Systemic amyloidosis from A (AA) to T (ATTR): a review.

Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each caused by a different precursor protein which promotes amyloid formation and tissue deposition. Amyloidosis can be acquired or hereditary and can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues. Symptoms are usually insidious and nonspecific resulting in diagnostic delay. The field of amyloidosis has seen significant improvements over the past decade in diagnostic accuracy, prognosis prediction and management. The advent of mass spectrometry-based shotgun proteomics has revolutionized amyloid typing and has led to the discovery of new amyloid types. Accurate typing of the precursor protein is of paramount importance as the type dictates a specific management approach. In this article, we review each type of systemic amyloidosis to provide the practitioner with practical tools to improve diagnosis and management of these rare disorders.

Observation of topological transitions in interacting quantum circuits.

Topology, with its abstract mathematical constructs, often manifests itself in physics and has a pivotal role in our understanding of natural phenomena. Notably, the discovery of topological phases in condensed-matter systems has changed the modern conception of phases of matter. The global nature of topological ordering, however, makes direct experimental probing an outstanding challenge. Present experimental tools are mainly indirect and, as a result, are inadequate for studying the topology of physical systems at a fundamental level. Here we employ the exquisite control afforded by state-of-the-art superconducting quantum circuits to investigate topological properties of various quantum systems. The essence of our approach is to infer geometric curvature by measuring the deflection of quantum trajectories in the curved space of the Hamiltonian. Topological properties are then revealed by integrating the curvature over closed surfaces, a quantum analogue of the Gauss-Bonnet theorem. We benchmark our technique by investigating basic topological concepts of the historically important Haldane model after mapping the momentum space of this condensed-matter model to the parameter space of a single-qubit Hamiltonian. In addition to constructing the topological phase diagram, we are able to visualize the microscopic spin texture of the associated states and their evolution across a topological phase transition. Going beyond non-interacting systems, we demonstrate the power of our method by studying topology in an interacting quantum system. This required a new qubit architecture that allows for simultaneous control over every term in a two-qubit Hamiltonian. By exploring the parameter space of this Hamiltonian, we discover the emergence of an interaction-induced topological phase. Our work establishes a powerful, generalizable experimental platform to study topological phenomena in quantum systems.

Realization of a Λ System with Metastable States of a Capacitively Shunted Fluxonium.

We realize a Λ system in a superconducting circuit, with metastable states exhibiting lifetimes up to 8 ms. We exponentially suppress the tunneling matrix elements involved in spontaneous energy relaxation by creating a "heavy" fluxonium, realized by adding a capacitive shunt to the original circuit design. The device allows for both cavity-assisted and direct fluorescent readouts, as well as state preparation schemes akin to optical pumping. Since direct transitions between the metastable states are strongly suppressed, we utilize Raman transitions for coherent manipulation of the states.

Prevalence and predictors of thyroid functional abnormalities in newly diagnosed AL amyloidosis.

BACKGROUND: Data on the effect of systemic immunoglobulin light chain amyloidosis (AL amyloidosis) on thyroid function are limited. OBJECTIVE: To assess the prevalence of hypothyroidism in AL amyloidosis patients and determine its predictors. METHODS: 1142 newly diagnosed AL amyloidosis patients were grouped based on the thyroid-stimulating hormone (TSH) measurement at diagnosis: hypothyroid group (TSH above upper normal reference; >5 mIU L-1 ; n = 217, 19% of study participants) and euthyroid group (n = 925, 81%). Predictors for hypothyroidism were assessed in a binary multivariate model. Survival between groups was compared using the log-rank test and a multivariate analysis. RESULTS: Patients with hypothyroidism were older, more likely to present with renal and hepatic involvement and had a higher light chain burden compared to patients in the euthyroid group. Higher proteinuria in patients with renal involvement and lower albumin in patients with hepatic involvement were associated with hypothyroidism. In a binary logistic regression model, age ≥65 years, female sex, renal involvement, hepatic involvement, kappa light chain restriction and amiodarone use were independently associated with hypothyroidism. Ninety-three per cent of patients in the hypothyroid group with free thyroxine measurement had normal values, consistent with subclinical hypothyroidism. Patients in the hypothyroid group had a shorter survival compared to patients in the euthyroid group (4-year survival 36% vs 43%; P = 0.008), a difference that was maintained in a multivariate analysis. CONCLUSION: A significant proportion of patients with AL amyloidosis present with hypothyroidism, predominantly subclinical, which carries a survival disadvantage. Routine assessment of TSH in these patients is warranted.

Universal Stabilization of a Parametrically Coupled Qubit.

We autonomously stabilize arbitrary states of a qubit through parametric modulation of the coupling between a fixed frequency qubit and resonator. The coupling modulation is achieved with a tunable coupling design, in which the qubit and the resonator are connected in parallel to a superconducting quantum interference device. This allows for quasistatic tuning of the qubit-cavity coupling strength from 12 MHz to more than 300 MHz. Additionally, the coupling can be dynamically modulated, allowing for single-photon exchange in 6 ns. Qubit coherence times exceeding 20 µs are maintained over the majority of the range of tuning, limited primarily by the Purcell effect. The parametric stabilization technique realized using the tunable coupler involves engineering the qubit bath through a combination of photon nonconserving sideband interactions realized by flux modulation, and direct qubit Rabi driving. We demonstrate that the qubit can be stabilized to arbitrary states on the Bloch sphere with a worst-case fidelity exceeding 80%.

Utility of component analyses in subjects undergoing sublingual immunotherapy for peanut allergy.

BACKGROUND: Sublingual immunotherapy (SLIT) with peanut changes clinical and immune responses in most peanut-allergic individuals, but the response is highly variable. OBJECTIVE: We sought to examine the component-specific effects of peanut SLIT and determine whether peanut component testing could predict the outcome of a double-blind, placebo-controlled food challenge (DBPCFC) after 12 months of peanut SLIT. METHODS: We included 33 subjects who underwent peanut SLIT with a DBPCFC of 2500 mg of peanut protein performed after 12 months of therapy. Plasma samples from baseline and after 12 months of peanut SLIT were assayed using ImmunoCAP for IgE and IgG4 against whole peanut, Ara h 1, Ara h 2, Ara h 3, Ara h 8, and Ara h 9. RESULTS: Following 12 months of SLIT, 10 subjects (30%) passed the DBPCFC without symptoms and were considered desensitized. Subjects that failed the DBPCFC tolerated a median of 460 mg peanut protein (range: 10-1710 mg). The desensitized group had significantly lower baseline levels of IgE against peanut (median 40.8 vs. 231 kUA /L, P = 0.0082), Ara h 2 (median 17 vs. 113 kUA /L, P = 0.0082), and Ara h 3 (median 0.3 vs. 8.5 kUA /L, P = 0.0396). ROC curves indicated that baseline IgE against peanut and Ara h 2 were equally effective at discriminating between the two groups (AUC = 0.7957, P = 0.007752 for both). CONCLUSION AND CLINICAL RELEVANCE: In this cohort of subjects undergoing SLIT for peanut allergy, lower baseline levels of IgE against Ara h 2, Ara h 3, and peanut were associated with successful desensitization.

T cell epitope immunotherapy ameliorates allergic responses in a murine model of shrimp allergy.

BACKGROUND: Shellfish allergy is one of the most common food hypersensitivities worldwide but allergen-specific immunotherapy for shellfish allergy is not yet available. We believe that T cell peptide-based immunotherapy holds the potential for modulating allergic responses without IgE cross-linking. OBJECTIVE: We sought to identify the immunodominant T cell epitopes of tropomyosin, the major shrimp allergen of Metapenaeus ensis (Met e 1), and to evaluate their therapeutic effects in a Balb/c mouse model of Met e 1 hypersensitivity. METHODS: T cell epitopes of Met e 1 were first identified based on the proliferation and cytokine responses of splenocytes isolated from Met e 1-sensitized Balb/c mice upon stimulation by 18 synthetic peptides that span the full-length Met e 1. The immunodominant T cell peptides identified were then fed orally to Met e 1-sensitized Balb/c mice twice a week for four weeks. Allergic responses, serological antibody levels, intestinal histology and systemic and local cytokine profiles were compared between the treated and the untreated groups. RESULTS: Six major Met e 1 T cell epitopes were identified. Mice treated with the T cell epitope peptide mixture demonstrated an amelioration of systemic allergic symptoms and a significant reduction in Th2-associated antibody and cytokine responses. These benefits were accompanied by a shift to a balanced Th1/Th2 response, induction of IgG2a antibodies possessing in vitro and in vivo blocking activities and the induction of regulatory T cell responses. CONCLUSIONS AND CLINICAL RELEVANCE: T cell epitope-based oral immunotherapy is effective in reducing allergic responses towards shrimp tropomyosin. This is a novel strategy for clinical management of shellfish allergy and is a model for mechanistic studies of oral immunotherapy.

Osteitis and chronic rhinosinusitis: a review of the current literature.

Chronic rhinosinusitis is a common debilitating condition characterized by inflammation of the nose and paranasal sinuses. Osteitis is an associated finding but it is not clear whether it is cause or effect. This review will report on studies that have examined the role of osteitis in CRS, with the ultimate aim of clarifying the definition, pathogenesis and clinical implications of this relatively new clinical entity. Literature searches of Medline, EMBASE and CENTRAL using the search terms osteitis, rhinosinusitis, sinusitis, rhinitis, chronic disease, and recurrence were performed. 21 articles were identified and reviewed. The papers highlighted key pathological features including periosteal thickening, new woven bone formation, bone resorption, fibrosis and inflammatory cell infiltration. Radiological grading systems and basic science research into the role of matrix metalloproteinases and P-glycoprotein were also identified and reviewed.

Prevalence and behavioural risk factors of Staphylococcus aureus nasal colonization in community-based injection drug users.

The aims of this study were to identify Staphylococcus aureus nasal colonization prevalence, behavioural risk factors, and to determine staphylococcal protein A (spa) types in community-based injection drug users (IDUs). Nasal swabs were collected and methicillin susceptibility testing and spa/SCCmec typing were performed on S. aureus isolates. Generalized estimating equations were used to report adjusted odds ratios and 95% confidence intervals. Of the 440 participants, 24·1% were colonized and 5·7% had methicillin-resistant S. aureus (MRSA). Colonization was associated with age, employment/marital status, and the presence of scabs but not with sexually transmitted disease co-infection, HIV status, antibiotic use, hospitalization, or drug treatment programme participation. The USA300 MRSA clone spa types were most common, but 15/49 spa types were new to one of the international databases. Community-based IDUs appear to have different risk factors compared to IDUs from clinical studies. In addition, the number of newly identified spa types indicates a diverse, understudied population.

Qubit Architecture with High Coherence and Fast Tunable Coupling.

We introduce a superconducting qubit architecture that combines high-coherence qubits and tunable qubit-qubit coupling. With the ability to set the coupling to zero, we demonstrate that this architecture is protected from the frequency crowding problems that arise from fixed coupling. More importantly, the coupling can be tuned dynamically with nanosecond resolution, making this architecture a versatile platform with applications ranging from quantum logic gates to quantum simulation. We illustrate the advantages of dynamical coupling by implementing a novel adiabatic controlled-z gate, with a speed approaching that of single-qubit gates. Integrating coherence and scalable control, the introduced qubit architecture provides a promising path towards large-scale quantum computation and simulation.

Mass depopulation of laying hens in whole barns with liquid carbon dioxide: evaluation of welfare impact.

Appropriate emergency disaster preparedness is a key priority for agricultural agencies to allow effective response to serious avian disease outbreaks. There is a need to develop rapid, humane, and safe depopulation techniques for poultry that are widely applicable across a range of farm settings. Whole barn depopulation with carbon dioxide (CO(2)) has been investigated as a humane and efficient means of killing large numbers of birds in the event of a reportable disease outbreak. It has also been considered as a method for depopulating barns containing end-of-lay hens, particularly when there is limited local slaughter and rendering capacity. Determining the best method of humanely killing large flocks of birds remains problematic and is being investigated by a coordinated international effort. While whole barn depopulation using CO(2) inhalation has been explored, physiologic responses of chickens have not been characterized in field settings and assessment of animal welfare is hampered without this information. In this study, 12 cull laying hens were surgically instrumented with telemetry transmitters to record electroencephalographs, electrocardiographs, body temperature, and activity during 2 large-scale field CO(2) euthanasia trials of end-of-lay hens. The day following surgery, instrumented hens were placed in barns with other birds, barns were sealed, and animals were killed by CO(2) inhalation delivered via a specially designed liquid CO(2) manifold. Instrumented birds were monitored by infrared thermography, and ambient temperature, CO(2), and O(2) concentrations were recorded. Results from these studies indicate that instrumented hens lost consciousness within 2 min of CO(2) levels reaching 18 to 20%. Mild to moderate head shaking, gasping, and 1 to 2 clonic muscle contractions were noted in hens before unconsciousness; however, brain death followed rapidly (<5 min). Evaluation of welfare costs and benefits suggest clear advantages over catching and transporting cull hens for slaughter. The financial costs with this method are greater, however, than those estimated for traditional slaughter techniques. Results of these studies are being used to develop national protocols for whole barn depopulation of hens by CO(2) inhalation.

"Real-life" data of the efficacy and safety of belantamab mafodotin in relapsed multiple myeloma-the Mayo Clinic experience.

Belantamab mafodotin is a highly selective targeted therapy for multiple myeloma. It targets the B cell maturation antigen (BCMA) on plasma cells and showed promising results in several randomized clinical trials. We report the outcomes of 36 patients treated at Mayo Clinic. Our cohort received a median of eight prior lines of therapy. Six patients received belantamab in combination with other medications (pomalidomide, cyclophosphamide, thalidomide), 13 patients (36%) were 70 years or older, two patients had a creatinine of >2.5 mg/dL, and one patient was on dialysis. All three patients with renal failure received full dose belantamab. Chimeric antigen receptor (CAR-T) therapy was used prior to belantamab in seven patients and none of them responded to belantamab therapy. The overall response rate (ORR) was 33% (CR 6%, VGPR 8%, PR 19%), like the ORR reported in the DREAMM-2 trial. Keratopathy developed in 16 patients (43%), grade 1 in six patients, grade 2 in seven patients, and grade 3 in three patients. Eight percent discontinued therapy due to keratopathy. The median PFS and OS was 2 months and 6.5 months, respectively.

The outcome of patients with nephrogenic systemic fibrosis after successful kidney transplantation.

Nephrogenic systemic fibrosis (NSF) is a debilitating disease in patients with severely diminished kidney function. Currently, no standard treatment exists but improvement has been reported after restoration of kidney function. We retrospectively studied 17 NSF patients with and without successful kidney transplantation (KTx) to evaluate the effects of KTx on NSF. Nine of the 11 KTx developed NSF pretransplant whereas two developed NSF immediately after KTx with delayed graft function. Two of the six dialysis patients had previous failed kidney transplants. Age and sex were well matched. All but one patient was dialysis dependent at the time of NSF. Median follow-up was 35 months for KTx patients and 9 months for dialysis patients. Kidney transplants achieved adequate renal function with median serum creatinine of 1.4 (0.9-2.8) mg/dL and a glomerular filtration rate of 42 (19-60) mL/min/1.73 m(2). NSF improved in 54.6% of the transplanted patients and 50% of the nontransplanted patients (p = 0.86). Two KTx patients had complete resolution of their symptoms whereas four had partial improvement. Improvement in the dialysis patients was all partial. Successful KTx did not insure improvement in NSF and in fact appeared to have no significant benefit over dialysis.

Clinical characteristics and outcomes of obstetric patients admitted to the Intensive Care Unit: a 10-year retrospective review.

OBJECTIVE: To review the characteristics and health-related quality-of-life outcomes of obstetric patients admitted to the Intensive Care Unit. DESIGN: Retrospective cohort study. SETTING: A regional hospital in Hong Kong. PATIENTS: Consecutive obstetric patients admitted to the Intensive Care Unit of Pamela Youde Nethersole Eastern Hospital from January 1998 to December 2007. RESULTS: Fifty obstetric patients (mean [standard deviation] age, 31 [6] years; mean gestational age, 34 [9] weeks) were analysed. The most common obstetric cause of admission was postpartum haemorrhage (n=19, 38%), followed by pregnancy-associated hypertension (n=7, 14%). The commonest non-obstetric cause of admission was sepsis (n=7, 14%). The commonest intervention was arterial line insertion (n=33, 66%) and mechanical ventilation (n=29, 58%). Maternal mortality was 6% (n=3), while the perinatal mortality rate was 8% (n=4). The average Short Form-36 Health Survey scores of our patients were lower than the norm for the Hong Kong population of the same age and gender. CONCLUSION: Postpartum haemorrhage and pregnancy-associated hypertension were the most common causes of admission to our Intensive Care Unit. Overall mortality was low. Long-term health-related quality of life in discharged patients was lower than the norm of the Hong Kong population. Appropriate antenatal care is important in preventing obstetric complications. Continued psychosocial follow-up of discharged patients has to be implemented.

Improvement of cast nephropathy with plasma exchange depends on the diagnosis and on reduction of serum free light chains.

Cast nephropathy is the most common cause of renal disease in multiple myeloma, however, treatment with plasma exchange remains controversial even after 3 randomized controlled studies. We sought to determine the importance of diagnostic confirmation and goal directed therapy in the treatment of cast nephropathy in forty patients with confirmed multiple myeloma and renal failure who underwent plasma exchange. A positive renal response was defined as a decrease by half in the presenting serum creatinine and dialysis independence. No baseline differences were noted between eventual renal responders and non-responders. Three quarters of the patients with biopsy proven cast nephropathy resolved their renal disease when the free light chains present in the serum were reduced by half or more but there was no significant response when the reduction was less. The median time to a response was about 2 months. In patients without cast nephropathy, renal recovery occurred despite reductions in free light chain levels of the serum. No association was found between free light chains in the serum, urinary monoclonal proteins, overall proteinuria and cast nephropathy. We found that the relationship between renal recovery and free light chain reduction was present only in patients with biopsy proven cast nephropathy showing the importance of extracorporeal light chain removal in this disease.

Erythema dyschromicum perstans: A case report and systematic review of histologic presentation and treatment.

OBJECTIVE: Erythema dyschromicum perstans (EDP) can be difficult to diagnose and treat; therefore, we reviewed the literature to assess whether histology can be used to differentiate lichen planus pigmentosus (LPP) from EDP and determine which treatments are the most effective for EDP. We also present a case of a patient who was treated successfully with narrow-band ultraviolet B (NB-UVB). METHODS: A systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses was conducted up to July 2017 using four databases. RESULTS: Histologic analyses from the literature reveal a significant percentage of melanophages, lymphocytic infiltrates, and basal vacuolar degeneration in EDP, and a significant histologic overlap with LPP. The review of the literature on treatment outcomes showed that NB-UVB and tacrolimus were effective with minimal side effects. Clofazimine was effective, but demonstrated significant-to-intolerable side effects. Griseofulvin, isotretinoin, and dapsone provided unsatisfactory results as lesions recurred after discontinuation. Lasers were largely ineffective and may cause postinflammatory hyperpigmentation and fibrosis. CONCLUSION: A diagnosis of EDP should not be based on histologic findings alone. Clinical history, morphology, and distribution should be used to differentiate EDP and LPP. NB-UVB and tacrolimus are promising treatments for EDP with minimal side effects. This is the first report to our knowledge of sustained resolution of EDP after treatment with NB-UVB at long-term follow-up of 4 years. Larger studies are needed to confirm these findings.

Elevated pre-transplant C-reactive protein identifies a high-risk subgroup in multiple myeloma patients undergoing delayed autologous stem cell transplantation.

The significance of elevated C-reactive protein (CRP) prior to autologous stem cell transplantation (ASCT) in multiple myeloma (MM) has not been studied. We analyzed 1111 MM patients who underwent ASCT at Mayo Clinic from 2007 to 2015. A total of 840 patients (76%) received early ASCT (⩽12 months from diagnosis) and 271 patients (24%) received delayed ASCT (>12 months from diagnosis). Elevated CRP (> upper normal limit (8 mg/L)) was seen in 14% and 22% of patients undergoing early and delayed ASCT, respectively (P=0.003). There was no correlation of CRP with pre-transplant response, bone marrow plasma cell percentage or labeling index. Patients with an elevated CRP had a higher likelihood of having circulating plasma cells prior to ASCT (33 vs 19%; P<0.001). In the early ASCT cohort, the median overall survival (OS) in patients with normal and elevated CRP was not reached and 91 months respectively (P=0.011). In the delayed ASCT cohort, the median OS in respective groups were 73 and 30 months respectively (P<0.001), with elevated CRP being an independent prognostic marker on multivariate analysis (hazard ratio 2.0; 95% confidence interval, 1.0-3.8; P=0.045). Elevated pre-transplant CRP identifies a high-risk population especially in patients undergoing delayed ASCT and should be incorporated in the pre-transplant evaluation.

Publisher Correction: Random access quantum information processors using multimode circuit quantum electrodynamics.

In the original version of this Article, the affiliation details for Peter Groszkowski and Jens Koch were incorrectly given as 'Department of Physics, University of Chicago, Chicago, IL, 60637, USA', instead of the correct 'Department of Physics and Astronomy, Northwestern University, Evanston, Illinois 60208, USA'. This has now been corrected in both the PDF and HTML versions of the Article.