Non-susceptible Patients Research Articles

PHS119 - Health Care Cost in the Last Year of Life In People with a Private Health Policy from Colombia

To measure the real costs of terminal diseases treated in Colombia in people of a private health insurer policy and compare the level of complexity of the medical services. Retrospective review of 162 patients who died from January 1st to December 31th 2015 were studied. There were identified those patients susceptible to palliative care in accord with the McNamara criteria. Cost of attention were classified according to the susceptibility of palliative care and the level of complexity of the providers of health care. Costs were calculated using the cost per activity system. 56.8% of patients where susceptible of palliative care, corresponding to 92 patients. The median cost of attentions for susceptible population where $ 81,854,586 Colombian pesos (COP), 2.5 times higher than the median cost of attentions for non-susceptible patients ($ 32,932,218 COP). High complexity medical attentions has a large predominance in the average cost of the last year with 60% of the total, becoming 74% of the total in the last month of life. The weights of all levels II (medium complexity) are significantly reduced as of the end of life approaches, going from 35% in the last year to 13% in the proportion of the last month's cost. Home care cost (Level I ), represents 5% of costs in the last year, being 15% in the last month of life. Health care cost nearing death is expensivest than the cost attended in the hole life of a person, and requires an efficient management to improve a better quality of life. Patients susceptible to palliative care had significantly higher costs than those non susceptible. The level of complexity of the medical care is associated with higher health care costs. The cost-effectiveness of such level of care is questioned and further study warranted.

Sinusoidal obstruction syndrome/veno-occlusive disease complication in lymphoma patients treated with oxaliplatin-based regimen: A case series report

AimSOS/VOD is a relevant clinical syndrome that usually appears early after hematopoietic stem cell transplantation. The purpose of this article was to report a case series of SOS/VOD in non-susceptible patients and draw physicians’ attention to the plausible relationship between liver injury and oxaliplatin-based chemotherapy, preceding autologous transplantation. MethodsIn this study, we report a case series of SOS/VOD in 4 lymphoma patients following autologous transplantation. The data were collected between July 2013 and November 2015 by analyzing patient's characteristics and outcomes. ResultsWe noticed 4 severe cases of SOS with unusual presentations in patients who did exhibit few classical risk factors. These patients received R-DHAO before transplantation. ConclusionsPhysicians need to be aware that oxaliplatin-based regimen could contribute to SOS/VOD complications in hematological patients.

Bagging survival tree procedure for variable selection and prediction in the presence of nonsusceptible patients

BackgroundFor clinical genomic studies with high-dimensional datasets, tree-based ensemble methods offer a powerful solution for variable selection and prediction taking into account the complex interrelationships between explanatory variables. One of the key component of the tree-building process is the splitting criterion. For survival data, the classical splitting criterion is the Logrank statistic. However, the presence of a fraction of nonsusceptible patients in the studied population advocates for considering a criterion tailored to this peculiar situation.ResultsWe propose a bagging survival tree procedure for variable selection and prediction where the survival tree-building process relies on a splitting criterion that explicitly focuses on time-to-event survival distribution among susceptible patients.A simulation study shows that our method achieves good performance for the variable selection and prediction. Different criteria for evaluating the importance of the explanatory variables and the prediction performance are reported. Our procedure is illustrated on a genomic dataset with gene expression measurements from early breast cancer patients.ConclusionsIn the presence of nonsusceptible patients among the studied population, our procedure represents an efficient way to select event-related explanatory covariates with potential higher-order interaction and identify homogeneous groups of susceptible patients.

Biomarker Classifiers for Identifying Susceptible Subpopulations for Treatment Decisions

A main goal of pharmacogenomics is to develop genomic signatures to predict patients' responses to a drug or therapy for treatment decisions. Identification of patients who would have no beneficial effect or have the risk of developing adverse effects from an unnecessary treatment could save enormous cost in the healthcare system and clinical trials. This article presents an approach for developing a biomarker classifier for identifying a fraction of susceptible patients, who should be spared unnecessary treatment prior to treatment. The identification of susceptible patients involves two steps. The first step is to identify biomarkers of susceptibility from a mixture of biomarkers of susceptibility and biomarkers of response; the second step is to develop a classifier using an ensemble classification algorithm, as the number of susceptible patients is generally much smaller than the number of nonsusceptible patients. Selection of the biomarkers of susceptibility is essential to achieve good prediction accuracy. The ensemble algorithm significantly improves the prediction accuracy compared with the standard classifiers. The study shows that classifiers developed based on the biomarkers obtained by comparing the genomic profiles of responders to those of nonresponders may lead to a high misclassification error rate. Classifiers to identify a small fraction of the subpopulation should take imbalanced class sizes into consideration. A large sample size may be needed in order to ensure detection of a sufficient number of biomarkers and a sufficient number of susceptible subjects for classifier development and validation.

Safety of Exposure of Malignant Hyperthermia Non-Susceptible Patients and Their Relatives to Anaesthetic Triggering Agents

As the reliability of malignant hyperthermia normal in vitro contracture test results has been questioned, this study set out to determine the reliability of malignant hyperthermia normal results in New Zealand. Three hundred and twenty-nine anaesthetics were administered to malignant hyperthermia normal patients, identified through the Palmerston North Hospital malignant hyperthermia database. Anaesthetic records were retrieved and scrutinised for a malignant hyperthermia reaction using the Malignant Hyperthermia Clinical Grading Scale. Patients were exposed to one or more of eight triggering agents and multiple anaesthetic agents were administered in 41% of cases. Six variables were analysed, and although a minority of variables were abnormal in a small number of patients, none of the findings supported a malignant hyperthermia reaction. While the analysis was limited by the adequacy of the anaesthesia records, it was supported by negative DNA analysis in 55% of patients. This study supports several previous studies in demonstrating that patients in New Zealand tested non-susceptible to malignant hyperthermia can safely be given triggering agents.

Cure frailty models for survival data: Application to recurrences for breast cancer and to hospital readmissions for colorectal cancer

Owing to the natural evolution of a disease, several events often arise after a first treatment for the same subject. For example, patients with a primary invasive breast cancer and treated with breast conserving surgery may experience breast cancer recurrences, metastases or death. A certain proportion of subjects in the population who are not expected to experience the events of interest are considered to be 'cured' or non-susceptible. To model correlated failure time data incorporating a surviving fraction, we compare several forms of cure rate frailty models. In the first model already proposed non-susceptible patients are those who are not expected to experience the event of interest over a sufficiently long period of time. The other proposed models account for the possibility of cure after each event. We illustrate the cure frailty models with two data sets. First to analyse time-dependent prognostic factors associated with breast cancer recurrences, metastases, new primary malignancy and death. Second to analyse successive rehospitalizations of patients diagnosed with colorectal cancer. Estimates were obtained by maximization of likelihood using SAS proc NLMIXED for a piecewise constant hazards model. As opposed to the simple frailty model, the proposed methods demonstrate great potential in modelling multivariate survival data with long-term survivors ('cured' individuals).

Clinical and radiographic study of implant treatment outcome in periodontally susceptible and non‐susceptible patients: a prospective long‐term study

To evaluate the implant survival rate, periodontal and radiographic parameters of non-submerged screw implants with two different surfaces (TPS and SLA) in periodontally non-susceptible patients (NSP) and in patients with chronic adult periodontitis (CAP) or with generalized aggressive periodontitis (GAP). In 110 healthy partially edentulous subjects, 68 patients with CAP and 16 patients with GAP, a total of 513 implants were installed and followed for on average 48.1+/-25.9 months. Only fixed partial dentures were used as suprastructures. All patients were offered a supportive periodontal maintenance program. Smoking habits, health impairment, plaque score, bleeding on probing (BOP), type of surface, bone score, bone loss on radiographs and the number of failed implants were noted. Implant survival in the NSP and CAP group was 98% and 96% after 140 months (NS), but only 80% after 100 months in the GAP group (P=0.0026). The overall rate of implant loss was 4.7%, but 15.25% in the GAP group (6/16 patients). The average marginal bone loss for all implants was 0.12+/-0.71 mm on the mesial side and 0.11+/-0.68 mm on the distal side. Bone loss/year was 0.08+/-0.31 and 0.07+/-0.3 mm in the NSP group, but 0.17+/-0.2 and 0.17+/-0.19 mm in the GAP group. Only in the GAP group, was bone loss significantly related to BOP, age, inflammation, presence of plaque, probing depth. Implants with a TPS surface had a lower survival than implants with an SLA surface (93% vs. 97%; P=0.06), especially in the GAP group (80% vs. 83%; P=0.005). Smoking habits had a significant influence on implant survival only in the GAP group (P=0.07), declining in current smokers to 63%, and to 78% in former smokers. Overall, impaired general health had no significant influence (P=0.85). However, impaired health further reduced implant survival in the GAP group (survival: 71%). In a statistical model to predict the chance for implant failing, only periodontal classification (P=0.012) and implant surface type (P=0.027) were significant. Periodontally healthy patients and patients with CAP show no difference in peri-implant variables and implant survival rate, but patients with GAP have more peri-implant pathology, more marginal bone loss and a lower implant survival implant rate. SLA surface had a better prognosis than the TPS surface.

Follow-up of patients tested for malignant hyperthermia susceptibility

Malignant hyperthermia is an inherited disorder of skeletal muscle characterized by muscle contracture and hypermetabolic crisis following exposure to halogenated anaesthetics and depolarizing muscle relaxants. We planned this follow-up to get more information about the safety of non-triggering anaesthesia in susceptible patients; the safety of the use of trigger agents in non-susceptible patients and any minor sequelae following the biopsy. A questionnaire was sent to 244 patients tested for susceptibility between 1998 and 2004 enquiring about sequelae from the biopsy, subsequent experience with anaesthesia and difficulties encountered because of the investigation. Replies were received from 129 patients. Thirty-four complained about sequelae from the biopsy: 10 reported headache and nausea; 16 experienced pain and a lack of strength in the biopsed leg and 8 found the scar less than satisfactory. Ten patients found it difficult to find a diagnostic centre. Eighteen reported problems and/or delay when they had needed a subsequent anaesthetic. Fourteen patients found the anaesthesiologist reluctant to anaesthetize them and four experienced a delay. Forty-three patients received anaesthesia since their biopsy. Complete medical records were available for 24 anaesthetic exposures in 23 patients. No documented perioperative complications occurred. Only three non-susceptible patients received one trigger agent. It is safe to use trigger-free anaesthesia in susceptible patients. The difficulties encountered by patients to be anaesthetized and the management of the majority of non-susceptible patients during general anaesthesia show the need of more accurate educational programmes and methods for promoting patient-centred care.

Cumulative and Bolus In Vitro Contracture Testing with 4-Chloro-3-Ethylphenol in Malignant Hyperthermia Positive and Negative Human Skeletal Muscles

In this study we evaluated the in vitro effects of 4-chloro-3-ethylphenol (CEP) using cumulative (12.5-200 micromol/L) or bolus (75 and 100 micromol/L) administrations, on muscle specimens from malignant hyperthermia (MH) susceptible and MH nonsusceptible patients, respectively. In the cumulative CEP in vitro contracture test, contractures were significantly greater in the MH susceptible compared with the MH nonsusceptible muscles in all concentrations between 25 and 100 micromol/L. There was no overlap between the diagnostic groups at 75 micromol/L of CEP, so this test appears to be feasible for diagnosis of MH susceptibility. The two bolus tests are not diagnostically useful, as overlaps between the diagnostic groups were observed.

COST-EFFECTIVE PHARMACOLOGICAL PREVENTION OF ACUTE CORONARY SYNDROMES

The growing size of trials on primary and secondary prevention of acute coronary syndromes characterised by very broad inclusion criteria may seem logical to `trialists', who reason that the broader the inclusion criteria, the easier it is to recruit large numbers of patients in a short period of time and the more widely applicable are the results of the study. However, large trials with very broad inclusion criteria raise two grounds for concern for physicians. The first is that the broader the inclusion criteria for enrolment in a trial in order to prove a statistically significant benefit, the greater the heterogeneity of the study population which is likely to include both susceptible and non-susceptible patients to the tested treatment. The second is that this method of assessment rapidly increases the number of treatments that produce a statistically-significant improvement in prognosis within the same broad group of patients. On the contrary, the identification of potential responders to a specific treatment can provide a personalised form of medical care suited to the needs of each individual patient with an optimal cost–benefit ratio. This approach, however, represents a major challenge as it can only be based on the identification of homogeneous subgroups of patients with common risk factors for the development of acute coronary syndromes or of their recurrence. This challenge can only be overcome by a strong commitment in funding studies on the multiple causes of acute coronary syndromes.

Effects of veratridine on mechanical responses of human malignant hyperthermic muscle fibers.

To determine if alteration in the function of the sodium channel may in turn modify halothane-induced changes in mechanical responses of muscle bundles from patients susceptible to malignant hyperthermia (MH). Mechanical responses of muscle bundles from 12 MH-susceptible and 20 MH non-susceptible patients were measured prior to and during administration of halothane alone and in the presence of 10 microM veratridine, an inhibitor of sodium channel inactivation. Peak tension (PT), time to peak tension (TPT), positive peak of isometric tension derivative (+dP/dtmax) were used to characterize the inotropic state. Analysis of relaxation process was performed using half relaxation time (RT 1/2) and the negative peak of isometric tension derivative (-dP/dtmax). The ratio (R) = (+dP/dtmax)/(-dP/dtmax) was used to measure the coupling between contraction and relaxation under isometric condition. Veratridine significantly enhanced the 0.5, 1, 2 and 3 vol% halothane-induced contracture and induced a negative inotropic effect in MH-susceptible muscle bundles. R increased by nearly 90% indicating that the combined effects were more pronounced in the relaxation phase. In MH non-susceptible muscle, veratridine did not significantly enhance the effects of halothane. These results on cut MH-susceptible human muscle bundles support the hypothesis that halothane-induced contracture in MH can be modified by the binding of an inhibitor of sodium channel inactivation.

Analysis of anaesthesia in patients suspected to be susceptible to malignant hyperthermia before diagnostic in vitro contracture test.

It is well known that patients susceptible to malignant hyperthermia (MH) do not always develop clinical signs of MH at their first anaesthetic. Large material concerning this epidemiological problem do not exist. Therefore, we undertook the present investigation at the Danish Malignant Hyperthermia Register. Retrospective analysis of anaesthetics given to 371 patients before in vitro contracture test (IVCT) for susceptibility to MH or before death of MH. Patients (or relatives in the case of a dead patient) gave information about previous anaesthetics and anaesthetic charts were collected and reviewed. Fifteen patients died of clinical MH, 112 patients survived an episode of suspected MH, and 244 patients were relatives of the above. Of the 127 patients with clinical signs of MH, 37% had received anaesthesia before, and trigger agents (potent inhalational agents and/or suxamethonium) were used in 98% of patients with no statistical difference between MH-susceptible (MHS) and non-susceptible (MHN) patients. Emergency anaesthesia was more frequent in patients with fulminant MH compared to those with abortive forms of MH (P < 0.01). Of the 244 relatives, 48% had received anaesthesia before MH was suspected in the family and trigger agents were used in 44% of the anaesthetics without statistical difference between MHS and MHN relatives. In 17 cases, trigger agents were used for anaesthesia after MH was suspected in the family, but before IVCT. The clinical expressivity of the MHS phenotype was found to be 34%-54%.

Exclusion of defects in the skeletal muscle specific regions of the DHPR alpha 1 subunit as frequent causes of malignant hyperthermia.

The molecular defect predisposing to the majority of malignant hyperthermia (MH) cases is unknown, although various point mutations in the ryanodine receptor gene (RYR1) have been associated with susceptibility in...

Evaluation of 119 Anaesthetics Received After Investigation for Susceptibility to Malignant Hyperthermia

A questionnaire was sent to the first 371 patients investigated for MH susceptibility at the Danish MH Register, in order to assess sequelae from the muscle biopsy and possible subsequent anaesthetic complications. The purpose was to evaluate both the safety of anaesthetizing MH-susceptible (MHS) patients without the use of trigger agents, and the safety of giving trigger agents to non-susceptible (MHN) patients. Eighty-eight per cent of patients alive replied to the questionnaire. Of these, 22% complained about discomfort at the site of the biopsy, 2% had experienced problems when needing a subsequent anaesthetic, and 0.9% had had trouble when applying for life or accident insurance. The median observation period for all patients following the muscle biopsy was 5.5 years (range 27 months-11 years). During this period, 36 MHS patients had been anaesthetized 52 times (28 general and 23 regional anaesthetics, data missing in one case) without any MH-related complications. None of the patients had received prophylactic dantrolene. Three MHE patients had received non-trigger anaesthetic agents on three occasions without development of MH. Thirty-five MHN patients had been anaesthetized 64 times, and 13 of these MHN patients had received trigger agents 26 times without any signs of MH. An estimate of the probability of clinical MH developing in MHN patients subsequently anaesthetized with trigger agents was found to be 0-24.7% (95% confidence limits), whereas the probability of clinical MH developing in MHS patients anaesthetized with non-trigger agents was 0-9.7% (95% confidence limits).

Evaluation of 119 anaesthetics received after investigation for susceptibility to malignant hyperthermia

A questionnaire was sent to the first 371 patients investigated for MH susceptibility at the Danish MH Register, in order to assess sequelae from the muscle biopsy and possible subsequent anaesthetic complications. The purpose was to evaluate both the safety of anaesthetizing MH-susceptible (MHS) patients without the use of trigger agents, and the safety of giving trigger agents to non-susceptible (MHN) patients. Eighty-eight per cent of patients alive replied to the questionnaire. Of these, 22% complained about discomfort at the site of the biopsy, 2% had experienced problems when needing a subsequent anaesthetic, and 0.9% had had trouble when applying for life or accident insurance. The median observation period for all patients following the muscle biopsy was 5.5 years (range 27 months-11 years). During this period, 36 MHS patients had been anaesthetized 52 times (28 general and 23 regional anaesthetics, data missing in one case) without any MH-related complications. None of the patients had received prophylactic dantrolene. Three MHE patients had received non-trigger anaesthetic agents on three occasions without development of MH. Thirty-five MHN patients had been anaesthetized 64 times, and 13 of these MHN patients had received trigger agents 26 times without any signs of MH. An estimate of the probability of clinical MH developing in MHN patients subsequently anaesthetized with trigger agents was found to be 0-24.7% (95% confidence limits), whereas the probability of clinical MH developing in MHS patients anaesthetized with non-trigger agents was 0-9.7% (95% confidence limits).

Importance of fasting in the lymphocyte calcium test for malignant hyperthermia

Anaesthetic-induced increases in cytoplasmic free Ca2+ have been reported to be greater in lymphocytes from malignant hyperthermia (MH) susceptible patients than in those from controls, suggesting that this may be the basis for a less invasive test for MH susceptibility. In the present study the cytoplasmic Ca2+ concentrations of lymphocytes were monitored with indo-1 in 14 control subjects (nine fasted and five nonfasted) and five fasted MH susceptible and three fasted nonsusceptible patients, diagnosed by the halothane and caffeine contracture tests. No relationship was observed between MH susceptibility and Ca2+ concentrations in lymphocytes in the absence or presence of halothane. There was, however, a relationship in control subjects between fasting and the response of lymphocytes to halothane, with the halothane-induced Ca2+ increase being considerably larger in nonfasted subjects.

Age, fiber type composition and in vitro contracture responses in human malignant hyperthermia.

Muscle fiber typing and in vitro contracture tests were performed in 59 patients investigated for susceptibility to malignant hyperthermia (MH). Eighteen patients were found to be susceptible to MH. There was no difference in age or fiber type distribution between MH susceptible and non-susceptible patients. No correlation was found between age and fiber type distribution. Separate analyses for each diagnostic group revealed no relationship between age or fiber type distribution and response to halothane or caffeine. When all caffeine results were pooled, however, there was a significant effect of age on the caffeine specific concentration (the concentration eliciting a contracture of 1 g), but not on the caffeine threshold concentration (the minimal concentration eliciting an increase in tension). It is concluded that age and fiber type distribution have no influence on MH diagnosis, if the protocol of the European MH Group for evaluation of susceptibility to MH is followed.

Hepatic Dysfunction after Isoflurane Anesthesia

Four members of the Anesthetic and Life Support Advisory Committee of the Food and Drug Administration assessed the contribution of isoflurane (Forane) to 45 instances of hepatic dysfunction after isoflurane anesthesia reported to the FDA for 1981-1984. For 29 (64%) of the cases, at least three members concluded that nonanesthetic causes (e.g., hypoxia, sepsis, viral infection) explained the hepatic injury. For 16 cases (36%), two or more members concluded that isoflurane might be one of several possible causes of the hepatic injury. In the latter cases, patients tended to be younger, had undergone anesthesia of shorter duration for operations outside the chest and abdomen, had developed symptoms later, had higher plasma transaminase values but lower bilirubin values, and had a lower incidence of eosinophilia, anemia, transfusions, and congestive heart failure. The committee concluded that current evidence does not indicate a reasonable likelihood of an association between the use of isoflurane and the occurrence of postoperative hepatic dysfunction.

Phosphorylase Ratio and Susceptibility to Malignant Hyperthermia

The ratio of muscle phosphorylase a to total phosphorylase, expressed as a percent, was determined in vastus lateralis muscle of 26 patients to examine the efficacy of this parameter as a method for screening for susceptibility to malignant hyperthermia (MH). As standard screening, all patients also had muscle contracture responses determined to 2% halothane and 0.25-32 mM caffeine at 37 degrees C. Each drug was given separately and not combined. Nine patients were susceptible to MH, based upon caffeine threshold of 2 mM or less (seven patients) or a rapidly developing contracture tension to halothane of more than 400 mg (seven patients, including five with positive caffeine responses). Mean phosphorylase ratio in these nine patients was 14.5 +/- 2.0% (mean, SEM). In the 17 nonsusceptible patients mean phosphorylase ratio (12.4 +/- 1.9%) was not significantly different. The range of phosphorylase ratios in susceptible patients was 6.5-26% while 13 nonsusceptible patients had ratios greater than 6% and up to 29%. The unacceptably high number of false-positive responses in nonsusceptible patients precludes the use of phosphorylase ratio as a definitive diagnostic test.