out. Standardization of techniques, cutoff points for screening and diagnosis, as well as studies involving larger sample sizes would allow future meta-analyses.<br>Idade, obesidade e história familiar de diabetes são fatores de risco bem conhecidos para diabetes mellitus gestacional. Outros são controversos. O objetivo desta revisão é encontrar evidências na literatura que justifiquem a inclusão dessas condições entre os fatores de risco. Bases de dados MEDLINE, Cochrane, LILACS e Organização Pan-Americana da Saúde foram procuradas. A revisão incluiu artigos de 1992 a 2006. Palavras-chave foram usadas em combinação com diabetes mellitus gestacional separadamente e com cada um dos fatores de risco estudados. A qualidade metodológica dos estudos incluídos foi medida, totalizando 41 estudos. A maioria dos trabalhos que investigaram história materna de baixo peso, baixa estatura e baixa atividade física encontrou associação positiva com diabetes mellitus gestacional. Baixo nível sócio-econômico, fumo durante a gestação, alta paridade, pertencer a minorias e excessivo ganho de peso apresentam resultados conflitantes. Padronização de técnicas, pontos de corte para rastreamento e diagnóstico, assim como estudos envolvendo maiores amostras podem permitir futuras metanálises

Antihypertensive treatment changes and related clinical outcomes in older hospitalized patients

Background: Hypertension management in older patients represents a challenge, particularly when hospitalized. Objective: The objective of this study is to investigate the determinants and related outcomes of antihypertensive drug prescription in a cohort of older hospitalized patients. Methods: A total of 5671 patients from REPOSI (a prospective multicentre observational register of older Italian in-patients from internal medicine or geriatric wards) were considered; 4377 (77.2%) were hypertensive. Minimum treatment (MT) for hypertension was defined according to the 2018 ESC guidelines [an angiotensin-converting-enzyme-inhibitor (ACE-I) or an angiotensin-receptor-blocker (ARB) with a calcium-channel-blocker (CCB) and/or a thiazide diuretic; if &gt;80 years old, an ACE-I or ARB or CCB or thiazide diuretic]. Determinants of MT discontinuation at discharge were assessed. Study outcomes were any cause rehospitalization/all cause death, all-cause death, cardiovascular (CV) hospitalization/death, CV death, non-CV death, evaluated according to the presence of MT at discharge. Results: Hypertensive patients were older than normotensives, with a more impaired functional status, higher burden of comorbidity and polypharmacy. A total of 2233 patients were on MT at admission, 1766 were on MT at discharge. Discontinuation of MT was associated with the presence of comorbidities (lower odds for diabetes, higher odds for chronic kidney disease and dementia). An adjusted multivariable logistic regression analysis showed that MT for hypertension at discharge was associated with lower risk of all-cause death, all-cause death/hospitalization, CV death, CV death/hospitalization and non-CV death. Conclusions: Guidelines-suggested MT for hypertension at discharge is associated with a lower risk of adverse clinical outcomes. Nevertheless, changes in antihypertensive treatment still occur in a significant proportion of older hospitalized patients