Proteomic profiling for biomarker discovery in heparin-induced thrombocytopenia.

New analytical techniques can assess hundreds of proteins simultaneously with high sensitivity, facilitating the observation of their complex interplay and role in disease mechanisms. We hypothesized that proteomic profiling targeting proteins involved in thrombus formation, inflammation, and the immune response would identify potentially new biomarkers for heparin-induced thrombocytopenia (HIT). Four existing panels of the Olink proximity extension assay covering 356 proteins involved in thrombus formation, inflammation, and immune response were applied to randomly selected patients with suspected HIT (confirmed HIT, n=32; HIT ruled-out, n=38; positive heparin/PF4 [H/PF4] antibodies, n=28). The relative difference in protein concentration was analyzed using a linear regression model adjusted for sex and age. To confirm the test results, soluble P-selectin was determined using ELISA in above mentioned patients and an additional second dataset (n=49). HIT was defined as a positive heparin-induced platelet aggregation test (HIPA; washed platelet assay). Among 98 patients of the primary dataset, the median 4Ts score was 5 in patients with HIT, 4 in patients with positive heparin/PF4 antibodies, and 3 in patients without HIT. The median OD of a polyspecific heparin/PF4 ELISA was 3.0, 0.9, and 0.3, respectively. Soluble P-selectin remained statistically significant after multiple test adjustments. The area under the receiver-operating-characteristics-curve was 0.81 for Olink and 0.8 for ELISA. Future studies shall assess the diagnostic and prognostic value of soluble P-selectin in the management of HIT.

Accuracy of Diagnosing Heparin-Induced Thrombocytopenia.

Importance: Heparin-induced thrombocytopenia (HIT) is a life-threatening condition that requires urgent diagnostic clarification. However, knowledge of the diagnostic utility of the recommended diagnostic tests is limited in clinical practice. Objective: To evaluate the current diagnostic practice for managing the suspicion of HIT. Design, Setting, and Participants: This prospective diagnostic study was conducted from January 2018 to May 2021 among consecutive patients with suspected HIT from 11 study centers in Switzerland, Germany, and the United States. Detailed clinical data and laboratory information were recorded. Platelet factor 4/heparin antibodies were quantified using an automated chemiluminescent immunoassay (CLIA). A washed-platelet heparin-induced platelet activation (HIPA) test was used as a reference standard to define HIT. Exposures: Suspicion of HIT. Main Outcomes and Measures: The primary outcome was the diagnostic accuracy of the 4Ts score, the CLIA, and the recommended algorithm serially combining both tests. Results: Of 1448 patients included between 2018 and 2021, 1318 were available for the current analysis (median [IQR] age, 67 [57-75] years; 849 [64.6%] male). HIPA was positive in 111 patients (prevalence, 8.4%). The most frequent setting was intensive care unit (487 [37.0%]) or cardiovascular surgery (434 [33.0%]). The 4Ts score was low risk in 625 patients (46.8%). By 2 × 2 table, the numbers of patients with false-negative results were 10 (9.0%; 4Ts score), 5 (4.5%; CLIA), and 15 (13.5%; recommended diagnostic algorithm). The numbers of patients with false-positive results were 592 (49.0%; 4Ts score), 73 (6.0%; CLIA), and 50 (4.1%; recommended diagnostic algorithm), respectively. Conclusions and Relevance: In this diagnostic study of patients suspected of having HIT, when the recommended diagnostic algorithm was used in clinical practice, antibody testing was required in half the patients. A substantial number of patients were, however, still misclassified, which could lead to delayed diagnosis or overtreatment. Development of improved diagnostic algorithms for HIT diagnosis should be pursued.

Swiss Survey on current practices and opinions on clinical constellations triggering the search for PNH clones.

This national survey investigated the current practice in Switzerland by collecting participants' opinions on paroxysmal nocturnal hemoglobinuria (PNH) clone assessment and clinical practice. Aim: This study aimed to investigate clinical indications prompting PNH clones' assessment and physician's accessibility of a flow cytometry facility, and also to understand clinical attitudes on the follow-up (FU) of patients with PNH clones. Methods: The survey includes 16 multiple-choice questions related to PNH and targets physicians with a definite level of experience in the topic using two screener questions. Opinion on clinical management was collected using hypothetical clinical situations. Each participant had the option of being contacted to further discuss the survey results. This was an online survey, and 264 physicians were contacted through email once a week for 5 weeks from September 2020. Results: In total, 64 physicians (24.2%) from 23 institutions participated (81.3% hematologists and 67.2% from university hospitals). All had access to flow cytometry for PNH clone testing, with 76.6% having access within their own institution. The main reasons to assess for PNH clones were unexplained thrombosis and/or hemolysis, and/or aplastic anemia (AA). Patients in FU for PNH clones were more likely to be aplastic anemia (AA) and symptomatic PNH. In total, 61% of the participants investigated PNH clones repetitively during FU in AA/myelodysplastic syndromes patients, even when there was no PNH clone found at diagnosis, and 75% of the participants tested at least once a year during FU. Opinions related to clinical management were scattered. Conclusion: The need to adhere to guidelines for the assessment, interpretation, and reporting of PNH clones emerges as the most important finding, as well as consensus for the management of less well-defined clinical situations. Even though there are several international guidelines, clear information addressing specific topics such as the type of anticoagulant to use and its duration, as well as the indication for treatment with complement inhibitors in some borderline situations are needed. The analysis and the discussion of this survey provide the basis for understanding the unmet needs of PNH clone assessment and clinical practice in Switzerland.

Determination of Anti-Xa Inhibitor Plasma Concentrations Using a Universal Edoxaban Calibrator.

A universal calibrator for the determination of all anti-Xa inhibitors would support laboratory processes. We aimed to test the clinical performance of an anti-Xa assay utilizing a universal edoxaban calibrator to determine clinically relevant concentrations of all anti-Xa inhibitors. Following a pilot study, we enrolled 553 consecutive patients taking rivaroxaban, edoxaban, or apixaban from nine study centers in a prospective cross-sectional study. The Technochrom® anti-Xa assay was conducted using the Technoview® edoxaban calibrator. Using ultra-high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS), anti-Xa inhibitor drug concentrations were determined. Sensitivities and specificities to detect three clinically relevant drug concentrations (30 µgL-1, 50 µgL-1, 100 µgL-1) were determined. Overall, 300 patients treated with rivaroxaban, 221 with apixaban, and 32 with edoxaban were included. The overall correlation coefficient (rs) was 0.95 (95% CI 0.94, 0.96). An area under the receiver operating characteristic curve of 0.96 for 30 µgL-1, 0.98 for 50 µgL-1, and 0.99 for 100 µgL-1 was found. The sensitivities were 92.3% (95% CI 89.2, 94.6), 92.7% (89.4, 95.1), and 94.8% (91.1, 97.0), respectively (specificities 82.2%, 93.7%, and 94.4%). In conclusion, the clinical performance of a universal, edoxaban-calibrated anti-Xa assay was solid and most drug concentrations were predicted correctly.

Limited concordance of heparin/platelet factor 4 antibody assays for the diagnosis of heparin-induced thrombocytopenia: an analysis of the TORADI-HIT study.

BACKGROUND: Anecdotal reports suggest that the correlation between heparin/platelet factor 4 (PF4) antibody assays for the diagnosis of heparin-induced thrombocytopenia (HIT) is limited. OBJECTIVES: To investigate the correlation between widely used assays and examine possible factors contributing to variability. METHODS: This is a large, prospective cohort study with 10 participating tertiary care hospitals including 1393 patients with suspected HIT in clinical practice. HIT was defined by a positive heparin-induced platelet activation (HIPA) assay (washed platelet reference standard test). Three different immunoassays were used to measure heparin/PF4 antibodies: chemiluminescent immunoassay, enzyme-linked immunosorbent assay, and particle gel immunoassay. Various factors that could influence the assays were examined: sex (male or female), age (<65 years or ≥65 years), unfractionated heparin exposure, presence of thrombosis, cardiovascular surgery, and intensive care unit. Spearman's correlation coefficients were calculated. Z-scores and diagnostic odds ratios were determined in the aforementioned subgroups of patients. RESULTS: Among 1393 patients, 119 were classified as HIT-positive (prevalence, 8.5%). The median 4Ts score was 5 (IQR, 4-6) in patients with HIT compared with 3 (IQR, 2-4) in patients without HIT. Correlations (rs) between immunoassays were weak (0.53-0.65). Inconsistencies between immunoassays could not be explained by further analyses of z-scored test results and diagnostic odds ratios in subgroups of patients. CONCLUSION: The correlation between widely used heparin/PF4 antibody assays was weak, and key factors could not explain this variability. Standardization of immunoassays is requested to improve comparability.

A machine-learning model for reducing misdiagnosis in heparin-induced thrombocytopenia: A prospective, multicenter, observational study.

Background: Diagnosing heparin-induced thrombocytopenia (HIT) at the bedside remains challenging, exposing a significant number of patients at risk of delayed diagnosis or overtreatment. We hypothesized that machine-learning algorithms could be utilized to develop a more accurate and user-friendly diagnostic tool that integrates diverse clinical and laboratory information and accounts for complex interactions. Methods: We conducted a prospective cohort study including 1393 patients with suspected HIT between 2018 and 2021 from 10 study centers. Detailed clinical information and laboratory data were collected, and various immunoassays were conducted. The washed platelet heparin-induced platelet activation assay (HIPA) served as the reference standard. Findings: HIPA diagnosed HIT in 119 patients (prevalence 8.5%). The feature selection process in the training dataset (75% of patients) yielded the following predictor variables: (1) immunoassay test result, (2) platelet nadir, (3) unfractionated heparin use, (4) CRP, (5) timing of thrombocytopenia, and (6) other causes of thrombocytopenia. The best performing models were a support vector machine in case of the chemiluminescent immunoassay (CLIA) and the ELISA, as well as a gradient boosting machine in particle-gel immunoassay (PaGIA). In the validation dataset (25% of patients), the AUROC of all models was 0.99 (95% CI: 0.97, 1.00). Compared to the currently recommended diagnostic algorithm (4Ts score, immunoassay), the numbers of false-negative patients were reduced from 12 to 6 (-50.0%; ELISA), 9 to 3 (-66.7%, PaGIA) and 14 to 5 (-64.3%; CLIA). The numbers of false-positive individuals were reduced from 87 to 61 (-29.8%; ELISA), 200 to 63 (-68.5%; PaGIA) and increased from 50 to 63 (+29.0%) for the CLIA. Interpretation: Our user-friendly machine-learning algorithm for the diagnosis of HIT (https://toradi-hit.org) was substantially more accurate than the currently recommended diagnostic algorithm. It has the potential to reduce delayed diagnosis and overtreatment in clinical practice. Future studies shall validate this model in wider settings. Funding: Swiss National Science Foundation (SNSF), and International Society on Thrombosis and Haemostasis (ISTH).

Decision-Making among Experts in Advanced Hodgkin Lymphoma.

INTRODUCTION: In the treatment of advanced Hodgkin lymphoma (aHL), based on guidelines a multitude of treatment options are available. The availability of PET-guided decision-making and new therapeutic agents increase the complexity of the decision-making process. METHODS: Thirteen experts of Swiss university and cantonal hospitals in Switzerland were asked to describe their institutional decision-making practice in aHL. Variables influencing the decision-making process were identified, standardized, and converted into decision trees for analysis of consent and discrepancies. The algorithms of all participating experts were analyzed with the objective consensus methodology. RESULTS: Four decision criteria (age, fertility preservation, fitness, and interim PET) and 12 unique treatment regimens were identified. Consensus for the treatment of aHL for young and fit, as well as for older patients without comorbidity, was found. Large heterogeneity was identified with use of a variety of different regimens for unfit patients with aHL and for young female patients with a desire of fertility preservation. CONCLUSIONS: Four major decision criteria were identified allowing the representation of expert's approach to first-line treatment of aHL. Among Swiss experts, consensus for a PET-guided curative treatment of aHL was identified. The use of a multitude of treatment regimens was observed for older and comorbid (unfit) aHL patients, highlighting the need for clinical trials and recommendations for this group of patients.

A multicenter real-world evidence study in the Swiss treatment landscape of chronic myeloid leukemia.

BACKGROUND: The real-world experience of Swiss chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs) is largely unknown, in particular with regard to achievement of response per European Leukemia Net (ELN) criteria and adherence to ELN recommendations. METHODS: This was a retrospective, non-interventional, multicenter chart review of patients with newly diagnosed CML who had received first-line TKI and were solely treated with TKIs between 2010 and 2015, with a minimum follow-up of 18 months, at six Swiss hospitals. Effectiveness was evaluated according to ELN 2013 milestone achievements at 3, 6, 12 and 18 months, and at last follow-up. RESULTS: Data from 63 patients (56% men; median age at diagnosis 55 years) were collected (first-line imatinib [n = 27], nilotinib [n = 27], dasatinib [n = 8], or ponatinib [n = 1]). TKI switches (49 times) and dosing changes (165 times) due to intolerance or insufficient response were frequent. Compared with patients receiving first-line imatinib, a higher proportion of patients receiving first-line nilotinib or dasatinib achieved optimal response at all timepoints, irrespective of subsequent TKI therapy, and a higher proportion of patients treated with first-line nilotinib and dasatinib reached deep molecular response (BCR-ABL1IS ≤ 0.01%) at 18 months (42 and 38%, respectively, versus 27%). Patients who received nilotinib or dasatinib switched therapies less frequently than patients treated with imatinib, irrespective of subsequent TKI therapy. CONCLUSIONS: Although patient numbers were small, this real-world evidence study with patients with CML confirms that ELN guidelines are generally implemented in Swiss clinical practice, with a large proportion of patients achieving ELN 2013 milestones. While TKI use involved all inhibitors approved at the time of the study, an unexpectedly high number of TKI therapy switches suggests a clear difference in TKI use between registration trials and clinical practice.

Prothrombinase-Induced Clotting Time to Measure Drug Concentrations of Rivaroxaban, Apixaban, and Edoxaban in Clinical Practice: A Cross-Sectional Study.

Prothrombinase-induced clotting time (PiCT) is proposed as a rapid and inexpensive laboratory test to measure direct oral anticoagulant (DOAC) drug levels. In a prospective, multicenter cross-sectional study, including 851 patients, we aimed to study the accuracy of PiCT in determining rivaroxaban, apixaban, and edoxaban drug concentrations and assessed whether clinically relevant drug levels could be predicted correctly. Citrated plasma samples were collected, and the Pefakit® PiCT was utilized. Ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to measure drug concentrations. Cut-off levels were established using receiver-operating characteristics curves. We calculated sensitivities and specificities with respect to clinically relevant drug concentrations. Spearman's correlation coefficient between PiCT and drug concentrations was 0.85 in the case of rivaroxaban (95% CI 0.82, 0.88), 0.66 for apixaban (95% CI 0.60, 0.71), and 0.78 for edoxaban (95% CI 0.65, 0.86). The sensitivity to detect clinically relevant drug concentrations was 85.1% in the case of 30 µg L-1 (95% CI 82.0, 87.7; specificity 77.9; 72.1, 82.7), 85.7% in the case of 50 µg L-1 (82.4, 88.4; specificity 77.3; 72.5, 81.5), and 85.1% in the case of 100 µg L-1 (80.9, 88.4; specificity 73.2%; 69.1, 76.9). In conclusion, the association of PiCT with DOAC concentrations was fair, and the majority of clinically relevant drug concentrations were correctly predicted.

Accuracy of a Single, Heparin-Calibrated Anti-Xa Assay for the Measurement of Rivaroxaban, Apixaban, and Edoxaban Drug Concentrations: A Prospective Cross-Sectional Study.

Background: Applying a single anti-Xa assay, calibrated to unfractionated heparin to measure rivaroxaban, apixaban, and edoxaban would simplify laboratory procedures and save healthcare costs. Aim: We hypothesized that a heparin-calibrated anti-Xa assay would accurately measure rivaroxaban, apixaban, and edoxaban drug concentrations and correctly predict clinically relevant drug levels. Methods: This analysis is part of the Simple-Xa study, a prospective multicenter cross-sectional study conducted in clinical practice. Patients treated with rivaroxaban, apixaban, or edoxaban were included. Anti-Xa activity was measured using the Siemens INNOVANCE® Heparin assay. Drug concentrations were determined using ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). Cut-off levels were determined in a derivation dataset (50% of patients) and sensitivities and specificities were calculated in a verification dataset (50% of patients). Results: Overall, 845 patients were available for analysis. Correlation coefficients (r s ) between the heparin-calibrated anti-Xa assay and drug concentrations were 0.97 (95% CI 0.97, 0.98) for rivaroxaban, 0.96 (0.96, 0.97) for apixaban, and 0.96 (0.94, 0.99) for edoxaban. The area under the receiver operating characteristics curve (ROC) was 0.99 for all clinically relevant drug concentrations. In the verification dataset, the sensitivity was 94.2% (95% CI 90.8-96.6) for 30 µg L-1, 95.8% (92.4-98.0) for 50 µg L-1, and 98.7% (95.5-99.9) for 100 µg L-1. Specificities were 86.3% (79.2-91.7), 89.8% (84.5-93.7), and 88.7% (84.2-92.2), respectively. Conclusion: In a large prospective study in clinical practice, a strong correlation of heparin-calibrated anti-Xa measurements with LC-MS/MS results was observed and clinically relevant drug concentrations were predicted correctly.

Imitation of ß-lactam binding enables broad-spectrum metallo-ß-lactamase inhibitors.

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-ß-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential ß-lactamase stable ß-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.

Retinal Manifestation of an Epstein-Barr Virus-Associated Plasma Cell Neoplasm.

We report a case of an uncommon presentation of Epstein-Barr virus (EBV)-associated plasma cell neoplasm in a patient with a history of prostate cancer and hairy cell leukemia (HCL) in remission after chemotherapy. The diagnosis of an EBV-associated plasma cell neoplasm was challenging as initially the findings were also compatible with a recurrence of HCL. We highlight the value of diagnostic vitrectomy to achieve the diagnosis. Our particular case demonstrates the importance of diagnostic pars plana vitrectomy and aqueous analyses in patients with uveitis of an unknown cause to confirm the diagnosis.

Management of transthyretin amyloidosis.

Transthyretin amyloidosis (ATTR amyloidosis) is a disease caused by deposition of transthyretin fibrils in organs and tissues, which causes their dysfunction. The clinical heterogeneity of ATTR amyloidosis and the variable presentation of symptoms at early disease stages, historically meant treatment delays. Diagnostic tools and therapy options of ATTR amyloidosis have markedly improved in recent years. The first Swiss Amyloidosis Network (SAN) meeting (Zurich, Switzerland, January 2020) aimed to define a consensus statement regarding the diagnostic work-up and treatment for systemic amyloidosis, tailored to the Swiss healthcare system. A consortium of 45 clinicians and researchers from all Swiss regions and universities was selected by the SAN committee to represent all sub-specialty groups involved in care of patients with amyloidosis. A steering committee conducted the literature search and analysis, wrote the critical synthesis and elaborated a list of statements that were evaluated by all the participants. These recommendations will improve outcomes and quality of life for patients with ATTR amyloidosis. A global review of these guidelines is planned every 3 years with a formal meeting of all the involved experts.

Automated Thrombin Generation Assay for Rivaroxaban, Apixaban, and Edoxaban Measurements.

Background: The thrombin generation assay (TG) is a promising approach to measure the degree of anticoagulation in patients treated with direct oral anticoagulants (DOAC). A strong association with plasma drug concentrations would be a meaningful argument for the potential use to monitor DOAC. Objectives: We aimed to study the correlation of TG with rivaroxaban, apixaban, and edoxaban drug concentrations in a large, prospective multicenter cross-sectional study. Methods: Five-hundred and fifty-nine patients were included in nine tertiary hospitals. The Technothrombin® TG was conducted in addition to an anti-Xa assay; LC-MS/MS was performed as the reference standard. Results: Correlation (rs) between thrombin generation measurements and drug concentrations was -0.72 for peak thrombin generation (95% confidence interval, CI, -0.77, -0.66), -0.55 for area under the curve (AUC; 95% CI -0.61, -0.48), and 0.80 for lag time (95% CI 0.75, 0.84). In contrast, rs was 0.96 with results of the anti-Xa activity (95% CI 0.95-0.97). Sensitivity with regard to the clinically relevant cut-off value of 50 µgL-1 was 49% in case of peak thrombin generation (95% CI, 44, 55), 29% in case of AUC (95% CI, 24, 34), and 64% in case of lag time (95% CI, 58, 69). Sensitivity of the anti-Xa assay was 95% (95% CI, 92, 97). Conclusions: The correlation of thrombin generation measurements with DOAC drug concentrations was weak, and clinically relevant drug levels were not predicted correctly. Our results do not support an application of TG in the monitoring of DOAC.

Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

A universal anti-Xa assay for rivaroxaban, apixaban, and edoxaban measurements: method validation, diagnostic accuracy and external validation.

A universal anti-Xa assay for the determination of rivaroxaban, apixaban and edoxaban drug concentrations would simplify laboratory procedures and facilitate widespread implementation. Following two pilot studies analysing spiked samples and material from 698 patients, we conducted a prospective multicentre cross-sectional study, including 867 patients treated with rivaroxaban, apixaban or edoxaban in clinical practice to comprehensively evaluate a simple, readily available anti-Xa assay that would accurately measure drug concentrations and correctly predict relevant levels in clinical practice. Anti-Xa activity was measured by an assay calibrated with low-molecular-weight heparin (LMWH) in addition to ultra-high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). As an external validation, LMWH-calibrated anti-Xa activity was also determined in nine external laboratories. The LMWH-calibrated anti-Xa activity correlated strongly with rivaroxaban, apixaban or edoxaban drug levels [rs  = 0·98, 95% confidence interval (CI) 0·98-0·98]. The sensitivity for the clinically relevant cut-off levels of 30, 50 and 100 µg/l was 96·2% (95% CI 94·4-97·4), 96·4% (95% CI 94·4-97·7) and 96·7% (95% CI 94·3-98·1) respectively. Concordant results were obtained in the external validation study. In conclusion, a universal, LMWH-calibrated anti-Xa assay accurately measured rivaroxaban, apixaban and edoxaban concentrations and correctly predicted relevant drug concentrations in clinical practice.

Controlled emission time statistics of a dynamic single-electron transistor.

Quantum technologies involving qubit measurements based on electronic interferometers rely critically on accurate single-particle emission. However, achieving precisely timed operations requires exquisite control of the single-particle sources in the time domain. Here, we demonstrate accurate control of the emission time statistics of a dynamic single-electron transistor by measuring the waiting times between emitted electrons. By ramping up the modulation frequency, we controllably drive the system through a crossover from adiabatic to nonadiabatic dynamics, which we visualize by measuring the temporal fluctuations at the single-electron level and explain using detailed theory. Our work paves the way for future technologies based on the ability to control, transmit, and detect single quanta of charge or heat in the form of electrons, photons, or phonons.

Description of Hb Évora (HBA2: c.106T>C) on an Unexpected Allele in a Swiss Family.

α-Thalassemia (α-thal) is caused by DNA deletions or point mutations in the genes coding for the α-globin chains and can lead to hemolytic anemia in its carriers. If only one of the four α genes is affected, the mutation is mostly discovered by chance, as the carriers are asymptomatic. Hb Évora (HBA2: c.106T>C) is an Hb variant that leads to such an α-thal trait (αTα/αα) and thus, to mild microcytic hypochromic anemia. The mutation was first reported in 2001 and named Hb Évora in 2007 (based on the geographic origin of one of the studied families). It was found in four unrelated families originating from Portugal and the Philippines. We now report the discovery of Hb Évora not only in a proband with no known ancestors from either country, but also on an unexpected allele. Subsequently, her close relatives were studied, revealing the same mutation in her brother. No clear correlation between phenotype and genotype was observed.

Expert recommendation from the Swiss Amyloidosis Network (SAN) for systemic AL-amyloidosis.

Systemic amyloidosis is a heterogeneous group of diseases associated with protein misfolding into insoluble beta-sheet rich structures that deposit extracellularly in different organs, eventually compromising their function. There are more than 30 different proteins, known to be amyloidogenic with “light chain” (AL)-amyloidosis being the most common type, followed by transthyretin (ATTR)-, and amyloid protein A (AA)-amyloidosis. Systemic amyloidosis is a rare disease with an incidence of around 10 patients in 1 million inhabitants. Recently several new therapeutic options have been developed for subgroups of amyloidosis patients, and the introduction of novel therapies for plasma cell myeloma has led to an increase in the therapeutic armamentarium for plasma cell disorders, including AL amyloidosis. Among them, proteasome inhibitors, immunomodulatory agents (-imids), and monoclonal antibodies have been successfully introduced into clinical practice. Still, high-quality data from randomised controlled trials regarding the benefit of these cost-intensive drugs in AL amyloidosis are widely lacking, and due to the rarity of the disease many physicians will not gain routine experience in the management of these frail patients. The diagnosis of AL amyloidosis relies on a close collaboration between clinicians, pathologists, imaging experts, and sometimes geneticists. Diagnosis and treatment options in this complex disorder should be discussed in dedicated multidisciplinary boards. In January 2020, the first meeting of the Swiss Amyloidosis Network took place in Zurich, Switzerland. One aim of this meeting was to establish a consensus guideline regarding the diagnostic work-up and the treatment recommendations for systemic amyloidosis tailored to the Swiss health care system. Forty-five participants from different fields in medicine discussed many aspects of amyloidosis. These are the Swiss Amyloidosis Network recommendations which focus on diagnostic work-up and treatment of AL-amyloidosis.