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The development of vaccines has significantly contributed to the success of disease prevention. However, there has been a sharp decline in immunization rates since COVID-19 spread globally. Seemingly overnight, the world shut down and most non-essential medical procedures were postponed. Since the COVID-19 vaccine became available, and the world started going back to normal these vaccine rates have not recovered. In this paper, we review the published literature to explore how convenience factors, perceived risk of vaccination, media or anti-vaccination ideals/movements, and healthcare professionals affect an individual’s compliance to be vaccinated to better understand the factors that contribute to the change in overall vaccination rates.

The COVID-19 pandemic changed our world as we know it and continues to be a global problem three years since the pandemic began. Several vaccines were produced, but there was a considerable amount of societal turmoil surrounding them that has affected the way people view not only COVID-19 vaccines but all vaccines. We used a survey to compare how attitudes towards vaccination have changed in college students during the pandemic. An initial survey was administered in 2021, then a follow-up in 2022. Out of 316 respondents who answered the first survey, 192 completed the follow-up. The survey was designed to measure trends in changes to vaccine attitudes since the COVID-19 pandemic began. By comparing the first survey in 2021 and the follow-up, we found that roughly 55% of respondents’ vaccine attitudes did not change, roughly 44% of respondents’ attitudes towards vaccines became more positive, and only about 1% of the respondents’ vaccine attitudes became more negative. Improved view of vaccines was associated with political views and increased trust in medicine and the healthcare system. Worsened opinions of vaccines were associated with a belief that the COVID-19 vaccine affected fertility.

Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States. Most infections are mild and clear without treatment in 1 to 2 years. Some HPV strains result in persistent infection, which can cause various cancers, including cervical, penile, anal, mouth, and throat cancers. Vaccines have been developed that provide protection against the highest risk HPV strains. Despite HPV vaccines having been proven to be safe and effective, uptake has been low. Religiosity has been negatively correlated with HPV vaccine uptake in some studies. It is hypothesized that religiosity and Christian religious affiliation could impact parents’ decision to vaccinate their children against HPV via teachings and beliefs about sexual behaviors. A survey was distributed to participants to determine what factors, including religiosity and views about sex, impacted HPV vaccination. The survey results (n = 442) were analyzed using confirmatory factor analysis, structural equation modeling, and univariate factor analysis. The association between religious practice and vaccine attitudes were complex, with religious practice slightly positively correlated with pro-vaccine attitudes and vaccine knowledge, but also with the belief that religious adherence to expectations surrounding sexual behavior will protect children from HPV infection, as well as more negative views towards vaccines, in general.

The genetic and molecular basis of flagellar motility has been investigated for several decades, with innovative research strategies propelling advances at a steady pace. Furthermore, as the phenomenon is examined in diverse bacteria, new taxon-specific regulatory and structural features are being elucidated. Motility is also a straightforward bacterial phenotype that can allow undergraduate researchers to explore the palette of molecular genetic tools available to microbiologists. This study, driven primarily by undergraduate researchers, evaluated hundreds of flagellar motility mutants in the Gram-negative plant-associated bacterium Agrobacterium fabrum . The nearly saturating screen implicates a total of 37 genes in flagellar biosynthesis, including genes of previously unknown function.

Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (41 [16%] of 252]), fatigue (37 [15%]), elevated aspartate aminotransferase (33 [13%]), and elevated alanine aminotransferase (24 [10%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (78 [31%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission. Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.

Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia. We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed. Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2. Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses. Ambit Biosciences/Daiichi Sankyo.

The genetic and molecular basis of flagellar motility has been investigated for several decades, with innovative research strategies propelling advances at a steady pace. Furthermore, as the phenomenon is examined in diverse bacteria, new taxon-specific regulatory and structural features are being elucidated. Motility is also a straightforward bacterial phenotype that can allow undergraduate researchers to explore the palette of molecular genetic tools available to microbiologists. This study, driven primarily by undergraduate researchers, evaluated hundreds of flagellar motility mutants in the Gram-negative plant-associated bacterium Agrobacterium fabrum. The nearly saturating screen implicates a total of 37 genes in flagellar biosynthesis, including genes of previously unknown function.

Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50–1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41. From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50–1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4–30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. Kura Oncology.

Among patients with IDH1 -mutated relapsed or refractory leukemia, daily oral ivosidenib, an IDH1 inhibitor, induced molecular clearance of leukemic cells from bone marrow in 21% of patients and was associated with transfusion independence and a low rate of serious adverse events.

Background and Objective Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib. Methods The pharmacokinetic profile of gilteritinib was assessed from five clinical studies. Results Dose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20–450 mg). Median maximum concentration was reached 2–6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function. Conclusions Gilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment. Clinical Trial Registration NCT02014558, NCT02456883, NCT02571816.