Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19

Importance Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures Organ support–free days, assigning a value of −1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support–free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support–free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI 90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT0437258

Utilizing heat regeneration within hydraulic pressure accumulator

Tekniikan kehittyessä toimilaitteiden ja järjestelmien suunnittelussa ja toteutuksessa laitteiden ja koneiden energia- ja kustannustehokkuus nousevat jatkuvasti tärkeämpään rooliin. Hydraulisilla toimilaitteilla saavutetaan korkea tehotiheys, mutta järjestelmien kokonaishyötysuhde on usein heikko. Hyötysuhdetta voidaan nostaa lisäämällä järjestelmiin energian talteenotto, jolloin työkierroista voidaan normaalisti hukkaan menevää energiaa varastoida ja käyttää uudelleen seuraavassa työkierrossa. Hydraulisissa energian talteenottojärjestelmissä energiaa varastoidaan tyypillisesti hydraulipaineakkuihin. Paineakuissa energia varastoituu puristamalla paineakun kaasutilavuudessa olevaa kaasua. Puristusvaiheen aikana kaasun lämpötila nousee ja lämpö alkaa virrata paineakusta ympäristöön. Tämä energian virtaaminen ympäristöön muodostaa merkittävimmän yksittäisen paineakun hyötysuhdetta laskevan tekijän. Tämän työn tavoitteena oli nostaa mäntäpaineakun hyötysuhdetta hyödyntämällä lämmön regenerointia. Lämmön regeneroinnilla pyritään varastoimaan kaasussa puristusvaiheessa syntyvä lämpöenergia lämpöregeneraattoriin ja luovuttamaan energia takaisin kaasuun paineakun purkusyklin aikana. Työssä suunniteltu lämpöregeneraattori perustui faasimuutosmateriaalien hyödyntämiseen energiavarastona. Faasimuutosmateriaalit soveltuvat erinomaisesti lämpövarastoiksi, sillä ne kykenevät sitomaan suuren määrän energiaa faasimuutoksen aikana, jolloin työssä suunniteltu lämpöregeneraattori saatiin mahdutettua mäntäpaineakun sisälle. Työssä saatujen mittaustuloksien perusteella pääteltiin, että lämpöregeneraattorin dynamiikan merkitys nousi merkittävämmäksi kuin lämpöregeneraattorin kyky varastoida lämpöenergiaa. Lämpöregeneraattorin hidas dynamiikka ei mahdollista tehokasta energian talteenottoa nopeista puristus- tai purkusykleistä, ja tämän takia lämpöregeneraattorista saatava hyöty jäi pieneksi. Työssä toteutetulla lämpöregeneraattorilla saavutettiin parhaimmillaan 3 prosenttiyksikön hyötysuhteen nousu verrattaessa samaan mäntäpaineakkuun ilman lämmön regenerointia.As new technological advances are made the importance of energy efficiency and cost effective solutions are even more important when designing and producing new machine systems. Hydraulic systems offer great performance in different actuators, but the general efficiency of the whole hydraulic systems is usually low. Energy efficiency can be improved by utilizing energy recovery systems. With energy recovery some of the normally wasted energy can be recovered and used in the next work cycle. Hydraulic energy recovery systems usually store energy in hydraulic pressure accumulators. Within the hydraulic pressure accumulator, energy is stored by compressing gas inside the accumulator’s gas volume. When compressing gas, heat builds up within the gas and temperature difference between the gas and its surroundings causes heat energy to flow out of the gas. This energy flow is the single most significant factor lowering energy efficiency of the accumulator. The goal of this study was to increase the efficiency of piston type hydraulic pressure accumulator by utilizing heat regeneration. With heat regeneration, heat energy that is generated in the gas during compression cycle is stored in the heat regenerator to be released during the following decompression cycle. Heat regenerator designed in this study utilizes phase change materials to store heat energy. Phase change materials absorb a lot of energy during phase change and thus they are commonly used as heat storages. The results obtained in this study indicate that the dynamic properties of the heat regenerator are more important than the capability to store heat energy. Low dynamic properties prevent the heat regenerator from storing and releasing energy effectively during fast compression and decompression cycles. With the heat regenerator designed in this study the energy efficiency of the accumulator increased by maximum of 3 percentage units when compared to the same accumulator without heat regeneration