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Telecommunications offers an alternative or supplement to community-based interventions as a means of extending healthcare services and improving health outcomes in remote settings but can fail to reach target communities and achieve the desired impact if barriers to access are not overcome. We conducted seven focus group discussions and 26 interviews with community health workers, community leaders, and female members of the public who declared that they had or had not previously accessed free audio health messages provided via a mobile platform in two rural communities of Mali, Koulikoro and Bougouni. A content analysis showed that participants accessed and trusted health information from a range of sources, including radio, telephone and television, as well as town criers, local relays and community health centres. Barriers to access faced by women included economic factors, lack of network or electricity, and social factors such as illiteracy, cultural restrictions and being unaware of mobile communication. Through analysis and interpretation of the participants' responses, we have made recommendations for future campaigns for the dissemination of health-related information for women in remote settings., (© 2024. The Author(s).)

Musca flies (Diptera: Muscidae) have been found culpable in the mechanical transmission of several infectious agents, including viruses, bacteria, protozoans, and helminths, particularly in low-income settings in tropical regions. In large numbers, these flies can negatively impact the health of communities and their livestock through the transmission of pathogens. In some parts of the world, Musca sorbens is of particular importance because it has been linked with the transmission of trachoma, a leading cause of preventable and irreversible blindness or visual impairment caused by Chlamydia trachomatis, but the contribution these flies make to trachoma transmission has not been quantified and even less is known for other pathogens. Current tools for control and monitoring of house flies remain fairly rudimentary and have focused on the use of environmental management, insecticides, traps, and sticky papers. Given that the behaviors of flies are triggered by chemical cues from their environment, monitoring approaches may be improved by focusing on those activities that are associated with nuisance behaviors or with potential pathogen transmission, and there are opportunities to improve fly control by exploiting behaviors toward semiochemicals that act as attractants or repellents. We review current knowledge on the odor and visual cues that affect the behavior of M. sorbens and Musca domestica, with the aim of better understanding how these can be exploited to support disease monitoring and guide the development of more effective control strategies., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: We aimed to evaluate the characteristics, clinical outcomes, and blood product transfusion (BPT) rates of patients undergoing cardiac transplant (CT) while receiving uninterrupted anticoagulation and antiplatelet therapy., Methods: A retrospective, single-center, and observational study of adult patients who underwent CT was performed. Patients were classified into four groups: (1) patients without anticoagulation or antiplatelet therapy (control), (2) patients on antiplatelet therapy (AP), (3) patients on vitamin K antagonists (AVKs), and (4) patients on dabigatran (dabigatran). The primary endpoints were reoperation due to bleeding and perioperative BPT rates (packed red blood cells (PRBC), fresh frozen plasma, platelets). Secondary outcomes assessed included morbidity and mortality-related events., Results: Of the 55 patients included, 6 (11%) received no therapy (control), 8 (15%) received antiplatelet therapy, 15 (27%) were on AVKs, and 26 (47%) were on dabigatran. There were no significant differences in the need for reoperation or other secondary morbidity-associated events. During surgery patients on dabigatran showed lower transfusion rates of PRBC (control 100%, AP 100%, AVKs 73%, dabigatran 50%, p = 0.011) and platelets (control 100%, AP 100%, AVKs 100%, dabigatran 69%, p = 0.019). The total intraoperative number of BPT was also the lowest in the dabigatran group (control 5.5 units, AP 5 units, AVKs 6 units, dabigatran 3 units; p = 0.038); receiving significantly less PRBC (control 2.5 units, AP 3 units, AVKs 2 units, dabigatran 0.5 units; p = 0.011). A Poisson multivariate analysis showed that only treatment on dabigatran reduces PRBC requirements during surgery, with an expected reduction of 64.5% (95% CI: 32.4%-81.4%)., Conclusions: In patients listed for CT requiring anticoagulation due to nonvalvular atrial fibrillation, the use of dabigatran and its reversal with idarucizumab significantly reduces intraoperative BPT demand., (© 2024 The Author(s). Clinical Transplantation published by John Wiley & Sons Ltd.)

Aim: To evaluate the impact of haemophilia A without inhibitors on humanistic outcomes in patients and caregivers. Herein, we report a cross-sectional analysis of the baseline data of persons with haemophilia (PWH) participating in the prospective study HEMOLIFE., Methods: These data are part of a prospective, observational, and multicentre study currently being conducted in 20 hospitals in Spain by haematologists. We included subjects 12 years or older diagnosed with haemophilia. The evaluations included the Maladjustment Scale, Haemophilia-Specific Quality of Life Questionnaire for Adults (HaemoQol)/HaemoQol Short Form (Children), haemophilia-specific version of the Work Productivity and Impairment Questionnaire plus the Classroom Impairment Questionnaire (WPAI+CIQ:HS), Haemophilia Activity List (HAL)/Paediatric Haemophilia Activities List (pedHAL), visual analogue scale (VAS) for evaluating pain, Coping Pain Questionnaire-Reduced (CAD-R), and Hospital Anxiety and Depression Scale (HADS)., Results: A total of 81 PWH were recruited at 18 centres; 66 PWH were ≥18 years (i.e., adults), and PWH 15 were <18 years (i.e., paediatric patients). Out of the 79 evaluable subjects, 16 (20%) showed an impact of haemophilia on daily life, and the areas most affected were "leisure time" (58% showed maladjustment) and "work/studies" (47% showed maladjustment). Patients reported a higher impact of haemophilia on quality of life (mean [SD] of the transformed score) in the dimensions of "sport" (49.4 [28.6]), "physical health" (40.5 [25.8]) and "future" (37.7 [28.9]). In adults, according to HAL scores, greater impairment of function was observed in "lying/sitting/kneeling/standing," "function of legs" and "leisure activities and sports," with mean normalized scores of 64.7, 65.1 and 69.0, respectively. Productivity was mostly impacted by presenteeism. The pain was infrequent and moderate. According to the HADS scores, nine (11.5%) patients had clinical anxiety and depression., Conclusion: PWH without inhibitors exhibited impairments in adjustment, quality of life and functionality, especially related to leisure and sports activities, and exhibit relevant levels of anxiety and depression., (© 2024 The Author(s). Haemophilia published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: The authors declare no conflict of Interest.

Abstract: The prognostic impact of achieving and in particular maintaining measurable residual disease (MRD) negativity in multiple myeloma is now established; therefore, identifying among MRD-negative patients the ones at higher risk of losing MRD negativity is of importance. We analyzed predictors of unsustained MRD negativity in patients enrolled in the FORTE trial (NCT02203643). MRD was performed by multiparameter flow cytometry (sensitivity of 10-5) at premaintenance and every 6 months thereafter. The cumulative incidence (CI) of MRD resurgence and/or progression was analyzed in MRD-negative patients. A total of 306 of 474 (65%) MRD-negative patients were analyzed. After a median follow-up of 50.4 months from MRD negativity, 185 of 306 (60%) patients were still MRD negative and progression free, 118 (39%) lost their MRD-negative status, and 3 patients (1%) died without progression. Amp1q vs normal (4-year CI, 63% vs 34), ≥2 concomitant high-risk cytogenetic abnormalities vs 0 (4-year CI, 59% vs 33%), circulating tumor cells at baseline (high vs low at 4-year CI, 62% vs 32%), and time-to-reach MRD negativity postconsolidation vs preconsolidation (4-year CI, 46% vs 35%) were associated with a higher risk of unsustained MRD negativity in a multivariate Fine-Gray model. During the first 2 years of maintenance, patients receiving carfilzomib-lenalidomide vs lenalidomide alone had a lower risk of unsustained MRD negativity (4-year CI, 20% vs 33%)., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Limited data are available on the concordance between multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) for minimal residual disease (MRD) detection in a large trial for multiple myeloma (MM) patients., Methods: MRD was explored in the FORTE trial for transplant-eligible MM patients randomised to three carfilzomib-based induction-intensification-consolidation treatments and carfilzomib-lenalidomide (KR) vs R maintenance. MRD was assessed by 8-colour 2nd-generation flow cytometry in patients with ≥very good partial response before maintenance. NGS was performed in case of suspected complete response (CR) in a correlative subanalysis. Biological/prognostic concordance between MFC and NGS, conversion to MRD negativity during maintenance, and 1-year/2-year sustained MRD negativity were explored., Findings: Between September 28, 2015 and December 22, 2021, 2020 samples were available for MFC and 728 for the simultaneous MFC/NGS correlation in the "suspected CR population". Median follow-up was 62 months. Biological agreement was 87% at the 10 -5 and 83% at the 10 -6 cut-offs. A remarkable prognostic concordance was observed: hazard ratios in MFC-MRD and NGS-MRD-negative vs -positive patients were 0.29 and 0.27 for progression-free survival (PFS) and 0.35 and 0.31 for overall survival, respectively (p < 0.05). During maintenance, 4-year PFS was 91% and 97% in 1-year sustained MFC-MRD-negative and NGS-MRD-negative patients (10 -5 ), respectively, and 99% and 97% in 2-year sustained MFC-MRD-negative and NGS-MRD-negative patients, regardless of treatment received. The conversion rate from pre-maintenance MRD positivity to negativity during maintenance was significantly higher with KR vs R both by MFC (46% vs 30%, p = 0.046) and NGS (56% vs 30%, p = 0.046)., Interpretation: The significant biological/clinical concordance between MFC and NGS at the same sensitivity suggests their possible use in the evaluation of one of the currently strongest predictors of outcome., Funding: Amgen, Celgene/Bristol Myers Squibb, Multiple Myeloma Research Foundation., Competing Interests: SO has received honoraria from Amgen, Celgene/Bristol Myers Squibb, and Janssen; has served on the advisory boards for Adaptive Biotechnologies, Janssen, Amgen, and Takeda. EG has received speaker honoraria from Werfen. LP has received honoraria from Celgene, Takeda, Amgen, Bristol Myers Squibb, and Janssen; has served on the advisory boards for Celgene, Bristol Myers Squibb, Amgen, and Janssen; has received consultancy fees from Janssen. MD has received honoraria for lectures from GlaxoSmithKline, Sanofi, and Janssen; has served on the advisory boards for GlaxoSmithKline, Sanofi, and Bristol Myers Squibb. APJ is a full-time employee of and has received stock or stock options from Adaptive Biotechnologies. FP has served on the advisory boards for Celgene, Bristol Myers Squibb, Janssen, Amgen, and GlaxoSmithKline. ML has received honoraria from Gilead Sciences, Daiichi Sankyo, AbbVie, MSD, Novartis, Jazz Pharmaceuticals, Sanofi, and Grifols; has received support for travel, accommodations, and expenses from Gilead Sciences. RM has received honoraria from Janssen, Celgene, Takeda, and Amgen; has served on the advisory boards for Janssen, Celgene, Takeda, Bristol Myers Squibb, and Amgen; has received consultancy fees from Janssen, Takeda, and Sanofi. IRK is a full-time employee of and has received stock or stock options from Adaptive Biotechnologies. AB has served on the advisory boards for Amgen, Janssen, Takeda, Celgene, and GlaxoSmithKline. MC has received honoraria from Janssen, Celgene, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Takeda, AbbVie, Sanofi, Pfizer, and Adaptive Biotechnologies; has served on the advisory boards for Janssen, Bristol Myers Squibb, Sanofi, Amgen, GlaxoSmithKline, and Pfizer; has served on the speakers’ bureaus for Janssen, Celgene, and Sanofi. PM has received honoraria from and/or served on scientific boards for AbbVie, Alexion, Amgen, AstraZeneca, Astellas, BeiGene, Bristol Myers Squibb/Celgene, Gilead, GlaxoSmithKline, Incyte, Janssen, Jazz, Novartis, Pfizer, Roche, Sanofi, and Takeda. MB has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and AbbVie; has served on the advisory boards for Janssen and GlaxoSmithKline; has received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and Mundipharma. EZ has received honoraria from Janssen, Bristol Myers Squibb, Amgen, and Takeda. FG has received honoraria from Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, and GlaxoSmithKline; has served on the advisory boards for Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Roche, Adaptive Biotechnologies, Oncopeptides, bluebird bio, and Pfizer. The other authors declare no competing financial interests., (© 2023 The Author(s).)

Hemophilia, a congenital coagulopathy characterized by a deficiency in coagulation factor VIII (hemophilia A) or factor IX (hemophilia B), results in a tendency of bleeding proportional to the lacking factor. Most bleeds in patients with hemophilia occur in their joints and muscles, and because of these bleeding episodes, patients may end up developing musculoskeletal alterations resulting from hemophilic arthropathy, even receiving hemostatic treatment. The third edition of the World Federation of Hemophilia's Guidelines for the Management of Hemophilia defines 12 principles that encompass all the different types of multidisciplinary care required by people with hemophilia, one of these being clinical and epidemiological research. The expected number of patients with hemophilia across the world has been estimated at 1125 000, most of them undiagnosed, and the total number of patients with severe hemophilia at 418 000 males. Data available from medium and high-income countries show that the prevalence at birth (incidence) and the prevalence of hemophilia differ, which means that patients with hemophilia are at a disadvantage in terms of life expectancy as compared with the general population. In medium-to-high-income countries, the life expectancy disadvantage of patients with hemophilia A and B as compared with the rest of the population is 30% and 24%, respectively. This life expectancy disadvantage is much greater in countries with more limited access to treatments for hemophilia., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Humanitarian emergencies can lead to population displacement, food insecurity, severe health system disruptions, and malaria epidemics among individuals who are immunologically naive. We aimed to assess the impact of different vector control interventions on malaria disease burden during humanitarian emergencies., Methods: In this systematic review and meta-analysis, we searched ten electronic databases and two clinical trial registries from database inception to Oct 19, 2020, with no restrictions on language or study design. We also searched grey literature from 59 stakeholders. Studies were eligible if the population was affected by a humanitarian emergency in a malaria endemic region. We included studies assessing any vector control intervention and in which the primary outcome of interest was malaria infection risk. Reviewers (LAM, JF-A, KC, BP, and LP) independently extracted information from eligible studies, without masking of author or publication, into a database. We did random-effects meta-analyses to calculate pooled risk ratios (RRs) for randomised controlled trials, odds ratios (ORs) for dichotomous outcomes, and incidence rate ratios (IRR) for clinical malaria in non-randomised studies. Certainty of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO, CRD42020214961., Findings: Of 12 475 studies screened, 22 studies were eligible for inclusion in our meta-analysis. All studies were conducted between Sept 1, 1989, and Dec 31, 2018, in chronic emergencies, with 616 611 participants from nine countries, evaluating seven different vector control interventions. Insecticide-treated nets significantly decreased Plasmodium falciparum incidence (RR 0·55 [95% CI 0·37-0·79]; high certainty) and Plasmodium vivax incidence (RR 0·69 [0·51-0·94]; high certainty). Evidence for an effect of indoor residual spraying on P falciparum (IRR 0·57 [95% CI 0·53-0·61]) and P vivax (IRR 0·51 [0·49-0·52]) incidence was of very low certainty. Topical repellents were associated with reductions in malaria infection (RR 0·58 [0·35-0·97]; moderate certainty). Moderate-to-high certainty evidence for an effect of insecticide-treated chaddars (equivalent to shawls or blankets) and insecticide-treated cattle on malaria outcomes was evident in some emergency settings. There was very low certainty evidence for the effect of insecticide-treated clothing., Interpretation: Study findings strengthen and support WHO policy recommendations to deploy insecticide-treated nets during chronic humanitarian emergencies. There is an urgent need to evaluate and adopt novel interventions for malaria control in the acute phase of humanitarian emergencies., Funding: WHO Global Malaria Programme., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Lenalidomide and dexamethasone (Rd)-based triplets, in particular carfilzomib-Rd (KRd) and daratumumab-Rd (DaraRd), represent a standard of care in lenalidomide-sensitive multiple myeloma (MM) patients in first relapse. Meta-analysis of randomized clinical trials (RCT), suggested better outcome with DaraRd. Trying to address this issue in clinical practice, we collected data of 430 consecutive MM patients addressed to Rd-based triplets in first relapse between January 2017 and March 2021. Overall, the most common used regimen was DaraRd, chosen in almost half of the cases (54.4%), followed by KRd (34.6%). Different triplets were used much less commonly. In an attempt to limit the imbalance of a retrospective analysis, we conducted a propensity score matching (PSM) comparison between DaraRd and KRd. After PSM, efficacy of DaraRd versus KRd was similar in terms of overall-response rate (ORR) (OR: 0.9, P=0.685) as well as of very good partial response (VGPR) or better (OR: 0.9, P=0.582). The median progression-free survival (PFS) was significantly longer for DaraRd (29.8 vs. 22.5 months; P=0.028). DaraRd was tolerated better, registering a lower rate of grade 3-4 non-hematological toxicity (OR: 0.4, P<0.001). With the limitations of any retrospective analysis, our real-life PSM comparison between DaraRd and KRd, in first-relapse MM patients, showed better tolerability and prolonged PFS of DaraRd, although with some gaps of performance, in particular of DaraRd, with respect to RCT. Carfilzomib-containing regimens, like KRd, still remain a valid second-line option in the emerging scenario of first-line daratumumab-based therapy.

Background: Patients with newly diagnosed multiple myeloma and high-risk cytogenetic abnormalities (HRCA) represent an unmet medical need. In the FORTE trial, lenalidomide and dexamethasone plus carfilzomib (KRd) induction resulted in a higher proportion of patients with at least a very good partial response as compared with carfilzomib, cyclophosphamide, and dexamethasone (KCd), and carfilzomib plus lenalidomide maintenance prolonged progression-free survival compared with lenalidomide maintenance. In this prespecified analysis of the FORTE trial, we described the outcomes of enrolled patients according to their cytogenetic risk., Methods: The UNITO-MM-01/FORTE was a randomised, open-label, phase 2 trial done at 42 Italian academic and community practice centres, which enrolled transplant-eligible patients with newly diagnosed multiple myeloma aged 18-65 years. Eligible patients had newly diagnosed multiple myeloma based on standard International Myeloma Working Group criteria, a Karnofsky performance status of at least 60%, and had not received any previous treatment with anti-myeloma therapy. At enrolment, patients were stratified according to International Staging System stage (I vs II/III) and age (<60 years vs 60-65 years) and randomly assigned (1:1:1) to KRd plus autologous stem-cell transplantation (ASCT; four 28-day induction cycles with KRd, melphalan at 200 mg/m 2 and ASCT [MEL200-ASCT], followed by four 28-day KRd consolidation cycles), 12 28-day KRd cycles, or KCd plus ASCT (four 28-day induction cycles with KCd, MEL200-ASCT, and four 28-day KCd consolidation cycles), using a web-based system (block randomisation, block size of 12). Carfilzomib was administered at 20 mg/m 2 on days 1 and 2 of cycle 1, followed by 36 mg/m 2 intravenously administered on days 8, 9, 15, and 16 of cycle 1, and then 36 mg/m 2 intravenously administered for all subsequent doses on days 1, 2, 8, 9, 15, 16; lenalidomide 25 mg was administered orally on days 1-21; cyclophosphamide 300 mg/m 2 was administered orally on days 1, 8, and 15; and dexamethasone 20 mg was administered orally or intravenously on days 1, 2, 8, 9, 15, 16, 22, and 23. After the consolidation phase, patients were stratified according to induction-consolidation treatment and randomly assigned (1:1; block size of 8) to maintenance treatment with carfilzomib plus lenalidomide or lenalidomide alone. Carfilzomib 36 mg/m 2 was administered intravenously on days 1-2 and days 15-16, every 28 days for up to 2 years, and lenalidomide 10 mg was administered orally on days 1-21 every 28 days until progression or intolerance in both groups. The primary endpoints were the proportion of patients with at least a very good partial response after induction with KRd versus KCd and progression-free survival with carfilzomib plus lenalidomide versus lenalidomide alone as maintenance treatment. In this preplanned analysis, we included patients enrolled in the FORTE trial with complete cytogenetic data on del(17p), t(4;14), t(14;16), del(1p), gain(1q) (3 copies), and amp(1q) (≥4 copies) assessed by fluorescence in-situ hybridisation analysis on CD138-positive sorted cells. We assessed progression-free survival, overall survival, minimal residual disease negativity, and 1-year sustained minimal residual disease negativity according to the presence of zero, one, and two or more HRCA across treatment groups. The FORTE trial is ongoing, and registered with ClinicalTrials.gov, NCT02203643., Findings: Between Feb 23, 2015, and April 5, 2017, 477 patients were enrolled, of whom 396 (83%) had complete cytogenetic data and were analysed (176 [44%] of whom were women and 220 [56%] were men). The median follow-up from first randomisation was 51 months (IQR 46-56). 4-year progression-free survival was 71% (95% CI 64-78) in patients with zero HRCA, 60% (95% CI 52-69) in patients with one HRCA, and 39% (95% CI 30-50) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of progression or death was similar in patients with one HRCA (hazard ratio [HR] 1·33 [95% CI 0·90-1·97]; p=0·15) and higher in patients with two or more HRCA (HR 2·56 [95% CI 1·74-3·75]); p<0·0001) across the induction-intensification-consolidation groups. Moreover, the risk of progression or death was also higher in patients with two or more HRCA versus those with one HRCA (HR 1·92 [95% CI 1·34-2·76]; p=0·0004). 4-year overall survival from the first randomisation was 94% (95% CI 91-98) in patients with zero HRCA, 83% (95% CI 76-90) in patients with one HRCA, and 63% (95% CI 54-74) in patients with two or more HRCA. Compared with patients with zero HRCA, the risk of death was significantly higher in patients with one HRCA (HR 2·55 [95% CI 1·22-5·36]; p=0·013) and two or more HRCA (HR 6·53 [95% CI 3·24-13·18]; p<0·0001). Patients with two or more HRCA also had a significantly higher risk of death than those with one HRCA (HR 2·56 [95% CI 1·53-4·28]; p=0·0004). The rates of 1-year sustained minimal residual disease negativity were similar in patients with zero HRCA (53 [35%] of 153] and with one HRCA (57 [41%] of 138) and were lower in patients with two or more HRCA (25 [24%] of 105). The median duration of follow-up from second randomisation was 37 months (IQR 33-42). 3-year progression-free survival from the second randomisation was 80% (95% CI 74-88) in patients with zero HRCA, 68% (95% CI 59-78) in patients with one HRCA, and 53% (95% CI 42-67) in patients with two or more HRCA. The risk of progression or death was higher in patients with one HRCA (HR 1·68 [95% CI 1·01-2·80]; p=0·048) and two or more HRCA (2·74 [95% CI 1·60-4·69], p=0·0003) than in patients with zero HRCA., Interpretation: This preplanned analysis of the FORTE trial showed that carfilzomib-based induction-intensification-consolidation regimens are effective strategies in patients with standard risk (zero HRCA) and high-risk (one HRCA) myeloma, resulting in similar rates of progression-free survival and 1-year sustained minimal residual disease negativity. Despite promising progression-free survival, patients with ultra-high-risk disease (those with 2 or more HRCA) still have an increased risk of progression and death and therefore represent an unmet medical need., Funding: Amgen and Celgene/Bristol Myers Squibb., Competing Interests: Declaration of interests RM has received honoraria from Janssen, Celgene, Takeda, and Amgen; has served on the advisory boards for Janssen, Celgene, Takeda, Bristol Myers Squibb, and Amgen; and has received consultancy fees from Janssen, Takeda, and Sanofi. PM has received honoraria from Celgene, Janssen, Takeda, Bristol Myers Squibb, Amgen, Novartis, Gilead, Jazz, Sanofi, AbbVie, and GlaxoSmithKlin; and has served on scientific advisory boards for Celgene, Janssen, Takeda, Bristol Myers Squibb, Amgen, Jazz, Sanofi, AbbVie, and GlaxoSmithKline. LP has received honoraria from Celgene, Takeda, Amgen, Bristol Myers Squibb, and Janssen; has served on the advisory boards for Celgene, Bristol Myers Squibb, Amgen, and Janssen; and has received consultancy fees from Janssen. BG has received honoraria from Amgen, Bristol Myers Squibb, Janssen, and Takeda; and has served on the advisory boards for Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Sanofi, and Takeda. AP has served on the advisory board for Amgen; has received support for meeting fees, travel, and lodging expenses from Amgen, Celgene, and Janssen; and has received non-financial support from Celgene, Janssen, Roche, Takeda, and Amgen. NG has received research grants from Celgene and Janssen Pharmaceutical; has received sponsorship for clinical studies from Janssen Pharmaceutical and Millennium Pharmaceutical; has served on the advisory boards for Celgene, Takeda, and Janssen Pharmaceutical; and has received support for attending meetings from Janssen Pharmaceutical, Celgene, and Bristol Myers Squibb. AG has received honoraria from Celgene, Takeda, Amgen, and Janssen; and has served on the advisory boards for Takeda and Janssen. MC has received advisory fees from Celgene, Janssen, and Takeda; and has received research funding from Celgene. SB has received honoraria from Sanofi, Celgene, Takeda, and Janssen. EZ has received honoraria from and served on the advisory boards for Janssen, Bristol Myers Squibb, Takeda, Sanofi, Amgen, GlaxoSmithKline, and Oncopeptides. AB has served on the advisory boards for Amgen, Janssen, Celgene, GlaxoSmithKline, and Takeda. MB has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and AbbVie; has served on the advisory boards for Janssen and GlaxoSmithKline; and has received research funding from Sanofi, Celgene, Amgen, Janssen, Novartis, Bristol Myers Squibb, and Mundipharma. FG has received honoraria from Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, and GlaxoSmithKline; and has served on the advisory boards for Amgen, Celgene, Janssen, Takeda, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, Roche, Adaptive Biotechnologies, Oncopeptides, bluebird bio, and Pfizer. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Over 90% of severe malaria (SM) cases occur in African children. Parenteral artesunate is currently the recommended treatment for SM. Studies of parasite clearance in paediatric SM cases are needed for assessment of therapeutic outcomes but are lacking in Africa., Methods: Severe malaria patients were recruited in the children's emergency ward at Ho Teaching Hospital, Ghana, in 2018. Blood samples were taken upon admission, every 24 h for 3 days and 1 week after treatment, and DNA extracted. Parasitaemia and parasite densities were performed by microscopy at enrolment and the follow-up days wherever possible. Relative parasite density was measured at each timepoint by duplex qPCR and parameters of parasite clearance estimated., Results: Of 25 evaluable SM patients, clearance of qPCR-detectable parasites occurred within 48 h for 17 patients, but three out of the remaining eight were still qPCR-positive on day 3. Increased time to parasite clearance was seen in children ≥5 years old, those with lower haemoglobin levels and those with a high number of previous malaria diagnoses, but these associations were not statistically significant., Conclusion: We examined parasite clearance dynamics among paediatric cases of SM. Our observations suggest that daily sampling for qPCR estimation of P. falciparum peripheral density is a useful method for assessing treatment response in hospitalised SM cases. The study demonstrated varied parasite clearance response, thus illuminating the complex nature of the mechanism in this important patient group, and further investigations utilizing larger sample sizes are needed to confirm our findings., Competing Interests: The authors have no conflicts to declare., (Crown Copyright © 2022 Published by Elsevier Ltd on behalf of World Federation of Parasitologists.)

Purpose: High levels of circulating tumor plasma cells (CTC-high) in patients with multiple myeloma are a marker of aggressive disease. We aimed to confirm the prognostic impact and identify a possible cutoff value of CTC-high for the prediction of progression-free survival (PFS) and overall survival (OS), in the context of concomitant risk features and minimal residual disease (MRD) achievement., Methods: CTC were analyzed at diagnosis with two-tube single-platform flow cytometry (sensitivity 4 × 10 -5 ) in patients enrolled in the multicenter randomized FORTE clinical trial (ClinicalTrials.gov identifier: NCT02203643). MRD was assessed by second-generation multiparameter flow cytometry (sensitivity 10 -5 ). We tested different cutoff values in series of multivariate (MV) Cox proportional hazards regression analyses on PFS outcome and selected the value that maximized the Harrell's C-statistic. We analyzed the impact of CTC on PFS and OS in a MV analysis including baseline features and MRD negativity., Results: CTC analysis was performed in 401 patients; the median follow-up was 50 months (interquartile range, 45-54 months). There was a modest correlation between the percentage of CTC and bone marrow plasma cells ( r = 0.38). We identified an optimal CTC cutoff of 0.07% (approximately 5 cells/µL, C-index 0.64). In MV analysis, CTC-high versus CTC-low patients had significantly shorter PFS (hazard ratio, 2.61; 95% CI, 1.49 to 2.97, P < .001; 4-year PFS 38% v 69%) and OS (hazard ratio, 2.61; 95% CI, 1.49 to 4.56; P < .001; 4-year OS 68% v 92%). The CTC levels, but not the bone marrow plasma cell levels, affected the outcome. The only factor that reduced the negative impact of CTC-high was the achievement of MRD negativity (interaction P = .039)., Conclusion: In multiple myeloma, increasing levels of CTC above an optimal cutoff represent an easy-to-assess, robust, and independent high-risk factor. The achievement of MRD negativity is the most important factor that modulates their negative prognostic impact.

Background: The main goal of this post hoc analysis of the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study was to evaluate the rate of short- and long-term infectious and non-infectious complications occurring after ASCT in patients with multiple myeloma (MM). Methods: The analysis included all patients with MM from the CALM study who underwent ≥1 ASCT. The primary endpoint of the analysis was to determine the rate of infectious and non-infectious complications after ASCT and to compare them in three time periods: 0−100 days, 101 days−1 year, and >1 year after the first transplant. Results: The analysis included a total of 3552 patients followed up for a median of 56.7 months (range 0.4−108.1). Complication rates decreased with the time from ASCT with 24.85 cases per 100 patient-years from day 0 to 100 days after the transplant, and <2.31 cases per 100 patient-years from the 101st day. At 100 days after ASC T, 45.7% of patients had complications, with infectious events being twice as frequent as non-infectious complications. Bacterial infections (6.5 cases per 100 patient-years, 95% CI: 6.1−7.0) and gastrointestinal complications (4.7 cases per 100 patient-years, 95% CI: 4.3−5.1) were the most common early events. The pattern of complications changed with time from ASCT. The presence of complications after ASCT was not associated with overall survival. Conclusions: Our data provide a solid basis for comparing ASCT-related complications to those caused by emerging treatments in multiple myeloma, such as CAR T-cell therapy and other immunotherapies.

Objectives: Autologous stem cell transplantation is the gold standard for eligible newly diagnosed multiple myeloma patients. Patients are usually hospitalized for administration of mobilization chemotherapy. We aimed to assess safety and efficacy of mobilization therapy with low-dose (2 g/m 2 ) and intermediate-dose (3-4 g/m 2 ) cyclophosphamide administered as outpatient., Methods: A total of 176 consecutive newly diagnosed transplant-eligible myeloma patients receiving outpatient mobilization were retrospectively evaluated. Induction therapy was mainly performed with new drugs (91%)., Results: Chemotherapy was very well tolerated with 16.6% of patients having all-grade adverse events (AEs) and only 1.2% having severe AEs. The most frequently reported AEs were nausea and vomiting grade 1-2 (6.8%). Only 5.7% of patients required hospitalization for AEs. Stem cell collection was successful in 93.1% of patients, with a median CD34 + harvest of 8.7 × 10 6 /kg. Target for 2 autologous stem cell transplantation (at least 6 CD34 +  × 10 6 /kg) was reached by 76.3% of patients. Administration of plerixafor on demand was necessary in 12.1% of patients., Conclusions: Outpatient mobilization with low- and intermediate-dose cyclophosphamide appears an efficient and safe procedure, with minimal and manageable AEs and low rate of hospitalization., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Gender-related factors might affect vulnerability to Covid-19. The aim of this study was to describe the role of gender on clinical features and 28-day mortality in Covid-19 patients., Methods: Observational study of Covid-19 patients hospitalized in Bergamo, Italy, during the first three weeks of the outbreak. Medical records, clinical, radiological and laboratory findings upon admission and treatment have been collected. Primary outcome was 28-day mortality since hospitalization., Results: 431 consecutive adult patients were admitted. Female patients were 119 (27.6%) with a mean age of 67.0 ± 14.5 years (vs 67.8 ± 12.5 for males, p = 0.54). Previous history of myocardial infarction, vasculopathy and former smoking habits were more common for males. At the time of admission PaO 2 /FiO 2 was similar between men and women (228 [IQR, 134-273] vs 238 mmHg [150-281], p = 0.28). Continuous Positive Airway Pressure (CPAP) assistance was needed in the first 24 h more frequently in male patients (25.7% vs 13.0%; p = 0.006). Overall 28-day mortality was 26.1% in women and 38.1% in men (p = 0.018). Gender did not result an independent predictor of death once the parameters related to disease severity at presentation were included in the multivariable analysis (p = 0.898). Accordingly, the Kaplan-Meier survival analysis in female and male patients requiring CPAP or non-invasive ventilation in the first 24 h did not find a significant difference (p = 0.687)., Conclusion: Hospitalized women are less likely to die from Covid-19; however, once severe disease occurs, the risk of dying is similar to men. Further studies are needed to better investigate the role of gender in clinical course and outcome of Covid-19.

Backgrounds: Validated tools for predicting individual in-hospital mortality of COVID-19 are lacking. We aimed to develop and to validate a simple clinical prediction rule for early identification of in-hospital mortality of patients with COVID-19., Methods and Findings: We enrolled 2191 consecutive hospitalized patients with COVID-19 from three Italian dedicated units (derivation cohort: 1810 consecutive patients from Bergamo and Pavia units; validation cohort: 381 consecutive patients from Rome unit). The outcome was in-hospital mortality. Fine and Gray competing risks multivariate model (with discharge as a competing event) was used to develop a prediction rule for in-hospital mortality. Discrimination and calibration were assessed by the area under the receiver operating characteristic curve (AUC) and by Brier score in both the derivation and validation cohorts. Seven variables were independent risk factors for in-hospital mortality: age (Hazard Ratio [HR] 1.08, 95% Confidence Interval [CI] 1.07-1.09), male sex (HR 1.62, 95%CI 1.30-2.00), duration of symptoms before hospital admission <10 days (HR 1.72, 95%CI 1.39-2.12), diabetes (HR 1.21, 95%CI 1.02-1.45), coronary heart disease (HR 1.40 95% CI 1.09-1.80), chronic liver disease (HR 1.78, 95%CI 1.16-2.72), and lactate dehydrogenase levels at admission (HR 1.0003, 95%CI 1.0002-1.0005). The AUC was 0.822 (95%CI 0.722-0.922) in the derivation cohort and 0.820 (95%CI 0.724-0.920) in the validation cohort with good calibration. The prediction rule is freely available as a web-app (COVID-CALC: https://sites.google.com/community.unipa.it/covid-19riskpredictions/c19-rp)., Conclusions: A validated simple clinical prediction rule can promptly and accurately assess the risk for in-hospital mortality, improving triage and the management of patients with COVID-19., Competing Interests: The authors have declared that no competing interests exist.

n the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction therapy was prospectively evaluated in transplant-ineligible patients with multiple myeloma. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. The analysis presented here (median follow-up of 71 months) is focused on maintenance treatment and on subgroup analyses defined according to the International Myeloma Working Group Frailty Score. Of the 654 evaluable patients, 217 were in the lenalidomide-dexamethasone arm, 217 in the melphalan-prednisone-lenalidomide arm and 220 in the cyclophosphamide-prednisone-lenalidomide arm. With regards to the Frailty Score, 284 (43%) patients were fit, 205 (31%) were intermediate-fit and 165 (25%) were frail. After induction, 402 patients were eligible for maintenance therapy (lenalidomide arm, n=204; lenalidomide-prednisone arm, n=198). After a median duration of maintenance of 22.0 months, progression-free survival from the start of maintenance was 22.2 months with lenalidomide-prednisone vs 18.6 months with lenalidomide (hazard ratio 0.85, P =0.14), with no differences across frailty subgroups. The most frequent grade ≥3 toxicity was neutropenia (10% of lenalidomide-prednisone and 21% of lenalidomide patients; P =0.001). Grade ≥3 non-hematologic adverse events were rare (<15%). In fit patients, melphalan-prednisone-lenalidomide significantly prolonged progression-free survival compared to cyclophosphamide-prednisone-lenalidomide (hazard ratio 0.72, P =0.05) and lenalidomide-dexamethasone (hazard ratio 0.72, P =0.04). Likewise, a trend towards a better overall survival was noted for patients treated with melphalan-prednisone-lenalidomide or cyclophosphamide-prednisone-lenalidomide, as compared to lenalidomide-dexamethasone. No differences were observed in intermediate-fit and frail patients. This analysis showed positive outcomes of maintenance with lenalidomide-based regimens, with a good safety profile. For the first time, we showed that fit patients benefit from a full-dose triplet regimen, while intermediate-fit and frail patients benefit from gentler regimens. ClinicalTrials.gov registration number: NCT01093196., (Copyright© 2020 Ferrata Storti Foundation.)

Plerixafor inhibits CXCR4, thus inducing the mobilization of hematopoietic stem/progenitor cells in lymphoma and multiple myeloma (MM) patients eligible for autologous stem cell transplantation (ASCT). However, the kinetics of plerixafor-induced mobilization of lymphocyte subsets is poorly known. Here, we evaluated the graft content, the engraftment, and the immunological reconstitution of MM patients receiving plerixafor. Thirty-seven patients undergoing one or tandem ASCT were enrolled. After mobilization with cyclophosphamide plus G-CSF, plerixafor was added at hematological recovery regardless of CD34 + cell count. We evaluated the number of CD34 + , CD34 + /CD38 - , CD3 + , CD4 + , CD8 + , CD19 + , CD56 + /CD3 - , CD4 + /CD25 + /FOXP3 + , and CD138 + /CD38 + cells on each apheresis. Hematological and immunological recovery were determined at 30 days, 3, 6, 9, and 12 months after ASCT. Overall, 34/37 patients mobilized a median of 10.1 × 10 6 CD34 + cells/Kg (IQ 7.7-13.4). Patients with <20/µL CD34 + cells at plerixafor administration (18/33) had a significantly higher CD34 + cell fold increase, but not a higher absolute number, than 16/33 patients with ≥20/µL CD34 + cells. A similar CD34 + and immune graft composition was reported. A higher number of CD3 + and CD8 + cells/µL was observed at 3 months after first ASCT (p < 0.05) in the group with ≥20 CD34 + cells/µL. Thus, in MM patients, the timing of plerixafor administration influences immunological recovery.

Bortezomib-melphalan-prednisone (VMP) and continuous lenalidomide-dexamethasone (Rd) represent the standard treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (MM). To date, no randomized trial has compared VMP to Rd, and there is no evidence of the optimal treatment for newly diagnosed MM, particularly in patients with high-risk cytogenetics [del(17p), t(4;14) or t(14;16)]. We pooled together data from patients with newly diagnosed MM treated with VMP or Rd induction followed by lenalidomide maintenance 10 mg (Rd-R) enrolled in the GIMEMA-MM-03-05 and EMN01 trials, to evaluate the efficacy of these treatments in different subgroups of patients, focusing on those with standard- and high-risk cytogenetics. Overall, 474 patients were analyzed (VMP: 257 patients; Rd-R: 217 patients). No differences in progression-free survival (hazard ratio=0.96) and overall survival (hazard ratio=1.08) were observed between standard-risk patients treated with VMP or Rd-R, whereas among the high-risk patients, the probabilities of progression (hazard ratio=0.54) and death (hazard ratio=0.73) were lower in the patients treated with VMP than in those treated with Rd-R. In particular, standard-risk patients >75 years benefited less from VMP than from Rd-R (hazard ratio for progression-free survival=0.96; hazard ratio for overall survival=1.81). In this non-randomized analysis, VMP and Rd-R were equally effective in younger (≤75 years), standard-risk patients, while older ones (>75 years) benefited more from Rd-R. In high-risk patients, VMP improved progression-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196)., (Copyright© 2020 Ferrata Storti Foundation.)

Correct definition of the level of risk of invasive fungal infections is the first step in improving the targeting of preventive strategies. We investigated the potential relationship between pre-hospitalization exposure to sources of fungi and the development of invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia after their first course of chemotherapy. From January 2010 to April 2012, all consecutive acute myeloid leukemia patients in 33 Italian centers were prospectively registered. Upon first admission, information about possible pre-chemotherapy risk factors and environmental exposure was collected. We recorded data regarding comorbid conditions, employment, hygienic habits, working and living environment, personal habits, hobbies, and pets. All invasive fungal infections occurring within 30 days after the first course of chemotherapy were recorded. Of the 1,192 patients enrolled in this study, 881 received intensive chemotherapy and were included in the present analysis. Of these, 214 developed an invasive fungal infection, including 77 proven/probable cases (8.7%). Of these 77 cases, 54 were proven/probable invasive mold infections (6.1%) and 23 were proven yeast infections (2.6%). Upon univariate analysis, a significant association was found between invasive mold infections and age, performance status, diabetes, chronic obstructive pulmonary disease, smoking, cocaine use, job, hobbies, and a recent house renovation. Higher body weight resulted in a reduced risk of invasive mold infections. Multivariate analysis confirmed the role of performance status, job, body weight, chronic obstructive pulmonary disease, and house renovation. In conclusion, several hospital-independent variables could potentially influence the onset of invasive mold infections in patients with acute myeloid leukemia. Investigation of these factors upon first admission may help to define a patient's risk category and improve targeted prophylactic strategies. (Clinicaltrial.gov: NCT01315925), (Copyright© Ferrata Storti Foundation.)

Background: Several population-based and cohort studies have reported an increased risk of second cancers in lymphoproliferative disorders (LPDs). The cause of second cancers in LPDs is probably multifactorial, and the relative contribution of treatments, genetic predisposition, and immune dysfunction typical of LPDs is still unclear., Patients and Methods: We retrospectively studied 230 patients with Waldenström macroglobulinemia (WM) to assess the frequency, characteristics, and predictive factors of second cancers and to evaluate whether patients with WM are at higher risk of second cancers compared with an age- and sex-matched control population., Results: In a competing-risk model, the cumulative incidence of solid cancers was 6% at 5 years, 11% at 10 years, and 17% at 15 years, whereas the incidence of hematologic malignancies was 4% at 5 years, 7% at 10 years, and 8% at 15 years. Compared with an age- and sex-matched population, the overall risk of second cancers was 1.7-fold higher than expected (95% confidence interval [CI], 1.22-2.38; P = .002). Patients with WM were at increased risk for diffuse large B-cell lymphoma (DLBCL) (standardized incidence ratio [SIR], 8.64; 95% CI, 3.88-19.22; P < .0001), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (SIR 9.5; 95% CI, 3.6-25.3; P < .0001), and brain cancer (SIR, 7.59; 95% CI, 1.9-30.4; P < .0001). The risk of a second hematologic malignancy was 5-fold higher in treated than in untreated patients (P = .08)., Conclusion: Patients with WM are at increased risk of DLBCL, MDS/AML, and brain cancers compared with the general population. Further studies are needed to clarify whether the increased incidence of second cancers is related to treatments, to the immunologic impairment associated with the disease, or to genetic predisposition., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We evaluated the risk of transformation of asymptomatic immunoglobulin (Ig) M monoclonal gammopathy (aIgM MG) into symptomatic lymphoproliferative disease in 287 patients all analyzed for bone marrow histopathology and immunophenotyping. This series included 201 patients with IgM MG of undetermined significance (IgM MGUS) and 86 with smoldering Waldenström's macroglobulinemia (sWM). After a median of 50 months (range, 12-322 months), 32 cases of aIgM-MG (11.1%) evolved into symptomatic malignant lymphoproliferative disease, as follows: symptomatic WM (n=26), non-Hodgkin lymphoma (n=6). The cumulative transformation percentage at 5 and 10 years was 8% and 19.5%, respectively. The parameters significantly correlated with evolution were, at univariate analysis, BM lymphoplasmacytic infiltration, high erythrocyte sedimentation rate, serum MC, serum IgM size, and serum IgA size. Among patients with aIgM-MG, those at high risk of evolution were patients with sWM, a distinct entity with serum IgM monoclonal protein≥3 g/dL and/or ≥10% bone marrow lymphoplasmacytic infiltration.