Treatment selection using prototyping in latent-space with application to depression treatment

Machine-assisted treatment selection commonly follows one of two paradigms: a fully personalized paradigm which ignores any possible clustering of patients; or a sub-grouping paradigm which ignores personal differences within the identified groups. While both paradigms have shown promising results, each of them suffers from important limitations. In this article, we propose a novel deep learning-based treatment selection approach that is shown to strike a balance between the two paradigms using latent-space prototyping. Our approach is specifically tailored for domains in which effective prototypes and sub-groups of patients are assumed to exist, but groupings relevant to the training objective are not observable in the non-latent space. In an extensive evaluation, using both synthetic and Major Depressive Disorder (MDD) real-world clinical data describing 4754 MDD patients from clinical trials for depression treatment, we show that our approach favorably compares with state-of-the-art approaches. Specifically, the model produced an 8% absolute and 23% relative improvement over random treatment allocation. This is potentially clinically significant, given the large number of patients with MDD. Therefore, the model can bring about a much desired leap forward in the way depression is treated today.

Prevalence of drug-drug interactions in older people before and after hospital admission: analysis from the OPERAM trial

(N = 351) Background Drug-drug interactions (DDIs) are highly prevalent in older patients but little is known about prevalence of DDIs over time. Our main objective was to assess changes in the prevalence and characteristics of drug-drug interactions (DDIs) during a one-year period after hospital admission in older people, and associated risk factors. Methods We conducted a sub-study of the European OPERAM trial (OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people), which assessed the effects of a structured medication review (experimental arm) compared to usual care (control arm) on reducing drug-related hospital readmissions. All OPERAM patients (≥70 years, with multimorbidity and polypharmacy, hospitalized in four centers in Bern, Brussels, Cork and Utrecht between December 2016 and October 2018, followed over 1 year) who were alive at hospital discharge and had full medication data during the index hospitalization (at baseline i.e., enrolment at admission, and at discharge) were included. DDIs were assessed using an international consensus list of potentially clinically significant DDIs in older people. The point-prevalence of DDIs was evaluated at baseline, discharge, and at 2, 6 and 12 months after hospitalization. Logistic regression models were performed to assess independent variables associated with changes in DDIs 2 months after baseline. Results Of the 1950 patients (median age 79 years) included, 1045 (54%) had at least one potentially clinically significant DDI at baseline; point-prevalence rates were 58, 57, 56 and 57% at discharge, and 2, 6 and 12 months, respectively. The prevalence increased significantly from baseline to discharge (P < .001 [significant only in the control group]), then remained stable over time (P for trend .31). The five most common DDIs –all pharmacodynamic in nature– accounted for 80% of all DDIs and involved drugs that affect potassium concentrations, centrally-acting drugs and antithrombotics. At 2 months, DDIs had increased in 459 (27%) patients and decreased in 331 (19%). The main factor predictive of a change in the prevalence of DDIs was hyperpolypharmacy (≥10 medications). Conclusions DDIs were very common; their prevalence increased during hospitalization and tended to remain stable thereafter. Medication review may help control this increase and minimize the risk of adverse drug events.

The Poised Cannula Technique Reduces the Stereotactic Error of the Fiducial-Less Frameless DBS Procedure

<b><i>Background:</i></b> In this study, we describe a technique of optimizing the accuracy of frameless deep brain stimulation (DBS) lead placement through the use of a cannula poised at the entry to predict the location of the fully inserted device. This allows real-time correction of error prior to violation of the deep gray matter. <b><i>Methods:</i></b> We prospectively gathered data on radial error during the operative placements of 40 leads in 28 patients using frameless fiducial-less DBS surgery. Once the Nexframe had been aligned to target, a cannula was inserted through the center channel of the BenGun until it traversed the pial surface and a low-dose O-arm spin was obtained. Using 2 points along the length of the imaged cannula, a trajectory line was projected to target depth. If lead location could be improved, the cannula was inserted through an alternate track in the BenGun down to target depth. After intraoperative microelectrode recording and clinical assessment, another O-arm spin was obtained to compare the location of the inserted lead with the location predicted by the poised cannula. <b><i>Results:</i></b> The poised cannula projection and the actual implant had a mean radial discrepancy of 0.75 ± 0.64 mm. The poised cannula projection identified potentially clinically significant errors (avg 2.07 ± 0.73 mm) in 33% of cases, which were reduced to a radial error of 1.33 ± 0.66 mm (<i>p</i> = 0.02) after correction using an alternative BenGun track. The final target to implant error for all 40 leads was 1.20 ± 0.52 mm with only 2.5% of errors being &#x3e;2.5 mm. <b><i>Conclusion:</i></b> The poised cannula technique results in a reduction of large errors (&#x3e;2.5 mm), resulting in a decline in these errors to 2.5% of implants as compared to 17% in our previous publication using the fiducial-less method and 4% using fiducial-based methods of DBS lead placement.

How Much Scaphoid Can be Safely Resected? A Biomechanical Analysis of the Effects of Distal Scaphoid Resection

Background: Resection of the distal pole of the scaphoid has been advocated as a simple alternative to other wrist salvage procedures for scaphoid nonunion advanced collapse and scaphotrapezio-trapezoid arthritis. However, the extent of scaphoid that may be resected without adversely affecting carpal kinematics has never been clearly defined. Methods: Seven cadaveric upper extremities were tested in a custom motion wrist simulator. A 3-stage sequential sectioning of the distal scaphoid protocol was performed in 25% increments then cyclic active wrist flexion-extension and dart thrower’s motion trials were recorded. Results: The extent of distal scaphoid resection had no effect on overall wrist range of motion. The lunate assumed a more extended position following resection of the distal scaphoid compared to intact. At 25%, 50%, and 75% of distal scaphoid resection, the lunate extended to 13.32° ± 9.4°, 23.43° ± 7.5°, and 15.81° ± 16.9°, respectively. The capitate migrated proximally with 25% and 50% distal scaphoidectomy, and proximally and radially with 75% of the scaphoid resected. Resection of 75% of the scaphoid resulted in unstable wrist kinematics. Conclusions: Resection of up to 25% of the distal scaphoid did not significantly influence carpal kinematics and induced mild lunate extension deformity. Resection of 50% of the scaphoid induced further and potentially clinically significant lunate extension and dorsal intercalated segment instability. Further removal of 75% of the distal scaphoid induced capitate migration radially and unpredictable wrist kinematics. Consequently, removal of over 25% of the scaphoid should be avoided or supplemented with partial wrist fusion.

Economic analysis of the prevalence and clinical and economic burden of medication error in England

ObjectivesTo provide national estimates of the number and clinical and economic burden of medication errors in the National Health Service (NHS) in England.MethodsWe used UK-based prevalence of medication errors (in prescribing, dispensing, administration and monitoring) in primary care, secondary care and care home settings, and associated healthcare resource use, to estimate annual number and burden of errors to the NHS. Burden (healthcare resource use and deaths) was estimated from harm associated with avoidable adverse drug events (ADEs).ResultsWe estimated that 237 million medication errors occur at some point in the medication process in England annually, 38.4% occurring in primary care; 72% have little/no potential for harm and 66 million are potentially clinically significant. Prescribing in primary care accounts for 34% of all potentially clinically significant errors. Definitely avoidable ADEs are estimated to cost the NHS £98 462 582 per year, consuming 181 626 bed-days, and causing/contributing to 1708 deaths. This comprises primary care ADEs leading to hospital admission (£83.7 million; causing 627 deaths), and secondary care ADEs leading to longer hospital stay (£14.8 million; causing or contributing to 1081 deaths).ConclusionsUbiquitous medicines use in health care leads unsurprisingly to high numbers of medication errors, although most are not clinically important. There is significant uncertainty around estimates due to the assumption that avoidable ADEs correspond to medication errors, data quality, and lack of data around longer-term impacts of errors. Data linkage between errors and patient outcomes is essential to progress understanding in this area.

Effect of Alemtuzumab Infusions on Vital Signs

Background: Alemtuzumab efficacy and safety were established in phase 3 randomized trials. We characterize vital signs during and after the first alemtuzumab infusion course. Methods: Patients with relapsing-remitting multiple sclerosis commercially prescribed alemtuzumab 12 mg/day on 5 consecutive days (initial course) were enrolled in this prospective, observational study. Preinfusion medications included methylprednisolone, antihistamine, and antipyretics. Primary end point: change from precourse baseline in vital signs during and 2 hours after each alemtuzumab infusion. Secondary end points: infusion duration and serious adverse events (AEs) starting within 24 hours and within 7 days after infusion (AEs collected up to 15 days after treatment). Potentially clinically significant vital sign abnormalities were based on predefined thresholds from literature review. Results: In the 304 patients treated, minimal increases in mean systolic (≤8 mm Hg) and diastolic (≤3 mm Hg) blood pressures from precourse baseline were observed on infusion days 3 to 5. An increase in mean heart rate (20 beats per minute) during the first infusion day normalized by day 2, and smaller increases (5 beats per minute) occurred during subsequent infusions. Serious AEs occurred in two patients (0.7%) during or within 24 hours after infusion and in three patients (1.0%) within 7 days. Mean/median infusion duration was 4 hours. Vital sign abnormalities with potential clinical significance occurred in 62.5% of patients. Conclusions: Although most patients had potentially clinically significant vital sign abnormalities, mean changes from baseline during and after infusion of the first alemtuzumab course were clinically insignificant. No new safety signals were detected.