Articoli di riviste sul tema "Therater – history"

Incisional hernia repairisone of themostfrequentsurgicalprocedures in General Surgerydue to thehighprevalence of thispathology Thesurgicaltechniqueinvolvesthe use ornot of prostheticmesh, depending onthesurgeon, however, anothercommonproblemistherecurrence of the hernia after a plasty, due to multiplefactorsthatwerestudied in thisresearch, beingnecessary to haveknownthefollow-up of thesepatients in theirpostoperativeperiod and whatcommoncharacteristicstheypresentedthatconditionedthepatients to presentthesepostoperativecomplications and evensurgicalreoperations. Itiswidelydemonstratedthattherecurrence of incisional hernia plastyis a conditionthat can be prevented, knowingtheconditioningriskfactors. Itisimperative to knowtheway in whichpatientshavebeenapproached, theirfollow-up and theirtherapy, determine whichriskfactorswererelevantaccording to thepathology to be studied and thusproposeanalternativesolution, thusreducingmorbidity and mortality. In ourpatients, thesurgicalreoperationsthatnotonlyaffectthequality of life of thepatientsbutalsothegreaterconsumption of material and economicresources in theInstitution. Objective: to determine themostfrequentriskfactorsassociatedwithrecurrence in patientswith a history of incisional hernia plasty at the Naval Medical Center. Material And Methods: 48 electronic records of patientswith a history of abdominal wall hernia plastywereanalyzed. Descriptive and inferentialanalysiswascarriedout in order to associateriskfactorswithrecurrence of incisional hernia. Results: No statisticallysignificantresultswerefoundfortheassociation of obesity, surgicalsiteinfection and smoking withrecurrence of incisional hernia. However, in oursampleobesitywaspresent in 54% of thepatients and 25% overweight. Conclusions: In Naval Medical Center, therate of patientswithincisional hernia plastyislimited, however, overweight andobesityis a characteristicthatourpopulationpresents in common and thatclearly determines multiplecomplications, such as recurrence in this case, requiring a narrowapproach to thiscondition.

Picking winners in electoral contests is a popular sport in Germany,as in many places elsewhere. During the 2002 campaign for theBundestag, pre-election polls tracked the horse race of party supportalmost daily. Election junkies were invited to enter online sweepstakes.They could also bet real money, albeit in limited quantity, onthe parties’ fortunes on WAHL$TREET, a mock stock market runby Die Zeit and other media. As usual, election night witnessed therace of the networks to project the winner the second the pollswhere voters had cast their ballots closed. But in 2002, there wasalso one newcomer in the business of electoral prophecy: a statisticalforecast based on insights from electoral research.

BackgroundFarber disease is frequently misdiagnosed as polyarticular juvenile idiopathic arthritis or seronegative rheumatoid arthritis which leads to a delay in diagnosis for many patients. Farber disease is an ultra-rare lysosomal storage disease caused by mutations in the ASAH1 gene. The resulting deficiency of the acid ceramidase enzyme leads to accumulation of the pro-inflammatory and pro-apoptotic sphingolipid ceramide. Accumulation of ceramide throughout the body leads to the symptoms of Farber disease. Cardinal symptoms include joint disease (polyarticular arthritis and contractures), subcutaneous nodules, and a hoarse or weak voice due to laryngeal nodules. The phenotypic spectrum of Farber disease ranges from rapidly progressive disease causing death in infancy to moderate or slowly progressive disease with survival into late adulthood. Symptoms may vary in severity across patients and phenotypes.ObjectivesTo further define the symptoms of Farber disease, including joint disease, subcutaneous nodules, dysphonia, and osteolysis, which can lead to referral to rheumatology or related specialties. To understand the clinical presentation and broad phenotypic spectrum of this rare disease to aid in clinical diagnosis and reduce diagnostic delay.MethodsThe Observational and Cross-Sectional Cohort Study of the Natural History and Phenotypic Spectrum of Farber Disease (NCT03233841) was the first systematic clinical study of the natural history of Farber disease. The study collected retrospective and prospective data on living and deceased patients, including demographics, clinical presentation, phenotype, diagnostic history, and patient reported outcomes.Results45 patients with Farber disease (27 living, 18 deceased) who had or had not undergone hematopoietic stem cell transplant (HSCT) were enrolled from 16 centers in 9 countries. A cohort of 24 living non-HSCT patients were followed prospectively. The patients represented the broad phenotypic spectrum of Farber disease, from rapidly progressive (severe) to slowly progressive (attenuated). In patients whose data was available for analysis, the average age of patients at enrollment was 7.2 years (range 1 to 28 years). The average age of onset of joint disease (arthritis and/or contractures) was 15 months (range 3 months to 7 years), of subcutaneous nodules was 13 months (range 3 months to 5 years), and of dysphonia was 13 months (range birth to 8 years). The average time from onset of symptoms to Farber disease diagnosis was 2 years (range <1 to 12 years). At baseline, the mean number of joints affected with active arthritis was 11.3 (range 0-36) and the mean number affected with contractures was 18 (range 0-38). 12.5% of patients were reported to have a bone disorder such as osteoporosis or osteolysis. The Child Health Assessment Questionnaire Disability Index (CHAQ) ranging from 0 (no impairment) to 3 (unable to do) was high, with mean scores of 2.62-3.00 across visits.ConclusionData from the Farber disease natural history study further defined the cardinal symptoms, phenotypic spectrum, and high disease-related burden in patients with Farber disease. The large number of joints affected with arthritis or contractures reflects that patients with Farber disease are often referred to rheumatology and can be misdiagnosed with polyarticular juvenile idiopathic arthritis or seronegative rheumatoid arthritis. Demographic information and numbers of patients enrolled indicate that Farber disease is likely not as rare as previously thought. ASAH1 genetic testing for adult and pediatric patients referred to the rheumatology clinic with symptoms including polyarticular arthritis, subcutaneous nodules, dysphonia, or osteolysis, may shorten the time to diagnosis in patients with Farber disease.Disclosure of InterestsLothar Seefried Speakers bureau: Aceragen, Amgen, Alexion, Biomarin, Chiesi, KyowaKirin, Novartis, Theramex, and UCB, Consultant of: Amgen, Alexion, Biomarin, Chiesi, KyowaKirin, Novartis, Theramex, and UCB, Grant/research support from: Alexion, KyowaKirin and Novartis, Kathleen Crosby Employee of: Aceragen, Alexander Solyom Employee of: Aceragen

BackgroundDysmobility Syndrome (DS) is a novel concept to characterize musculoskeletal (MSK) health. DS includes parameters for osteoporosis, sarcopenia and falls[1]. It has been associated with fractures and mortality in community dwelling older adults[2-4]but has never been applied to patients with rheumatic and musculoskeletal diseases (RMD).ObjectivesTo study the prevalence of DS and the association of DS with frailty and major osteoporotic fractures (MOF) in patients with inflammatory and non-inflammatory RMD.MethodsPatients with inflammatory and non-inflammatory RMD aged 65 and older were recruited at a tertiary rheumatology hospital. DS was defined using published cut-offs[1, 2]of the following parameters: Osteoporosis (DXA T-score ≤ -2.5), obesity (DXA % body fat > 30% in men; > 40% in women), low appendicular lean mass (ALM/height2<7.26 kg/m2in men; < 5.45 kg/m2in women), low grip strength (< 30kg in men; < 20kg in women), slow gait speed (< 1.0 m/s) and falls (history of one or more falls within last year). A score of ≥ 3 was defined as having DS. The FRAIL-scale5was used to quantify frailty. Historical data on MOF as defined by FRAX (https://frax.shef.ac.uk/frax/) was collected.Results141 patients (103 women/38 men) were included in the analysis. Mean age was 73 years. Of the total population, 80% had an inflammatory RMD (of those 45% had Rheumatoid Arthritis) as their primary diagnosis. Patients with non-inflammatory diseases had either degenerative spine and/or joint disease and/or fibromyalgia. Mean disease duration was 5 years. Mean DS score was 2.8 (for more demographic data see Table 1). 81/141 (57.5%) participants met DS criteria. DS was more common in women compared to men (63.1 vs. 42.1%, p= 0.0252) and in inflammatory RMD compared to non-inflammatory (61,1 vs. 42.9%, p=0.0811). Patients with DS reported fractures twice as often as those without DS (33,3 vs. 16.6%, p=0.0261). The frequency of individuals with a history of MOF increased with DS score (see Figure 1). Additionally, there was a significant association between DS and FRAIL scores in a univariate linear regression analysis (R2=0,22, p<0.001).ConclusionThis primary study to explore the prevalence of DS in patients with RMD showed that more than half of participants met DS criteria. Similar to studies of community dwelling older adults, fractures were more common in patients with DS. Importantly, a positive association of frailty and DS was seen. Further studies are needed to examine whether DS can be used clinically to better characterize overall MSK health in patients with RMD and whether a standardized management of DS will improve outcomes in these patients.References[1]Binkley N. Osteoporos Int. 2013;24(12):2955-9.[2]Buehring B. J Bone Miner Res. 2018;33(9):1622-9.[3]Hong N. Arch Osteoporos. 2018;13(1):86.[4]Looker AC. Osteoporos Int. 2015;26(1):93-102.[5]Morley JE. J Nutr Health Aging. 2012;16(7):601-8.Table 1.Study demographicsVariableTotaln = 141Femalesn = 103Malesn = 38p-value% Inflammatory RMD80.177.786.80.226Age [years] (SD)72.9(5.2)73.0(5.1)72.7(5.6)0.737Height [cm] (SD)165.3(9.0)161.5(6.2)175.6(6.9)< 0.001Weight [kg] (SD)77.9(15.1)76.1(15.5)82.8(12.9)0.019ALM/height2[kg/m2](SD)6.99(1.17)6.79(1.07)7.51(1.28)0.001Body fat [%] (SD)41.5(7.91)44.7(6.40)33.0(4.72)< 0.001Lowest BMD T-score (SD)-1.6(1.16)-1.7(1.21)-1.4(1.01)0.227Grip strength [kg] (SD)19.0(10.2)14.8(6.79)30.3(9.38)< 0.001Gait speed [m/s] (SD)0.95(0.31)0.89(0.27)1.110.36< 0.001Dysmobility Score (SD)2.8(1.30)2.9(1.30)2.5(1.25)0.054Simple Frail Score (SD)2.6(1.35)2.7(1.28)2.3(1.49)0.085Figure 1.Frequency of individuals with history of MOF by Dysmobility Syndrome (DS) Score. The frequency of individuals with a history of MOF increased with the DS Score (p=0.0509). Note: Only 3 individuals had a DS score of 0 and only 2 had a DS score of 6.AcknowledgementsThe OsteoSys Study was funded by grants EFRE.NRW.(EFRE-0800411, EFRE-0800427, LS-1-1-019c) and noChro.(13GW0338B) - PI Prof. Nina Babel.Disclosure of InterestsBjoern Buehring Speakers bureau: Alexion, Biogen, Boehringer-Ingelheim, Gilead/ Galapagos, MSD,Sanofi Genzyme, UCB, Consultant of: Amgen, Gilead/ Galapagos, Theramex, UCB, Roshnak Parvaee: None declared, Celina Mueller: None declared, Ioana Andreica: None declared, David Kiefer: None declared, Uta Kiltz: None declared, Styliani Tsiami: None declared, Maryam Pourhassan: None declared, Timm Westhoff: None declared, Rainer Wirth: None declared, Xenofon Baraliakos: None declared, Nina Babel: None declared, Juergen Braun: None declared.

INTRODUCTION: Cancer pathogenesis is usually characterized by a long evolutionary process where genomic driver events accumulate over time, conferring advantage to distinct subclones, allowing their expansion and progression. METHODS: To investigate the multiple myeloma (MM) evolutionary history, we characterized the mutational processes' landscape and activity over time utilizing a large cohort of 89 whole genomes and 973 exomes. To improve the accuracy of mutational signatures analysis, we analyzed both the 3' and 5' nucleotide context of each mutation and we developed the novel fitting algorithm mmSig, which fits the entire mutational catalogue of each patient with the mutational signatures involved in MM pathogenesis. The contribution of each mutational signature was then corrected based on the cosine similarity between the original 96-mutational profile and the reconstructed profile generated without that signature. To reconstruct the genetic evolutionary history of each patient's cancer, we integrated two approaches. First dividing all mutations into clonal (early) or subclonal (late), then subdivided the clonal mutations into duplicated mutations (present on two alleles and therefore acquired before the duplication) or non-duplicated mutations (detected on a single allele), reflecting either pre-gain and post-gain mutations on the minor allele, or post-gain mutations acquired on one of the duplicated alleles. RESULTS Eight mutational signatures were identified, seven of which showed significant similarity with the most recent mutational signature catalogue (i.e SBS1, SBS2, SBS5, SBS8, SBS9, SBS13 and SBS18). The new mutational signature (named SBS-MM1) was observed only among relapsed patients exposed to alkylating agents (i.e melphalan). The etiology of this specific signature was further confirmed by analyzing recent whole genomes public data from human-induced pluripotent stem cells exposed to melphalan (Kucab et al, Cell 2019). Reconstructing the chronological activity of each mutational signature, we identified four different routes to acquire the full mutational spectrum in MM based on the differential temporal activity of AID (SBS9) and APOBEC (SBS2 and SBS13). Our data indicate that AID activity is not limited to the first contact with the GC, but persists in the majority of patients, behaving similarly to a B-memory cells, capable of re-entering the germinal center upon antigen stimulation to undergo clonal expansion several times before MM diagnosis. Next, we confirmed the clock-like nature (i.e constant mutation rate) of SBS5 in MM and other post-germinal center disorders such as chronic lymphocytic leukemia and B-cell lymphomas. Based on the SBS5 mutation rates and the corrected ratio between duplicated and non-duplicated mutations within large chromosomal gains, we could time the acquisition of the first copy number gain during the life history of each MM patient. Intriguingly, the first MM chromosomal duplication was acquired on average 38 years (ranges 11-64) before sample collection. In 23/27 (85%) cases the first multi gain event occurred before 30 years of age, and in 13/27 (48%) before 20 years reflecting a long and slow process potentially influenced and accelerated by extrinsic and intrinsic factors. DISCUSSION Our analysis provides a glimpse into the early stages of myelomagenesis, where acquisition of the first key drivers precedes cancer diagnosis by decades. Defining the time window when transformation occurs opens up for new avenues of research: to identify causal mechanisms of disease initiation and evolution, to better define the optimal time to start therapy, and ultimately develop early prevention strategies. Disclosures Bolli: CELGENE: Honoraria; JANSSEN: Honoraria; GILEAD: Other: Travel expenses. Corradini:Janssen: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; BMS: Other: Travel Costs. Anderson:Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Other: Scientific Founder; Oncopep: Other: Scientific Founder; Amgen: Consultancy, Speakers Bureau; Sanofi-Aventis: Other: Advisory Board. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Papaemmanuil:Celgene: Research Funding. Avet-Loiseau:takeda: Consultancy, Other: travel fees, lecture fees, Research Funding; celgene: Consultancy, Other: travel fees, lecture fees, Research Funding. Munshi:Adaptive: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Oncopep: Consultancy; Abbvie: Consultancy. Landgren:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract STUDY QUESTION Does the application of reference ranges for sex steroids and the modified Ferriman-Gallwey (mFG) scale established in the community from which the study sample was drawn, combined with the most conservative polycystic ovary morphology (PCOM) criteria to the recognised diagnostic criteria for polycystic ovary syndrome (PCOS) improve the certainty of diagnosis of PCOS in non-healthcare-seeking women? SUMMARY ANSWER Despite application of the stringent definitions of the elements used to diagnose PCOS in a non-healthcare seeking community-based sample, the risk of diagnostic uncertainty remains. WHAT IS KNOWN ALREADY There is heterogeneity in prevalence estimates for PCOS due, in part, to lack of standardisation of the elements comprising the recognised National Institutes of Health (NIH), Rotterdam and Androgen Excess Society (AE-PCOS) diagnostic criteria. The AE-PCOS Society proposed refinements to the definitions of biochemical androgen excess and PCOM that can now be incorporated into these sets of diagnostic criteria to estimate PCOS prevalence. STUDY DESIGN, SIZE, DURATION An Australian cross-sectional study of 168 non-healthcare-seeking women. PARTICIPANTS/MATERIALS, SETTING, METHODS The 168 included women were aged 18–39 years, euthyroid and normoprolactinemic, not recently pregnant, breast feeding or using systemic hormones. Each provided menstrual history and assessment of the mFG, had measurement of sex steroids by liquid chromatography, tandem mass spectrometry, and a pelvic ultrasound. The presence of PCOS was determined using modified (m) NIH, Rotterdam, and AE-PCOS criteria according to AE-PCOS Society recommendations. MAIN RESULTS AND THE ROLE OF CHANCE Overall, 10.1% of the included participants met the mNIH PCOS criteria, which requires the presence of menstrual dysfunction, while 18.5% met the mRotterdam and 17.5% the AE-PCOS criteria, with the latter requiring hyperandrogenism. Eight of the 27 participants with menstrual dysfunction, 10 of 31 women with PCOM, and 39 of 68 women with hyperandrogenism had no other feature of PCOS. Of the 19 participants with hyperandrogenaemia, 10 met the mNIH criteria (52.5%) and 14 met both the mRotterdam and AE-PCOS criteria (78.9%). Women who had the combination of hyperandrogenism and PCOM explained the greatest discrepancy between the mNIH and the other criteria. LIMITATIONS, REASONS FOR CAUTION Clinical androgenisation relied on participant self-assessment, which has been shown to be valid when compared with clinician assessment. The sample size was a function of both the strict inclusion criteria and the requirements of non-healthcare-seeking women having a blood draw and pelvic ultrasound which may have introduced a selection bias. WIDER IMPLICATIONS OF THE FINDINGS Despite applying stringent cut-offs for serum androgens, the mFG scale and the ovarian follicle count, these criteria remain arbitrary. Accordingly, healthy women may be captured by these criteria, and misidentified as having PCOS, while women with the condition may be missed. Consequently, PCOS remains a diagnosis to be made with care. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by the Grollo-Ruzzene Foundation. Dr S.R.D. is an NHMRC Senior Principal Research Fellow (Grant no. 1135843). S.R.D. has been paid for developing and delivering educational presentations for Besins Healthcare, BioFemme and Pfizer Australia, has been on Advisory Boards for Theramex, Abbott Laboratories, Mayne Pharmaceuticals and Roche and a consultant to Lawley Pharmaceuticals and Que Oncology and has received has received institutional grant funding for Que Oncology research; there are no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER N/A

Background High risk smoldering multiple myeloma (HRSMM), defined as having immunoparesis and at least 95% abnormal plasma cells/all plasma cells by advanced flow cytometry, has a risk of progression to multiple myeloma of about 75% after 5 years of diagnosis. These patient have no symptoms and current standard is to follow them without treatment. Isatuximab is an IgG1 monoclonal antibody that binds to CD38 highly expressed in myeloma cells. Isatuximab has activity as monotherapy (overall response rate (ORR) 35%), with lenalidomide/dexamethasone (ORR 56%) and pomalidomide/dexamethasone (ORR 62%) in relapsed MM. We designed a phase II study to test the efficacy of isatuximab in high risk smoldering myeloma. Our study is registered in clinicaltrials.gov as NCT02960555. Methods The primary endpoint of the study is the ORR of isatuximab 20 mg/kg IV days 1, 8, 15, 22 cycle 1; days 1, 15 cycles 2-6 and day 1 cycles 7-30 in high risk smoldering myeloma. 24 patients were accrued in the first stage (of maximum 61 patients). Secondary endpoints are PFS, OS, clinical benefit rate (CBR). Exploratory endpoints are quality of life analysis (QoL), MRD, molecular/immune characterization using DNA/RNA sequencing of myeloma cells and the microenvironment before and after treatment. Results 24 patients with HRSMM were accrued from 02/08/2017 until 12/21/2018 (Table 1). All patients are evaluable for response. Best responses: ORR (≥PR) 15(62.5%), CR MRD- flow at 10-5 1 (5%), VGPR 4 (17%), PR 10 (42%), minor response (MR) 4 (18%), stable disease 5 (21%); CBR (≥MR) 79%. Median number of cycles received were 11.5 (range 6-30). Five patients have stopped treatment (one has completed the study, one with heavy history of smoking was diagnosed with squamous cell cancer of the tongue, one could no longer travel to treatments due to relocation, two progressed to active multiple myeloma after 16 and 6 cycles of treatment, respectively). There have been no deaths. DNA/RNA seq is ongoing for biomarkers of response. There were 5 grade 3 severe treatment-related adverse events (RAE) which resolved to baseline: dyspnea -related to infusion reaction (n=2), headache (n=1), ANC decrease (n=1), urinary tract infection (n=1). Most common grade 1-2 related adverse events (n): nausea (7), vomit (5), WBC decrease (3), diarrhea (3), fatigue (6), headache (4), mucositis (4), myalgia (4) and infusion reaction (3). In patients with available QoL functional scores (n=9 at baseline and n=7 after 6 months of therapy), isatuximab was effective in reducing their anxiety and worry of progression to multiple myeloma. Isatuximab also improved general QoL scores by the end of cycle 6 of treatment which were now comparable to those in the general population (Figure 1). Conclusion Isatuximab is very well tolerated, results in high response rates in HRSMM and has the potential to change the natural history of this disease. In ongoing QoL analysis, initial data shows improvement in QoL and decreased cancer worry after isatuximab treatment. Immune-genomic analysis is ongoing and may identify patients that benefit the most from treatment. Disclosures Manasanch: celgene: Honoraria; merck: Research Funding; quest diagnostics: Research Funding; sanofi: Research Funding; BMS: Honoraria; Sanofi: Honoraria. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Merck: Consultancy. Lee:Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding. Kaufman:Janssen: Other: travel/lodging, Research Funding. Thomas:Xencor: Research Funding; BMS: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Mailankody:Takeda Oncology: Research Funding; Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; CME activity by Physician Education Resource: Honoraria. Lendvai:Janssen: Employment. Neelapu:Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Merck: Consultancy, Research Funding; Allogene: Consultancy; Cellectis: Research Funding; Poseida: Research Funding; Karus: Research Funding; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Cell Medica: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Landgren:Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC. OffLabel Disclosure: Isatuximab for the treatment of smoldering myeloma

Introduction Peripheral neuropathy (PN) is a common disorder that can be caused by amyloid light-chain amyloidosis (AL). AL is a rare disorder caused by the deposition of amyloid fibers, originating from malignant plasma cells. Amyloid deposition in peripheral nerves causes PN and is present in 35% of patients with newly diagnosed AL. Diagnosis of AL can be difficult, leading to under-recognition, diagnostic delay, and delayed treatment. Virtually all instances of AL are preceded by monoclonal gammopathy of undetermined significance (MGUS). MGUS is relatively common with a reported prevalence of 4.2% in the general Caucasian population over the age of 50 years. Although MGUS is usually considered asymptomatic, a significant proportion of affected individuals develop PN. However, we are not aware of any studies assessing how PN affects risk of MGUS progression to AL. We were therefore motivated to conduct a large population-based study including 15,351 Swedish individuals with MGUS diagnosed 1986-2013. Methods Participants diagnosed with MGUS between 1986-2013 were recruited from a registry of a nationwide network of hematology- and oncology centers and the Swedish Patient Registry. We then cross-linked data on recorded diagnoses of AL and PN from the Swedish Patient Registry, diagnoses of lymphoproliferative disorders form the Swedish Cancer Registry, and dates of death from the Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study. A multi-state survival model was created. At inclusion, participants started providing person time into the PN or the non-PN states depending on whether they had a previous diagnosis of PN. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time in the PN state after that. We then created a Cox proportional hazard regression model with AL as the endpoint. Participants were censored at diagnosis of other lymphoproliferative disorders. We adjusted for sex, age, and year of MGUS diagnosis. Results We included 15,351 participants with MGUS. Of those, 996 participants provided person-time with PN (6.5%). About half of those had PN at MGUS diagnosis (55%). A total of 174 cases of AL were recorded, with AL being more common among those who had PN (2.1% vs 1.0% p=0.002). Those who had PN had a 2.3-fold increased risk of AL as compared to those who did not have PN (hazard ratio (HR): 2.3; 95% confidence interval (95% CI): 1.5-3.7; p<0.001). The results were similar for those who had PN at MGUS diagnosis and those who did not. More than half of AL cases (53%) were diagnosed within one year after MGUS diagnosis. The rate was even higher among those with PN, with 82% of AL cases among those who presented with PN being diagnosed within one year after MGUS diagnosis. In the first year after inclusion, the incidence of AL was 15.2 and 6.1 per 1000 person-years for participants with and without PN respectively (HR: 1.8; 95% CI:1.0-3.4; p=0.04). Participants with PN continued to have an increased risk of progression to AL after the first year with an incidence of AL of 2.6 per 1000 person-years as compared to 1.1 per 1000 person-years among participants who did not have PN (HR:2.4; 95% CI: 1.1-5.0; p=0.02) (Figure). Discussion In this large population-based study, including 15,351 individuals with MGUS, we found that individuals with MGUS who develop PN have an increased risk of progression to AL. In fact, individuals with MGUS who have PN at MGUS diagnosis might already have AL. This risk of AL was highest during the first year after MGUS diagnosis with participants with PN having a higher risk than those who did not have PN. PN continued to be associated with a higher risk of MGUS progression to AL throughout the study period. This is the largest study that we are aware of assessing the association of PN and MGUS progression to AL. Since this is a registry-based study based on recorded diagnoses, some clinical data, including MGUS isotype, is not available. These findings suggest that increased awareness of PN as a feature of MGUS might decrease diagnostic delay and improve outcomes for patients with AL. Figure Disclosures Landgren: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract STUDY QUESTION What are appraisals, coping strategies and emotional reactions of patients to coronavirus disease 2019 (COVID-19) fertility clinic closures? SUMMARY ANSWER Clinic closure was appraised as stressful due to uncertainty and threat to the attainability of the parenthood goal but patients were able to cope using strategies that fit the uncertainty of the situation. WHAT IS KNOWN ALREADY Psychological research on COVID-19 suggests that people are more anxious than historical norms and moderately to extremely upset about fertility treatment cancellation owing to COVID-19. STUDY DESIGN, SIZE, DURATION The study was of cross-sectional design, comprising a mixed-methods, English language, anonymous, online survey posted from April 9 to 21 to social media. Eligibility criteria were being affected by COVID-19 fertility clinic closure, 18 years of age or older and able to complete the survey in English. In total, 946 people clicked on the survey link, 76 did not consent, 420 started but did not complete the survey and 450 completed (48% completion, 446 women, four men). PARTICIPANTS/MATERIALS, SETTING, METHODS Overall 74.7% (n = 336) of respondents were residents in the UK with an average age of 33.6 years (SD = 4.4) and average years trying to conceive, 3.5 years (SD = 2.22). The survey comprised quantitative questions about the intensity of cognitive appraisals and emotions about clinic closure, and ability to cope with clinic closure. Open-text questions covered their understanding of COVID-19 and its effect on reproductive health and fertility plans, concerns and perceived benefits of clinic closure, and knowledge about closure. Sociodemographic information was collected. Descriptive and inferential statistics were used on quantitative data. Thematic qualitative analysis (inductive coding) was performed on the textual data from each question. Deductive coding grouped themes from each question into meta-themes related to cognitive stress and coping theory. MAIN RESULTS AND THE ROLE OF CHANCE Most patients (81.6%, n = 367) had tests or treatments postponed, with these being self (41.3%, n = 186) or publicly (46.4%, n = 209) funded. Patients appraised fertility clinic closure as having potential for a more negative than positive impact on their lives, and to be very or extremely uncontrollable and stressful (P ≤ 0.001). Most reported a slight to moderate ability to cope with closure. Data saturation was achieved with all open-text questions, with 33 broad themes identified and four meta-themes linked to components of the cognitive stress and coping theory. First, participants understood clinic closure was precautionary due to unknown effects of COVID-19 but some felt clinic closure was unfair relative to advice about getting pregnant given to the public. Second, closure was appraised as a threat to attainability of the parenthood goal largely due to uncertainty of the situation (e.g. re-opening, effect of delay) and intensification of pre-existing hardships of fertility problems (e.g. long time waiting for treatment, history of failed treatment). Third, closure taxed personal coping resources but most were able to cope using thought-management (e.g. distraction, focusing on positives), getting mentally and physically fit for next treatments, strengthening their social network, and keeping up-to-date. Finally, participants reported more negative than positive emotions (P ≤ 0.001) and, almost all participants reported stress, worry and frustration at the situation, while some expressed anger and resentment at the unfairness of the situation. Overall, 11.8% were not at all able to cope, with reports of intense feelings of hopelessness and deteriorating well-being and mental health. LIMITATIONS, REASONS FOR CAUTION The survey captures patient reactions at a specific point in time, during lockdown and before clinics announced re-opening. Participants were self-selected (e.g. UK residents, women, 48% starting but not completing the survey), which may affect generalisability. WIDER IMPLICATIONS OF THE FINDINGS Fertility stakeholders (e.g. clinics, patient support groups, regulators, professional societies) need to work together to address the great uncertainty from COVID-19. This goal can be met proactively by setting up transparent processes for COVID-19 eventualities and signposting to information and coping resources. Future psychological research priorities should be on identifying patients at risk of distress with standardised measures and developing digital technologies appropriate for the realities of fertility care under COVID-19. STUDY FUNDING/COMPETING INTEREST(S) University funded research. Outside of the submitted work, Prof. J.B. reports personal fees from Merck KGaA, Merck AB, Theramex, Ferring Pharmaceuticals A/S; grants from Merck Serono Ltd; and that she is co-developer of the Fertility Quality of Life (FertiQoL) and MediEmo apps. Outside of the submitted work, Dr R.M. reports personal or consultancy fees from Manchester Fertility, Gedeon Richter, Ferring and Merck. Outside of the submitted work, Dr S.G. reports consultancy fees from Ferring Pharmaceuticals A/S, Access Fertility and SONA-Pharm LLC, and grants from Merck Serono Ltd. The other authors declare no conflicts of interest. TRIAL REGISTRATION NUMBER N/A.

Background: Several studies have indicated that the depth and duration of treatment response in multiple myeloma are both reduced in the relapsed setting. With further lines of therapy, responses continue to weaken in depth and shorten in duration. The National Comprehensive Cancer Network (NCCN) Guidelines suggest that regimens may be repeated in the relapsed setting if there has been a duration of at least 6 months since that regimen was given; however, there is limited information regarding treatment response and duration in the setting of re-treating patients with agents previously utilized. Moreover, preliminary data has suggested that carfilzomib-based regimens in the frontline may be able to attain deeper and longer responses than alternative therapies, which has led to carfilzomib being used more frequently in the frontline. This motivated us to investigate the treatment response, depth, and safety of re-challenging patients with carfilzomib in the relapsed setting. Methods: In this retrospective chart review, we identified all patients who were treated with multiple courses of carfilzomib-based regimens at Memorial Sloan Kettering Cancer Center between January 1, 2014 and November 30, 2018. Our primary objectives were to assess the response, duration of response and treatment, and safety of re-exposure to carfilzomib-based regimens. Responses were assessed as per IMWG 2016 consensus criteria (Lancet Oncol 2016). In this review we describe the clinical course, safety, and efficacy of re-challenging patients with carfilzomib in the relapsed and refractory settings. Results: Fifteen patients were identified as having received multiple, independent lines of carfilzomib-based therapy. The median age of the cohort was 58 years (49-76) with 53% male (8); two patients had R-ISS stage 1, eight stage 2, and five stage 3 disease. Five of these patients received their initial carfilzomib in the frontline as part of KRD; four of whom attained a sCR with the fifth attaining a VGPR. The remaining ten patients received their initial carfilzomib in the second-line (4) or 3rd and subsequent lines (6). Upon re-exposure to carfilzomib, patients were heavily treated with a median of four lines of therapy (2-15). All but three patients had at least one adverse cytogenetic abnormality; eight with 17p-, five with 13q-, three with t4;14, and six with 1q+. Regimens utilized in the relapsed setting included KRD (N=4), KPD (N=3), Cyklone (N=2), KD + HDAC inhibitor (N=3), KD (N=1), KCD (N=1), and KRD + daratumumab (N=1). Four patients received carfilzomib at a dose of 27 mg/m2 while the remaining 10 received > 36 mg/m2. Responses were seen in all but four patients (two VGPR, five PR, and four MR), with one patient experiencing progression during carfilzomib with no response; notably, this patient only attained a MR to primary carfilzomib therapy and their second exposure was the 15th line of therapy. The median time to next therapy was 4.8 months (1.9-19.4) with one patient being bridged to autologous hematopoietic cell transplantation (HCT), one to allogeneic HCT, and three are currently receiving ongoing carfilzomib treatment (13.9, 2.8, 2.5 months with VGPR, MR, and PR, respectively). Exacerbation of baseline hypertension was identified in three patients, but these instances were treated successfully with standard medications with no further complications. No additional cardiovascular events were identified in the frontline or re-treatment settings. Conclusions: We report that in a heavily pre-treated, high risk patient cohort, patients previously treated with carfilzomib-based regimens may be safely re-challenged with carfilzomib. Importantly, none of these patients experienced cardiovascular adverse effects other than exacerbation of underlying hypertension, further supporting the ability to safely re-treat a select group of patients with carfilzomib. We conclude that depending on the patient and treatment history, re-challenging with carfilzomib at relapse may be appropriate salvage therapy, particularly as a bridge towards HCT and/or clinical trials. Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Lesokhin:Genentech: Research Funding; Serametrix Inc.: Patents & Royalties; Janssen: Research Funding; GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landau:Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Giralt:Amgen: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Jazz Pharmaceuticals: Consultancy; Actinium: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Kite: Consultancy. Landgren:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Merck: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: IMGN632 is a CD123-targeting ADC, comprised of a high affinity anti-CD123 antibody coupled to a DNA-alkylating payload of the novel IGN (indolinobenzodiazepine pseudodimer) class. An ongoing Phase I trial in patients with CD123-positive AML or BPDCN (NCT03386513) has reported encouraging efficacy and manageable tolerability with IMGN632 monotherapy. Preclinical data from AML mouse models demonstrate synergy in combinations with azacitidine and/or venetoclax1,2, supporting the clinical exploration of these combinations. Here we describe the ongoing Phase 1b/2 study actively enrolling patients to determine the safety, tolerability, and preliminary anti-leukemia activity of IMGN632 when administered in combination with azacitidine and/or venetoclax to patients with relapsed and frontline CD123-positive AML, and the single-agent activity of IMGN632 in patients with minimal residual disease (MRD)-positive AML after frontline treatment. M ethods and s tudy d esign : Adult patients with CD123-positive relapsed or refractory (R/R) AML, who are deemed appropriate for experimental therapy, are eligible to enroll as part of the dose escalation phase. Key exclusion criteria for all regimens include active central nervous system disease, and history of sinusoidal obstruction syndrome/venous occlusive disease of the liver. Three different combination regimens are being evaluated: Regimen A, IMGN632 plus azacitidine (632+AZA); Regimen B, IMGN632 plus venetoclax (632+VEN); and Regimen C, IMGN632 plus azacitidine and venetoclax (632+AZA+VEN). For each regimen, a Phase 1b dose escalation cohort in R/R patients will determine the recommended Phase 2 dose (RP2D) of IMGN632 for the specific combination. Escalation will follow a standard 3+3 design, with a starting dose for IMGN632 of 0.015 mg/kg administered intravenously on Day 7 of a 21- (632+VEN) or 28-day cycle (632+AZA, 632+AZA+VEN). Regimens A and B (the doublets) were initially explored to evaluate safety at increasing doses of IMGN632. Escalation of IMGN632 on Regimen C (the triplet) was allowed once the corresponding dose of IMGN632 was evaluated in each doublet combination (Figure). This will be followed by a Phase 2 dose expansion stage to further characterize the safety profile and assess antileukemia activity in frontline or relapsed AML patients, depending on the combination regimen. In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD-positivity to MRD-negativity, in fit and unfit AML subpopulations. NCT04086264 Figure Disclosures Daver: Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet:Incyte: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Stemline: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Montesinos:Celgene, Pfizer, Abbvie: Consultancy; Pfizer, Abbvie, Daiichi Sankyo: Research Funding; Astellas, Novartis, Janssen: Speakers Bureau. Wang:Genentech: Consultancy; PTC Therapeutics: Consultancy; Pfizer: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Stemline: Speakers Bureau; Astellas: Consultancy; Macrogenics: Consultancy. Aribi:Seattle Genetics: Consultancy. DeAngelo:Jazz: Consultancy; Shire: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Abbvie: Research Funding; Incyte Corporation: Consultancy; Forty-Seven: Consultancy; Glycomimetics: Research Funding; Autolos: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint Medicines Corporation: Consultancy, Research Funding; Takeda: Consultancy. Walter:Pfizer: Consultancy, Research Funding; Macrogenics: Research Funding; Amgen: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; ImmunoGen: Research Funding; Celgene: Consultancy, Research Funding; StemLine: Research Funding; BioLineRx: Consultancy, Research Funding; Genentech: Consultancy; Seattle Genetics: Research Funding; New Link Genetics: Consultancy; Agios: Consultancy, Research Funding; BiVictriX: Consultancy; Boston Biomedical: Consultancy; Amphivena: Current equity holder in publicly-traded company; Aptevo: Consultancy, Research Funding; Argenx: Consultancy; Arog: Research Funding; Astellas: Consultancy; Daiichi: Consultancy; Race Oncology: Consultancy; Kite: Consultancy; Selvita: Research Funding. Altman:Biosight: Research Funding; PrIME Oncology: Consultancy; France Foundation: Consultancy; PeerView: Consultancy; Fujifilm: Research Funding; Kartos: Research Funding; Celgene: Research Funding; ASH: Consultancy; Bristol-Myers Squibb: Consultancy; Immune Pharma: Consultancy; Janssen: Consultancy; Syros: Consultancy; Novartis: Consultancy; Genentech: Research Funding; Amphivena: Research Funding; Aprea: Research Funding; Amgen: Research Funding; ImmunoGen: Research Funding; Boehringer Ingelheim: Research Funding; Kura: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Other: DSMC; Daiichi Sanko: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cancer Expert Now: Consultancy. Advani:Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Abbvie: Research Funding; Takeda: Research Funding; OBI: Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding. Sloss:ImmunoGen, Inc.: Current Employment. Malcolm:ImmunoGen, Inc.: Current Employment. Zweidler-McKay:ImmunoGen, Inc.: Current Employment. OffLabel Disclosure: Phase 1b/2 trial of experimental therapy

Objectives The Journal of Urology (JU) and Urology have different policies regarding the publication of articles devoted to urologic history. JU stopped publishing full length historical articles in 2009. We wished to assess the pattern and frequency of historical article publishing in the two of the largest urologic journals. Methods We used a PubMed and manually based search of all articles from JU and Urology and categorized each article by subject, especially whether they were wholly and/or subtantially devoted to a historical subject. Results From 1973-2000, JU and Urology published 73 and 91 articles on the history of urology respectively. From 1997- 2008, JU experienced an increase in historical articles at a time when the History Forum was begun at the AUA Annual Meeting. Therafter, JU stopped publishing historical articles but Urology has published 35 from 2009-2017 at an average rate of 3.9 articles/year. Conclusions The journal Urology, but not JU, publishes a history of urology article about every 3 months. The study revealed the need for a journal wholly dedicated to the history of urology.

Abstract STUDY QUESTION Does the endometrial preparation protocol (artificial cycle (AC) vs natural cycle (NC) vs stimulated cycle (SC)) impact the risk of early pregnancy loss and live birth rate after frozen/thawed embryo transfer (FET)? SUMMARY ANSWER In FET, ACs were significantly associated with a higher pregnancy loss rate and a lower live birth rate compared with SC or NC. WHAT IS KNOWN ALREADY To date, there is no consensus on the optimal endometrial preparation in terms of outcomes. Although some studies have reported a higher pregnancy loss rate using AC compared with NC or SC, no significant difference was found concerning the pregnancy rate or live birth rate. Furthermore, no study has compared the three protocols in a large population. STUDY DESIGN, SIZE, DURATION A multicenter retrospective cohort study was conducted in nine reproductive health units in France using the same software to record medical files between 1 January 2012 and 31 December 2016. FET using endometrial preparation by AC, modified NC or SC were included. The primary outcome was the pregnancy loss rate at 10 weeks of gestation. The sample size required was calculated to detect an increase of 5% in the pregnancy loss rate (21–26%), with an alpha risk of 0.5 and a power of 0.8. We calculated that 1126 pregnancies were needed in each group, i.e. 3378 in total. PARTICIPANTS/MATERIALS, SETTING, METHODS Data were collected by automatic extraction using the same protocol. All consecutive autologous FET cycles were included: 14 421 cycles (AC: n = 8139; NC: n = 3126; SC: n = 3156) corresponding to 3844 pregnancies (hCG &gt; 100 IU/l) (AC: n = 2214; NC: n = 812; SC: n = 818). Each center completed an online questionnaire describing its routine practice for FET, particularly the reason for choosing one protocol over another. MAIN RESULTS AND THE ROLE OF CHANCE AC represented 56.5% of FET cycles. Mean age of women was 33.5 (SD ± 4.3) years. The mean number of embryos transferred was 1.5 (±0.5). Groups were comparable, except for history of ovulation disorders (P = 0.01) and prior delivery (P = 0.03), which were significantly higher with AC. Overall, the early pregnancy loss rate was 31.5% (AC: 36.5%; NC: 25.6%; SC: 23.6%). Univariable analysis showed a significant association between early pregnancy loss rate and age &gt;38 years, history of early pregnancy loss, ovulation disorders and duration of cryopreservation &gt;6 months. After adjustment (multivariable regression), the early pregnancy loss rate remained significantly higher in AC vs NC (odds ratio (OR) 1.63 (95% CI) [1.35–1.97]; P &lt; 0.0001) and in AC vs SC (OR 1.87 [1.55–2.26]; P &lt; 0.0001). The biochemical pregnancy rate (hCG &gt; 10 and lower than 100 IU/l) was comparable between the three protocols: 10.7% per transfer. LIMITATIONS, REASONS FOR CAUTION This study is limited by its retrospective design that generates missing data. Routine practice within centers was heterogeneous. However, luteal phase support and timing of embryo transfer were similar in AC. Univariable analysis showed no difference between centers. Moreover, a large number of parameters were included in the analysis. WIDER IMPLICATIONS OF THE FINDINGS Our study shows a significant increase in early pregnancy loss when using AC for endometrial preparation before FET. These results suggest either a larger use of NC or SC, or an improvement of AC by individualizing hormone replacement therapy for patients in order to avoid an excess of pregnancy losses. STUDY FUNDING/COMPETING INTEREST(S) The authors declare no conflicts of interest in relation to this work. G.P.-B. declares consulting fees from Ferring, Gedeon-Richter, Merck KGaA, Theramex, Teva; Speaker’s fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter, Theramex, Teva. N.C. declares consulting fees from Ferring, Merck KGaA, Theramex, Teva; Speaker’s fees or equivalent from Merck KGaA, Ferring. C.R. declares a research grant from Ferring, Gedeon-Richter; consulting fees from Gedeon-Richter, Merck KGaA; Speaker’s fees or equivalent from Merck KGaA, Ferring, Gedeon-Richter; E.M.d’A. declares Speaker’s fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Theramex, Teva. I.C-D. declares Speaker’s fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, IBSA. N.M. declares a research grant from Merck KGaA, MSD, IBSA; consulting fees from MSD, Ferring, Gedeon-Richter, Merck KGaA; Speaker’s fees or equivalent from Merck KGaA, MSD, Ferring, Gedeon-Richter, Teva, Goodlife, General Electrics. TRIAL REGISTRATION NUMBER N/A.

Introduction: Rare diseases present unique challenges to meet the numerous and varied needs of the rarediseases community and it is required to identify and address these needs. Significant financial andpersonnel resources are required to address these needs identified. The Office of Rare Diseases Research(ORDR) at the USA National Institutes of Health (NIH) has attempted to meet many of these needs incollaborative efforts with the research Institutes and Centers of NIH and other partners in the private andpublic sectors in the USA and around the world. Several of the activities of the NIH and the ORDR arepresented as possible collaborative efforts available to research investigators and include the Rare DiseasesClinical Research Network, the Bench-to-Bedside research program at NIH, the Genetic and Rare DiseasesInformation center, the genetic test development program, and the information on clinical research studiesmade available through Clinical trials.gov. The value of an appropriate family medical history is discussed asare the provisions of the Genetic Information Non-Discrimination Act of 2008 (GINA). Definitions of rare ororphan diseases vary from country to country and may cause some confusion to the rare diseases community.Conclusions: Rare diseases are not limited by geographical or historical boundaries and global partnershipsof the rare diseases community are experiencing rapid expansion to assist in the development of orphanproducts for the prevention, diagnosis and treatment of rare diseases and conditions. The unmet needs of therare diseases community require additional innovative research and educational programs to reach theextensive global populations affected by the thousands of different rare diseases including activities with theNational Organization for Rare Disorders and the Genetic Alliance.

Background and Objective: Explosives storage is considered one of the most dangerous working parts of mines where the people working there are exposed to all kinds of physical, chemical, and psychological risks and injuries that can negatively affect their health. Therefore, the current research aimed to provide a model for risk assessment of hazards in these warehouses. Materials and Methods: Firstly, using the Fine-Kinney risk assessment method, the effective criteria in determining the risks of explosives warehouse, including including intensity, probability and frequency of exposure were identified. Therafter, the weight of each criterion was calculated using Shannon's entropy method. Finally, the risks of explosives warehouses were determined and prioritized using the ARAS method. Results: Based on Shannon's entropy method calculations, the intensity criterion with a weight of 0.61 was assigned the most weight among the three investigated criteria. Moreover, among the various risks investigated, the use of any flame-producing devices in the warehouse (R14), non-use of special tools while opening the box of explosives (R17), and opening the boxes inside the warehouse (R7) were determined as the most important risks of explosives warehouses. Conclusion: In this study, intensity was determined as the most important criterion, and the use of any flame-producing devices in the warehouse was determined as the most important risk. The proposed method can be used as a risk assessment method to identify the risks in the warehouse of explosives.

Background: Monosodium glutamate (MSG), a commonly used flavouring, mediated hepatotoxic and pro-inflammatory responses. Azithromycin (AZT), an antibiotic with anti-inflammatory activity, may be co-consumed with MSG to present unknown outcomes on the liver, a major organ for the detoxification of xenobiotics. Aim: This study evaluated the effect of AZT and MSG on histologic and biochemical changes in rats’ liver. Methods: Thirty rats in five groups were for seven successive days orally exposed to groups 1, (distilled water 1 mL Kg−1), 2, (MSG 8000 mg/kg), 3, overdose AZT, OAZT (AZT 412.5 mg Kg−1), 4, therapeutic concentration AZT, TAZT, (AZT 82.5mg Kg−1), and 5, (TAZT 82.5 mg Kg−1 + MSG 8000 mg Kg−1). Liver function markers in therats’ serum and liver tissue, and changes in the liver histologic were assessed by acceptable protocols. The mean of numeric data were tested for significance at p value less than 0.05 by analysis of variance (ANOVA). Results: MSG treatment significantly (p<0.05) increased hepatic and serum alanine aminotransferase activity (ALT), aspartate aminotransferase activity (AST), alkaline phosphatase activity (ALP), total bilirubin concentration (T-BIL), and direct bilirubin concentration (D-BIL) but decreased albumin concentration (ALB) compared to control and others. TAZT treatment caused a significant (p<0.05) decrease in these effects unlike MSG and OATZ treatments while TAZT + MSG co-treatment significantly (p<0.05) reversed these effects compared to MSG-treated rats. Rats’ liver sections for rats in groups 2 and 3 showed severe hepatocellular degeneration and necrosis compared to others while those in group 4 (TAZT) showed the normal hepatic histo-architecture comparable to those in group 1 (control). Those in group 5 showed marked cellular swelling and leukocytic infiltration in only the centrilobular areas, suggesting active restorative responses. Conclusion: Thus, TAZT significantly mitigated the compromised histologic and biochemical integrities of liver function due to MSG treatment in rats via probable normalization of their enzymatic and non-enzymatic indicators of liver function. This suggests that TAZT could be useful in managing histologic and biochemical malfunction of rats’ liver due to MSG assault. Peer Review History: Received: 12 October 2023; Revised: 9 November; Accepted: 13 December, Available online: 15 January 2024 Academic Editor: Dr. Marwa A. A. Fayed, University of Sadat City, Egypt, maafayed@gmail.com Received file: Reviewer's Comments: Average Peer review marks at initial stage: 6.0/10 Average Peer review marks at publication stage: 7.0/10 Reviewers: Idoko Alexander, Caritas University, Enugu, Nigeria, idokoalexander1@gmail.com Dr. Dennis Amaechi, MrsFoluBabade Mini Estate, Flat 5 by Old Soldiers Quarter, Sabongari/Bwari, Abuja- Federal Capital Territory, Nigeria. amaechitoexcel@yahoo.com