The Likelihood Difference Heuristic and Binary Test Selection Given Situation-Specific Utilities

Consider the task of selecting a medical test to determine whether a patient has a particular disease. Normatively, this requires taking into account (i) the prior probability of the disease, (ii) the likelihood---for each available test---of obtaining a positive result if the medical condition is present or absent, respectively, and (iii) the utilities for both correct and incorrect treatment decisions based upon each possible test result. But these quantities may not be precisely known. Are there strategies that could help identify the test with the highest utility given incomplete information? Here we consider the Likelihood Difference Heuristic (LDH), a simple heuristic that selects the test with the highest difference between the likelihood of obtaining a true positive and a false positive test result, ignoring all other information. We prove that the LDH is optimal when the probability of the disease equals the therapeutic threshold, the probability for which treating the patient and not treating the patient have the same expected utility. By contrast, prominent models of the value of information from the literature, such as information gain, probability gain, and Bayesian diagnosticity, are not optimal under these circumstances. Further results show how, depending on the relationship of the therapeutic threshold and prior probability of the disease, it is possible to determine which likelihoods are more important for assessing tests' expected utilities. Finally, to illustrate the potential relevance for real-life contexts, we show how the LDH might be applied to choosing tests for screening of latent tuberculosis infection.

Case Report: Therapeutic Threshold for Rifampicin-Resistant Tuberculosis in a Patient from Maputo, Mozambique

ABSTRACTWe present a case of a patient in Mozambique, who initiated treatment for rifampicin-resistant tuberculosis (RR-TB) without proof of resistance. For this patient, we estimated the probability of RR-TB using likelihood ratios of clinical arguments. The probability of RR-TB in Mozambique, positive HIV status, and treatment failure after a first treatment and after retreatment were included as confirming arguments, and a rapid molecular test showing rifampicin susceptibility as excluding argument. The therapeutic threshold to start treatment for RR-TB is unknown, but probably lower than 47% and should be calculated to guide clinical decisions.

Intrathoracic infusion therapy of thymic peptides and chemical irritants for malignant pleural effusion: a meta-analysis of 24 randomized controlled trials

Background: To further determine the clinical efficacy and survival of intrathoracic infusion with TPs and chemical irritants and their therapeutic threshold and optimal control regimen to achieve a desired response in malignant pleural effusion (MPE). Methods: We collected all randomized controlled trials (RCTs) of TPs with chemical irritants from Chinese and English databases (from inception until September 2019), and performed a new meta-analysis following the PRISMA guidelines. We measured their bias risk, summarized data using meta-analysis, and evidence quality using the Grades of Recommendation Assessment, Development and Evaluation approach. Results: We collected 24 trials involving three TPs and platinum and 1,592 patients. Most trials had unclear bias risk. TPs with platinum significantly improved complete response [4.02 (3.12 to 5.18)] and quality of life [3.64 (2.34 to 5.66)], the 0.5-year overall survival (OS) rate [5.75 (3.02 to 10.92)], and 1-year OS rate [5.29, (1.71 to 16.36)], and reduced the treatment failure, myelosuppression, and gastrointestinal toxicity. For patients with moderate to large volume of pleural effusion, KPS score ≥50 to 60, or AST ≥3 months, the thymosin (200–300mg/time), thymopentin (2mg/time) or thymosin alpha 1 (3.2mg/time) with cisplatin (30–40mg/m 2 ), carboplatin (400mg/m 2 ), or oxaliplatin (100mg/m 2 ) are possible regimens for achieving a desired success, and low failure. Most results were robust and moderate quality. Conclusion: The moderate evidence suggests that the TPs with platinum is beneficial to the patient with MPE, and provides evidence for the therapeutic threshold and possible regimens that may achieve a desired success and reduce the failure.

P723 Therapeutic thresholds for golimumab serum concentrations during induction and maintenance: Results from the GO-LEVEL study

Background The exposure–response relationship associated with the use of golimumab for UC has been previously demonstrated in the PURSUIT trial programme. A significant association between serum golimumab concentrations (SGC) and favourable outcomes was observed during both induction and maintenance therapy. However, data regarding the optimal therapeutic SGC threshold is limited. Methods GO-LEVEL was an open-label, phase IV, investigator initiated study (NCT03124121) which included a prospective cohort of UC patients commencing golimumab induction therapy, as well as a cross-sectional cohort receiving maintenance treatment (>18 weeks from initiation). Patients commencing induction therapy all had disease activity objectively confirmed and were evaluated at weeks 6, 10 and 14. Patients receiving maintenance therapy were recruited either at the point of flare, or during stable remission. Clinical disease activity was evaluated using SCCAI and PRO2, and biochemical activity using FC and CRP. Combined clinical-biochemical remission was defined as SCCAI<3 as well as FC<250ug/g. SGC and anti-golimumab antibodies (AGA) were measured using a drug-sensitive ELISA (LISATRACKER, Theradiag). Fishers exact or Mann–Whitney U were used to compare groups, ROC analysis to identify therapeutic thresholds and Spearman’s rank coefficient (rs) for correlations. Results Thirty-nine patients were included in the induction cohort, of whom 15 (38%) achieved combined remission at week 6. The median SGC of those in combined remission was significantly higher than those who were not (5.0 vs. 3.1 μg/ml, respectively, p = 0.03). ROC curve analysis demonstrates 3.8 μg/ml as the optimal therapeutic threshold to achieve combined remission at week 6 (sensitivity 0.71, specificity 0.65, AUC 0.72). Significant, inverse correlations were also observed between week 6 SGC and PRO2, CRP and FC (rs −0.41 (p = 0.01), −0.47 (p = 0.004) and −0.40 (p = 0.02), respectively). However, week 6 SGC did not predict outcomes at week 10 or 14. Sixty-four patients were included in the maintenance cohort; 32 (50%) were in combined remission, 32 were not. The median SGC of those in combined remission was significantly higher (3.0 vs. 2.1 μg/ml, respectively, p = 0.003). ROC curve analysis demonstrates 2.4 μg/ml as the optimal therapeutic threshold to achieve combined remission (sensitivity 0.73, specificity 0.66, AUC 0.71). No AGA were detected in either cohort. Conclusion GO-LEVEL offers further evidence of the exposure-response relationship with golimumab. Clinicians may consider using therapeutic drug monitoring to optimise golimumab dosing aiming to achieve our suggested SGC therapeutic thresholds of 3.8 μg/ml at week 6 and 2.4 μg/ml during maintenance.

Thermal safety and effectiveness of tumor treating fields’ delivery to the abdomen as determined by computational simulations.

272 Background: Tumor Treating Fields (TTFields), an antimitotic cancer treatment, utilizes low intensity (1-3 V/cm), intermediate frequency (100-300 kHz), alternating electric fields delivered non-invasively by transducer arrays placed on skin over tumor region. Safety of TTFields has been established in pancreatic cancer (Phase II study; PANOVA; NCT01971281). A Phase 3 study in locally-advanced pancreatic cancer (PANOVA-3) and a phase 2 study in hepatocellular cancer are ongoing. Preclinical studies suggest that TTFields’ intensity correlates with treatment efficacy. Simulations can determine the thermal safety of TTFields by evaluating tissue heating due to field absorption and resultant risk of thermal damage. We used computational simulations to study the effectiveness of field distribution and associated heating in realistic phantoms during TTFields delivery to the abdomen. Methods: Delivery of TTFields to computational phantoms of a male (DUKE 3.0), a female (ELLA 3.0) and an obese male (FATS 3.0) was simulated. For each phantom, 6-8 different transducer array layouts to the abdomen were tested. Specific Absorption Rate (SAR) levels were calculated to assess the risk of thermal damage to tissues, and compared to the SAR control level of 10 W/kg per International Commission on Non-Ionizing Radiation Protection (ICNIRP) guidelines for occupational exposure (Health Physics 74 (4) 494; 1998). The field intensities were measured to determine the effectiveness of treatment delivery. Results: Altering the size and position of the arrays facilitates field intensities above the therapeutic threshold of 1 V/cm. Within the abdominal internal organs, the SAR values were generally below the ICNIRP recommended level of 10 W/kg. The maximum SAR levels did not exceed 20 W/kg. Conclusions: TTFields could be delivered at intensities above therapeutic threshold of 1 V/cm by strategizing the array size and placement. TTFields to the abdomen can be delivered to target gastrointestinal cancers without causing thermal damage to abdominal tissues. These results also indicate that TTFields delivery can be optimized in gastrointestinal cancers.

Onset of analgesic effect and plasma levels of controlled-release tramadol (Tramadol Contramid once-a-day) 200-mg tablets in patients with acute low back pain

Background and Aims: Tramadol hydrochloride, a centrally acting, synthetic analgesic, has been available in Europe since 1977 in a variety of formulations and in the United States since 1995. Its clinical efficacy was established in a variety of painful conditions (cancer pain, neuropathic pain, and osteoarthritis). Nonetheless, little published data exist regarding the relationship between analgesic onset and minimum therapeutic plasma levels. Tramadol Contramid* once-a-day (OAD) demonstrates a pharmacokinetic profile with a sharp initial absorption slope similar to the pharmacokinetic profile of the immediate- release tramadol, suggesting that both the immediaterelease and the once-daily (Contramid) formulation may produce a similar onset of analgesia.Methods: This multicentre, open-label, single-dose study examined the pharmacokinetics/pharmacodynamics of Tramadol Contramid OAD in patients with acute low back pain. Patients who signed informed consent were screened and washed-out of prior analgesics. Patients received one dose of Tramadol Contramid OAD 200 mg. The patients indicated the time of onset of pain relief (stopwatch method). Ratings of pain intensity and pain relief and pharmacokinetic samples were taken prior to dosing, at the onset of pain relief, and 3 and 6 hours postdose. No rescue medication was permitted until the end of the study (6-hour postdose). Adverse events were monitored throughout the study.Results: Forty of the 47 patients enrolled completed the study. Onset of perceptible pain relief was achieved within 1 hour for the majority of patients and at plasma levels, suggesting a therapeutic threshold between 50 and 100 ng/mL. Two patients did not experience any pain relief.Conclusions: The results of this exploratory study suggest that similar to immediate-release tramadol, onset of analgesia for this controlled-release formulation of tramadol (Tramadol Contramid OAD) occurs within 1 hour at a mean therapeutic threshold concentration of 56 ± 38 ng/mL.

The Limitation of Applying Heat to the External Lid Surface: A Case of Recalcitrant Meibomian Gland Dysfunction

The effects on the inner surface temperatures of the upper and lower eyelids of four commercial heat therapies were compared for an individual with recalcitrant meibomian gland dysfunction. Three therapies (Bruder mask, Blephasteam, and MiBoFlo) involved the application of heat to the external lid surface, and the fourth (LipiFlow) applied heat to the internal lid surface. Only LipiFlow was effective in elevating the inner surface temperatures to the reported 40°C therapeutic threshold for melting obstructed meibum.