Economic burden of adverse drug reactions and potential for pharmacogenomic testing in Singaporean adults.

Adverse drug reactions (ADRs) contribute to hospitalization but data on its economic burden is scant. Pre-emptive pharmacogenetic (PGx) testing can potentially reduce ADRs and its associated costs. The objectives of this study were to quantify the economic burden of ADRs and to estimate the breakeven cost of pre-emptive PGx testing in Singapore. We collected itemized costs for 1000 random non-elective hospitalizations of adults admitted to a tertiary-care general hospital in Singapore. The presence of ADRs at admission and their clinical characteristics were reported previously. The economic burden of ADRs was assessed from two perspectives: (1) Total cost and (2) incremental costs. The breakeven cost of PGx testing was estimated by dividing avoidable hospitalization costs for ADRs due to selected drugs by the number of patients taking those drugs. The total cost of 81 admissions caused by ADRs was US$570,404. Costs were significantly higher for bleeding/elevated international normalized ratio (US$9906 vs. US$2251, p = 6.58 × 10-3) compared to other ADRs, and for drugs acting on the blood coagulation system (US$9884 vs. US$2229, p = 4.41 × 10-3) compared to other drug classes. There were higher incremental laboratory costs due to ADRs causing or being present at admission. The estimated breakeven cost of a pre-emptive PGx test for patients taking warfarin, clopidogrel, chemotherapeutic and neuropsychiatric drugs was US$114 per patient. These results suggest that future studies designed to directly measure the clinical and cost impact of a pre-emptive genotyping program will help inform clinical practice and health policy decisions

Kinegami: Algorithmic Design of Compliant Kinematic Chains From Tubular Origami

Origami processes can generate both rigid and compliant structures from the same homogeneous sheet material. In this article, we advance the origami robotics literature by showing that it is possible to construct an arbitrary rigid kinematic chain with prescribed joint compliance from a single tubular sheet. Our “Kinegami” algorithm converts a Denavit–Hartenberg specification into a single-sheet crease pattern for an equivalent serial robot mechanism by composing origami modules from a catalogue. The algorithm arises from the key observation that tubular origami linkage design reduces to a Dubins path planning problem. The automatically generated structural connections and movable joints that realize the specified design can also be endowed with independent user-specified compliance. We apply the Kinegami algorithm to a number of common robot mechanisms and hand-fold their algorithmically generated single-sheet crease patterns into functioning kinematic chains. We believe this is the first completely automated end-to-end system for converting an abstract manipulator specification into a physically realizable origami design that requires no additional human input

A Tendon-Driven Origami Hopper Triggered by Proprioceptive Contact Detection

We report on experiments with a laptop-sized (0.23m, 2.53kg), paper origami robot that exhibits highly dynamic and stable two degree-of-freedom (circular boom) hopping at speeds in excess of 1.5 bl/s (body-lengths per second) at a specific resistance O(1) while achieving aerial phase apex states 25% above the stance height over thousands of cycles. Three conventional brushless DC motors load energy into the folded paper springs through pulley-borne cables whose sudden loss of tension upon touchdown triggers the release of spring potential that accelerates the body back through liftoff to flight with a 20W powerstroke, whereupon the toe angle is adjusted to regulate fore-aft speed. We also demonstrate in the vertical hopping mode the transparency of this actuation scheme by using proprioceptive contact detection with only motor encoder sensing. The combination of actuation and sensing shows potential to lower system complexity for tendon-driven robots. For more information: Kod*lab (link to kodlab.seas.upenn.edu

A Programmably Compliant Origami Mechanism for Dynamically Dexterous Robots

We present an approach to overcoming challenges in dynamical dexterity for robots through programmably compliant origami mechanisms. Our work leverages a one-parameter family of flat sheet crease patterns that folds into origami bellows, whose axial compliance can be tuned to select desired stiffness. Concentrically arranged cylinder pairs reliably manifest additive stiffness, extending the programmable range by nearly an order of magnitude and achieving bulk axial stiffness spanning 200–1500 N/m using 8 mil thick polyester-coated paper. Accordingly, we design origami energy-storing springs with a stiffness of 1035 N/m each and incorporate them into a three degree-of-freedom (DOF) tendon-driven spatial pointing mechanism that exhibits trajectory tracking accuracy less than 15% rms error within a (2 cm)^3 volume. The origami springs can sustain high power throughput, enabling the robot to achieve asymptotically stable juggling for both highly elastic (1 kg resilient shotput ball) and highly damped (“medicine ball”) collisions in the vertical direction with apex heights approaching 10 cm. The results demonstrate that “soft” robotic mechanisms are able to perform a controlled, dynamically actuated task

Renin-angiotensin system blockers and susceptibility to COVID-19:an international, open science, cohort analysis

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been postulated to affect susceptibility to COVID-19. Observational studies so far have lacked rigorous ascertainment adjustment and international generalisability. We aimed to determine whether use of ACEIs or ARBs is associated with an increased susceptibility to COVID-19 in patients with hypertension.Methods: In this international, open science, cohort analysis, we used electronic health records from Spain (Information Systems for Research in Primary Care [SIDIAP]) and the USA (Columbia University Irving Medical Center data warehouse [CUIMC] and Department of Veterans Affairs Observational Medical Outcomes Partnership [VA-OMOP]) to identify patients aged 18 years or older with at least one prescription for ACEIs and ARBs (target cohort) or calcium channel blockers (CCBs) and thiazide or thiazide-like diuretics (THZs; comparator cohort) between Nov 1, 2019, and Jan 31, 2020. Users were defined separately as receiving either monotherapy with these four drug classes, or monotherapy or combination therapy (combination use) with other antihypertensive medications. We assessed four outcomes: COVID-19 diagnosis; hospital admission with COVID-19; hospital admission with pneumonia; and hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis. We built large-scale propensity score methods derived through a data-driven approach and negative control experiments across ten pairwise comparisons, with results meta-analysed to generate 1280 study effects. For each study effect, we did negative control outcome experiments using a possible 123 controls identified through a data-rich algorithm. This process used a set of predefined baseline patient characteristics to provide the most accurate prediction of treatment and balance among patient cohorts across characteristics. The study is registered with the EU Post-Authorisation Studies register, EUPAS35296.Findings: Among 1 355 349 antihypertensive users (363 785 ACEI or ARB monotherapy users, 248 915 CCB or THZ monotherapy users, 711 799 ACEI or ARB combination users, and 473 076 CCB or THZ combination users) included in analyses, no association was observed between COVID-19 diagnosis and exposure to ACEI or ARB monotherapy versus CCB or THZ monotherapy (calibrated hazard ratio [HR] 0·98, 95% CI 0·84-1·14) or combination use exposure (1·01, 0·90-1·15). ACEIs alone similarly showed no relative risk difference when compared with CCB or THZ monotherapy (HR 0·91, 95% CI 0·68-1·21; with heterogeneity of &gt;40%) or combination use (0·95, 0·83-1·07). Directly comparing ACEIs with ARBs demonstrated a moderately lower risk with ACEIs, which was significant with combination use (HR 0·88, 95% CI 0·79-0·99) and non-significant for monotherapy (0·85, 0·69-1·05). We observed no significant difference between drug classes for risk of hospital admission with COVID-19, hospital admission with pneumonia, or hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis across all comparisons.Interpretation: No clinically significant increased risk of COVID-19 diagnosis or hospital admission-related outcomes associated with ACEI or ARB use was observed, suggesting users should not discontinue or change their treatment to decrease their risk of COVID-19.</p

Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A DESTINY-Breast01 Subgroup Analysis.

peer reviewed[en] UNLABELLED: DESTINY-Breast01 (NCT03248492) evaluated trastuzumab deruxtecan (T-DXd; DS-8201) in patients with heavily pretreated HER2-positive metastatic breast cancer (mBC). We present a subgroup of 24 patients with a history of treated brain metastases (BM), a population with limited treatment options. In patients with BMs, the confirmed objective response rate (cORR) was 58.3% [95% confidence interval (CI), 36.6%-77.9%], and the median progression-free survival (mPFS) was 18.1 months (95% CI, 6.7-18.1 months). In patients without BMs (n = 160), cORR was 61.3% and mPFS was 16.4 months. Eight patients (47.1%) experienced a best overall intracranial response of partial response or complete response. Seven patients (41.2%) had a best percentage change in brain lesion diameter from baseline consistent with stable disease. Two patients (8.3%) with BMs and two (1.3%) without BMs experienced progression in the brain. The safety profile of T-DXd was consistent with previous studies. The durable clinical activity of T-DXd in this population warrants further investigation. SIGNIFICANCE: Advances in treating HER2-positive metastatic breast cancer have greatly improved patient outcomes, but intracranial progression remains an important risk for which few therapeutic options are currently available. T-DXd demonstrated durable efficacy in patients with stable, treated BMs. This article is highlighted in the In This Issue feature, p. 2711

SJS/TEN 2019: From science to translation.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs