Exercise hyperthermia induces greater changes in gastrointestinal permeability than equivalent passive hyperthermia.

Hyperthermia and exertional heat illness increase gastrointestinal (GI) permeability, although whether the latter is only via hyperthermia is unclear. The aim of this pilot study was to determine whether different changes in GI permeability, characterized by an increased plasma lactulose:rhamnose concentration ratio ([L:R]), occurred in exercise hyperthermia in comparison to equivalent passive hyperthermia. Six healthy adult male participants (age 25 ± 5 years, mass 77.0 ± 6.7 kg, height 181 ± 6 cm, peak oxygen uptake [ V·O2peak ] 48 ± 8 ml.kg-1 .min-1 ) underwent exercise under hot conditions (Ex-Heat) and passive heating during hot water immersion (HWI). Heart rate (HR), rectal temperature (TCORE ), rating of perceived exertion (RPE), and whole-body sweat loss (WBSL) were recorded throughout the trials. The L:R ratio, peak HR, change in HR, and change in RPE were higher in Ex-Heat than HWI, despite no differences in trial duration, peak core temperature or WBSL. L:R was strongly correlated (p < 0.05) with HR peak (r = 0.626) and change in HR (r = 0.615) but no other variable. The greater L:R in Ex-Heat, despite equal TCORE responses to HWI, indicates that increased cardiovascular strain occurred during exercise, and exacerbates hyperthermia-induced GI permeability at the same absolute temperature.

Cost-effectiveness of low-dose colchicine after myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT).

AIMS: In the randomized, placebo-controlled Colchicine Cardiovascular Outcomes Trial (COLCOT) of 4745 patients enrolled within 30 days after myocardial infarction (MI), low-dose colchicine (0.5 mg once daily) reduced the incidence of the primary composite endpoint of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization. To assess the in-trial period and lifetime cost-effectiveness of low-dose colchicine therapy compared to placebo in post-MI patients on standard-of-care therapy. METHODS AND RESULTS: A multistate Markov model was developed incorporating the primary efficacy and safety results from COLCOT, as well as healthcare costs and utilities from the Canadian healthcare system perspective. All components of the primary outcome, non-cardiovascular deaths, and pneumonia were included as health states in the model as both primary and recurrent events. In the main analysis, a deterministic approach was used to estimate the incremental cost-effectiveness ratio (ICER) for the trial period (24 months) and lifetime (20 years). Over the in-trial period, the addition of colchicine to post-MI standard-of-care treatment decreased the mean overall per-patient costs by 47%, from $502 to $265 Canadian dollar (CAD), and increased the quality-adjusted life years (QALYs) from 1.30 to 1.34. The lifetime per-patient costs were further reduced (69%) and QALYs increased with colchicine therapy (from 8.82 to 11.68). As a result, both in-trial and lifetime ICERs indicated colchicine therapy was a dominant strategy. CONCLUSION: Cost-effectiveness analyses indicate that the addition of colchicine to standard-of-care therapy after MI is economically dominant and therefore generates cost savings.

A Cost-Effectiveness Analysis of Glecaprevir/Pibrentasvir Versus Existing Direct-Acting Antivirals to Treat Chronic Hepatitis C in Japan.

INTRODUCTION: The objective of the study was to evaluate the cost-effectiveness of glecaprevir/pibrentasvir versus other direct-acting antivirals (DAAs) for treating chronic hepatitis C virus (HCV) infections in Japan. METHODS: We developed a health state transition model to capture the natural history of HCV. A cost-effectiveness analysis of DAAs from the perspective of a public healthcare payer in Japan with a lifetime horizon over annual cycles was performed. Treatment attributes, baseline demographics, transition probabilities, health-state utilities, and costs data were extracted from publications. Costs and outcomes were discounted at 2% per annum. In the base case we focused on genotype 1 (GT1) treatment-naïve patients without cirrhosis. The scenario analysis examined a pan-genotype treatment in GT1-3 (i.e., portfolio), treatment-naïve, and treatment-experienced patients. The portfolio cost-effectiveness of DAAs was derived by calculating a weighted average of patient segments defined by treatment history, cirrhosis status, and genotype. RESULTS: The base case results indicated that glecaprevir/pibrentasvir was dominant (i.e., generating higher quality-adjusted life years [QALYs] and lower lifetime costs) compared to all other DAAs. The predicted lifetime risk of hepatocellular carcinoma was 3.66% for glecaprevir/pibrentasvir and sofosbuvir/ledipasvir, 4.99% for elbasvir/grazoprevir, and 5.27% for daclatasvir/asunaprevir/beclabuvir. In scenario analysis the glecaprevir/pibrentasvir (GLE/PIB) portfolio dominated the sofosbuvir (SOF)-based portfolio (namely sofosbuvir/ledipasvir in GT1-2 and sofosbuvir + ribavirin in GT3). The base case probabilistic sensitivity analysis (PSA) showed that glecaprevir/pibrentasvir was cost-effective in 93.4% of the simulations for a willingness-to-pay/QALY range of Japanese yen (JPY) 1.6-20 million. The PSA for the portfolio scenario indicated that the GLE/PIB portfolio was cost-effective in 100% of simulations until the willingness-to-pay/QALY reached JPY 5.2 million; this proportion decreased to 69.4% at a willingness-to-pay/QALY of JPY 20 million. Results were also robust in deterministic sensitivity analyses. CONCLUSION: In GT1 treatment-naïve non-cirrhotic patients GLE/PIB was a cost-effective strategy compared to other DAAs. When a pan-genotypic framework was used, the GLE/PIB portfolio dominated the SOF-based portfolio.

Cost-effectiveness model for a hypothetical monotherapy vs standard of care in adult patients with treatment-resistant depression.

BACKGROUND: Patients with treatment-resistant major depressive disorder (TRD) have limited treatment options. We developed an early stage cost-effectiveness model of TRD to explore the potential value of a hypothetical monotherapy relative to the standard of care (SOC). The relative impacts of the monotherapy's three differentiating features over SOC are explored: efficacy advantage, tolerability advantage, and price premium. METHODS: We adapted an existing economic model of TRD to evaluate the cost-effectiveness of a hypothetical monotherapy for TRD with a 25% efficacy advantage, a 10% tolerability advantage, and a 50% price premium over SOC (selective serotonin reuptake inhibitor plus atypical antipsychotics [SSRI + AAP]). The model is a hybrid of a decision tree that captures patients' outcomes after an 8-week acute treatment phase and a Markov model that simulates patients' depression course through a 10-month maintenance phase. Sensitivity (deterministic and probabilistic) and scenario analyses were conducted to characterize the relative impacts of the monotherapy's three differentiating features over SOC. RESULTS: Over the 12-month time horizon, the hypothetical monotherapy is shown to dominate SOC; it generates lower costs and higher quality-adjusted life years in comparison to SSRI + AAP. Sensitivity and scenario analyses showed that this dominance depends largely on the monotherapy's efficacy and tolerability advantages over SOC. Specifically, a monotherapy with ≥ 12% efficacy or ≥70% tolerability advantage (and a 50% price premium) will always be superior to SSRI + AAP. Between these two extremes, most profiles, nonetheless, generate incremental cost-utility ratios for the monotherapy, which fall below common payer willingness-to-pay thresholds. CONCLUSION: Our adaptation of an existing economic model of TRD provides a flexible platform for researchers to evaluate the efficacy/tolerability improvements required for a successful new TRD product and for decision-makers to assess the cost-effectiveness impact of uncertainties inherent in early stage product development in TRD.

Cost-effectiveness of elagolix versus leuprolide acetate for treating moderate-to-severe endometriosis pain in the USA.

AIM: To assess the cost-effectiveness of elagolix versus leuprolide acetate in women with moderate to severe endometriosis pain. METHODS: A Markov model was developed. The efficacy of leuprolide acetate was derived from statistical prediction models using elagolix trial data. Model inputs were extracted from Phase III clinical trials and published literature. RESULTS: Compared with leuprolide acetate, elagolix generated positive net monetary benefit (NMB) assuming a payer's willingness-to-pay threshold of US$100,000 per quality-adjusted life year over a 1-year time horizon: US$5660 for elagolix 150 mg and US$6443 for elagolix 200 mg. The 2-year NMBs were also positive. CONCLUSION: Elagolix was cost effective versus leuprolide acetate in the management of moderate to severe endometriosis pain over 1- and 2-year time horizons. Results were robust in sensitivity analyses.

Value of a Hypothetical Pharmacogenomic Test for the Diagnosis of Statin-Induced Myopathy in Patients at High Cardiovascular Risk.

We recently conducted two economic evaluations of a hypothetical pharmacogenomic test for statin-induced myopathy (SIM) in patients at high cardiovascular risk. Although the models differed in modeling technique and data inputs, both yielded similar results. We believe our approach to assessing the economic value of a diagnostic test was highly advantageous as it characterized the complete range of false-negative and false-positive test outcomes. We used a broad interpretation of test parameters that reflected physician and patient behavioral responses to the test results and accounted for patient adherence to treatment. Both economic evaluations indicated that a highly accurate pharmacogenomic test for SIM would provide a positive incremental net monetary benefit (INMB) for a provincial payer in Canada. However, the value of the test would depend on its ability to accurately diagnose patients when they experience musculoskeletal pain symptoms and guide patients with a test result indicating no SIM to adhere to treatment. Interestingly, our results indicated that a highly inaccurate test would still yield a positive INMB. We found this surprising result was driven by the imbalance of the risk of cardiovascular events outweighing the risk of rhabdomyolysis in patients at high cardiovascular risk. A highly accurate pharmacogenomic test for SIM in patients at high cardiovascular risk would provide economic value for payers. However, the economic and clinical value of the test would depend on the credibility of the test results and their success in influencing patients without SIM to adhere to therapy.

A Discrete Event Simulation Model to Assess the Economic Value of a Hypothetical Pharmacogenomics Test for Statin-Induced Myopathy in Patients Initiating a Statin in Secondary Cardiovascular Prevention.

BACKGROUND: Statin (HMG-CoA reductase inhibitor) therapy is the mainstay dyslipidemia treatment and reduces the risk of a cardiovascular (CV) event (CVE) by up to 35%. However, adherence to statin therapy is poor. One reason patients discontinue statin therapy is musculoskeletal pain and the associated risk of rhabdomyolysis. Research is ongoing to develop a pharmacogenomics (PGx) test for statin-induced myopathy as an alternative to the current diagnosis method, which relies on creatine kinase levels. The potential economic value of a PGx test for statin-induced myopathy is unknown. METHODS: We developed a lifetime discrete event simulation (DES) model for patients 65 years of age initiating a statin after a first CVE consisting of either an acute myocardial infarction (AMI) or a stroke. The model evaluates the potential economic value of a hypothetical PGx test for diagnosing statin-induced myopathy. We have assessed the model over the spectrum of test sensitivity and specificity parameters. RESULTS: Our model showed that a strategy with a perfect PGx test had an incremental cost-utility ratio of 4273 Canadian dollars ($Can) per quality-adjusted life year (QALY). The probabilistic sensitivity analysis shows that when the payer willingness-to-pay per QALY reaches $Can12,000, the PGx strategy is favored in 90% of the model simulations. CONCLUSION: We found that a strategy favoring patients staying on statin therapy is cost effective even if patients maintained on statin are at risk of rhabdomyolysis. Our results are explained by the fact that statins are highly effective in reducing the CV risk in patients at high CV risk, and this benefit largely outweighs the risk of rhabdomyolysis.

Economic Evaluation of a Pharmacogenomics Test for Statin-Induced Myopathy in Cardiovascular High-Risk Patients Initiating a Statin.

BACKGROUND: Statins are the mainstay hypercholesterolemia treatment and reduce the risk of cardiovascular events in patients. However, statin therapy is often interrupted in patients experiencing musculoskeletal pain or myopathy, which are common in this patient group. Currently, the standard tests for diagnosing statin myopathies are difficult to interpret. A pharmacogenomics (PGx) test to diagnose statin-induced myopathy would be highly desirable. METHODS: We developed a Markov state model to assess the cost-effectiveness of a hypothetical PGx test, which aims to identify statin-induced myopathy in high-risk, secondary prevention cardiovascular patients. The alternative strategy hypothesized is that physicians or patients interrupt the statin therapy in the presence of musculoskeletal pain. Our model includes health states specific to the PGx test outcome which assesses the impact of test errors. RESULTS: Assuming a perfect test, the results indicate that the PGx test strategy dominates when the test costs less than CAN$356, when the strategy is cost neutral. These results are robust to deterministic and probabilistic sensitivity analyses. CONCLUSION: Our base-case results show that a PGx test for statin-induced myopathy in a high-risk, secondary prevention of a cardiovascular event population would be a dominant solution for a test cost of CAN$356 or less. Furthermore, the modelling of the complete range of diagnostic test outcomes provide a broader understanding of the economic value of the pharmacogenomics test.

A model to assess the cost-effectiveness of pharmacogenomics tests in chronic heart failure: the case of ivabradine.

Pharmacogenomics (PGx) tests have the potential of improving the effectiveness of expensive new drugs by predicting the likelihood, for a particular patient, to respond to a treatment. The objective of this study was to develop a pharmacoeconomic model to determine the characteristics and the cost-effectiveness of a hypothetical PGx test, which would identify patients who are most likely to respond to an expensive treatment for chronic heart failure. For this purpose, we chose the example of ivabradine. Our results suggest that the use of a PGx test that could select a subgroup of patients to be treated with an expensive drug has the potential to provide more efficient drug utilization.

Maximal expected benefits from lowering cholesterol in primary prevention for a high-risk population.

AIMS: The objective of this study was to estimate the maximal clinical benefit that could be reasonably expected from a cholesterol-lowering intervention. MATERIALS AND METHODS: We used a hypothetical population at high risk of cardiovascular disease events from three risk assessment models including the Framingham risk function, the Score Canada and the Pooled Cohort Risk Assessment Equations. Our source population were all 55-year-old smoking men with diabetes, hypertension and low HDL. From this population, we identified two different subpopulations named "high" and "low", referring to their cholesterol levels which were set at 8.60 and 4.14 mmol/L respectively. Both subpopulations were identified for each risk assessment model in order to estimate the maximal impact of lowering cholesterol on cardiovascular disease events. RESULTS: Our extrapolations estimated that the maximal theoretical efficacy of a cholesterol-lowering intervention corresponds to a risk ratio ranging between 0.46 and 0.66 over a 10-year period. The number of events prevented during this period were between 21 and 29 per 100 patients which corresponds to a number needed to treat varying from 3.47 to 4.76. CONCLUSIONS: Our estimation showed the maximal clinical benefit that could be reasonably expected by an intervention that would lower total cholesterol in high-risk patients.

Cost-effectiveness of direct-acting antiviral regimen ombitasvir/paritaprevir/ritonavir in treatment-naïve and treatment-experienced patients infected with chronic hepatitis C virus genotype 1b in Japan.

OBJECTIVE: This study compared the cost-effectiveness of chronic hepatitis C virus (HCV) genotype 1b (GT1b) therapy ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) vs daclatasvir + asunaprevir (DCV/ASV) and no treatment in patients without cirrhosis. Cost-effectiveness analyses (CEAs) that compared OBV/PTV/r against DCV/ASV and sofosbuvir/ledipasvir (SOF/LDV) in Y93H mutation-negative, GT1b patients with and without cirrhosis were also included. METHODS: A health state transition model was developed to capture the natural history of HCV. A CEA over a lifetime horizon was performed from the perspective of the public healthcare payer in Japan. Costs, health utilities, and rates of disease progression were derived from published studies. Sustained virologic response (SVR) rates of OBV/PTV/r and DCV/ASV were extracted from Japanese clinical trials. Analyses were performed for treatment-naïve and -experienced patients. Alternative scenarios and input parameter uncertainty on the results were tested. RESULTS: OBV/PTV/r exhibited superior clinical outcomes vs comparators. For OBV/PTV/r, DCV/ASV, and no treatment, the lifetime risk of decompensated cirrhosis in treatment-naïve patients without cirrhosis was 0.4%, 1.4%, and 9.2%, and hepatocellular carcinoma was 6.5%, 11.4%, and 49.9%, respectively. Quality-adjusted life years (QALYs) were higher in treatment-naïve and -experienced patients without cirrhosis treated with OBV/PTV/r (16.41 and 16.22) vs DCV/ASV (15.83 and 15.66) or no treatment (11.34 and 11.23). In treatment-naïve and -experienced patients without cirrhosis, the incremental cost-effectiveness ratios (ICERs) of OBV/PTV/r vs DCV/ASV were JPY 1,684,751/QALY and JPY 1,836,596/QALY, respectively; OBV/PTV/r was dominant compared with no treatment. In scenario analysis, including GT1b patients with and without cirrhosis who were Y93H mutation-negative, the ICER of OBV/PTV/r vs DCV/ASV was below the Japanese willingness-to-pay threshold of JPY 5 million/QALY, while the ICER of SOF/LDV vs OBV/PTV/r was above this threshold; thus, OBV/PTV/r was cost-effective. CONCLUSION: OBV/PTV/r appears to be a cost-effective treatment for chronic HCV GT1b infection against DCV/ASV. OBV/PTV/r dominates no treatment in patients without cirrhosis.

Burden of illness of bone metastases in prostate cancer patients in Québec, Canada: A population-based analysis.

INTRODUCTION: Metastasis of prostate cancer (PC) to bone (metastatic bone disease, MBD) increases morbidity, but Canadian data are lacking on the associated healthcare resource utilization (HCRU) and costs. We quantified MBD-related HCRU and associated costs in this population, and assessed skeletal-related events (SREs), such as pathologic fracture, spinal cord compression, bone radiotherapy, and bone surgery. METHODS: We conducted a retrospective, population-based cohort study using the Québec health insurance agency database. Prescription drug and medical services data were retrieved for patients with ≥1 healthcare claim in 2001 with a PC diagnosis (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] code of 185.xx). Patients with ≥2 MBD-related claims or an SRE were compared with a matched-control group of PC patients without MBD. Patients were followed until death, loss to follow-up, or the end of available data (August 31, 2010). Costs (in 2012 Canadian dollars) were adjusted for age, year of MBD diagnosis, general health status, and baseline resource utilization. RESULTS: Compared with controls (n = 1671), MBD patients (n = 626) had significantly higher HCRU. Adjusted mean (95% confidence interval) all-cause healthcare costs were $11 820 (7248-16 058) higher, and MBD-related costs were $3 091 (1267-4861) higher in MBD patients than in controls. Nearly 50% of MBD patients received radiotherapy within 2.5 years of their MBD diagnosis, but most exited the study without experiencing other SREs. CONCLUSION: MBD imposes a heavy HCRU and cost burden among patients with PC in Canada. Effective therapy is needed to reduce the clinical and economic impact of MBD in this population.

Bias within economic evaluations - the impact of considering the future entry of lower-cost generics on currently estimated incremental cost-effectiveness ratios of a new drug.

BACKGROUND: Most economic evaluation models compare a new patented drug (NPRx) to a generic comparator. Drug costs within these models are usually limited to the retail cost of both drugs at the time of model conception. However, the retail cost of the NPRx is expected to drop once generic versions of this molecule are introduced following the expiration of the NPRx's patent. The objective of this study was to examine the impact on the incremental cost-effectiveness ratio (ICER) of the future introduction of lower-cost generic versions of the NPRx within the model's time horizon. METHODS: We examined the impact of this parameter with the use of two approaches: 1) a mathematical proof identifying its impact on the NPRx's ICER; and 2) applying this parameter to a previously published economic model comparing a NPRx to a generic comparator and identifying what would have been the NPRx's ICER had this model considered this parameter. RESULTS: As expected, both the mathematical proof and the application to the previously published economic model showed that considering the future introduction of lower-cost generic versions of the NPRx within the model's time horizon lowers the NPRx's ICER. The timing of the future entry of lower-cost generic molecules, their relative price compared to that of the patented version, and the discount rate applied to future costs all influenced the results. CONCLUSION: An ICER estimated within economic evaluations comparing NPRx to generic comparators which ignore the future introduction of lower-cost generic versions of the NPRx within the model's time horizon will tend to be overestimated. Inclusion of this parameter should be considered within future economic evaluations.

Value homophily benefits cooperation but motivates employing incorrect social information.

Individuals often judge others based on third-party gossip, rather than their own experience, despite the fact that gossip is error-prone. Rather than judging others on their merits, even when such knowledge is free, we judge based on the opinions of third parties. Here we seek to understand this observation in the context of the evolution of cooperation. If individuals are being judged on noisy social reputations rather than on merit, then agents might exploit this, eroding the sustainability of cooperation. We employ a version of the Prisoner׳s Dilemma, the Donation game, which has been used to simulate the evolution of cooperation through indirect reciprocity. First, we validate the proposition that adding homophily (the propensity to interact with others of similar beliefs) into a society increases the sustainability of cooperation. However, this creates an evolutionary conflict between the accurate signalling of ingroup status versus the veridical report of the behaviour of other agents. We find that conditions exist where signalling ingroup status outweighs honesty as the best method to ultimately spread cooperation.

Impact of mineral and bone disorder on healthcare resource use and associated costs in the European Fresenius medical care dialysis population: a retrospective cohort study.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is associated with mortality in patients with chronic kidney disease (CKD), but the economic consequences of SHPT have not been adequately studied in the European population. We assessed the relationship between SHPT parameters (intact parathyroid hormone [iPTH], calcium, and phosphate) and hospitalisations, medication use, and associated costs among CKD patients in Europe. METHODS: The analysis of this retrospective cohort study used records of randomly selected patients who underwent haemodialysis between January 1, 2005 and December 31, 2006 at participating European Fresenius Medical Care facilities in 10 countries. Patients had ≥ 1 iPTH value recorded, and ≥ 1 month of follow-up after a 3-month baseline period during which SHPT parameters were assessed. Time at risk was post-baseline until death, successful renal transplantation, loss to follow-up, or the end of follow-up. Outcomes included cost per patient-month, rates of hospitalisations (cardiovascular disease [CVD], fractures, and parathyroidectomy [PTX]), and use of SHPT-, diabetes-, and CVD-related medications. National costs were applied to hospitalisations and medication use. Generalised linear models compared costs across strata of iPTH, total calcium, and phosphate, adjusting for baseline covariates. RESULTS: There were 6369 patients included in the analysis. Mean ± SD person-time at risk was 13.1 ± 6.4 months. Patients with iPTH > 600 pg/mL had a higher hospitalisation rate than those with lower iPTH. Hospitalisation rates varied little across calcium and phosphate levels. SHPT-related medication use varied with iPTH, calcium, and phosphate. After adjusting for demographic and clinical variables, patients with baseline iPTH > 600 pg/mL had 41% (95% CI: 25%, 59%) higher monthly total healthcare costs compared with those with iPTH in the K/DOQI target range (150-300 pg/mL). Patients with baseline phosphate and total calcium levels above target ranges (1.13-1.78 mmol/L and 2.10-2.37 mmol/L, respectively) had 38% (95% CI: 27%, 50%) and 8% (95% CI: 0%, 17%) higher adjusted monthly costs, respectively. Adjusted costs were 25% (95% CI: 18%, 32%) lower among patients with baseline phosphate levels below the target range. Results were consistent in sensitivity analyses. CONCLUSIONS: These data suggest that elevated SHPT parameters increase the economic burden of CKD in Europe.

Factors affecting hospital stay in psychiatric patients: the role of active comorbidity.

BACKGROUND: Research on length of stay (LOS) of psychiatric inpatients is an under-investigated issue. In this naturalistic study factors which affect LOS of two groups of patients were investigated, focusing on the impact on LOS of medical comorbidity severe enough to require referral. METHODS: Active medical comorbidity was quantified using referral as the criterion. The study sample consisted of 200 inpatients with the diagnosis of schizophrenia and 228 inpatients suffering from bipolar disorder (type I or II). Jonckheere and Mann-Whitney tests were used to estimate the influence of referrals on LOS, and regression analyses isolated variables associated with LOS separately for each group. RESULTS: Half of the patients needed one or more referrals for a non-psychiatric problem. The most common medical condition of patients with bipolar disorder was arterial hypertension. Inpatients with schizophrenia suffered mostly from an endocrine/metabolic disease - 12% of referrals were for Hashimoto's thyroiditis. A positive linear trend was found between LOS and number of referrals; the effect was greater for schizophrenia patients. The effect of referrals on LOS was verified by regression in both groups. Overall, referred patients showed greater improvement in GAF compared to controls. CONCLUSIONS: To our knowledge this was the first study to investigate physical comorbidity in psychiatric inpatients using the criterion of referral to medical subspecialties. Comorbidity severe enough to warrant referral is a significant determinant of hospital stay. This insight may prove useful in health care planning. The results show lack of effective community care in the case of schizophrenia and negative symptoms may be the cause of this. Our findings call for more attention to be paid to the general medical needs of inpatients with severe mental health and concurrent severe medical comorbidity.