High-dose pulse methylprednisolone vs. dexamethasone standard therapy for severe and critical COVID-19 pneumonia: Efficacy assessment in a retrospective single-centre experience from Malaysia.

INTRODUCTION: The use of dexamethasone (DXM) has been associated with decreased mortality in the patients with hypoxemia during the coronavirus disease-2019 (COVID-19) pandemic, while the outcomes with methylprednisolone (MTP) have been mixed. This real-life study aimed to evaluate the outcomes of patients with severe respiratory failure due to COVID-19 who were treated with high doses of MTP. MATERIALS AND METHODS: This retrospective cohort study enrolled hospitalised patients between May 2021 and August 2021, aged 18 years and above, with severe respiratory failure defined by a ratio of oxygen saturation to fraction of inspired oxygen (SF ratio) of less than 235. The treatment protocol involved administering high-dose MTP for 3 days, followed by DXM, and the outcomes were compared with those of patients who received DXM alone (total treatment duration of 10 days for both groups). RESULTS: A total of 99 patients were enrolled, with 79 (79.8%) receiving pulse MTP therapy and 20 (20.2%) being treated with DXM only. The SF ratio significantly improved from a mean of 144.49 (±45.16) at baseline to 208 (±85.19) at 72 hours (p < 0.05), with a mean difference of 63.51 (p < 0.001) in patients who received ≤750 mg of MTP. Additionally, in patients who received >750 mg of MTP, the SF ratio improved from a baseline mean of 130.39 (±34.53) to 208.44 (±86.61) at 72 hours (p < 0.05), with a mean difference of 78.05 (p = 0.001). In contrast, patients who received DXM only demonstrated an SF ratio of 132.85 (±44.1) at baseline, which changed minimally to 133.35 (±44.4) at 72 hours (p = 0.33), with a mean difference of 0.50 (p = 0.972). The incidence of nosocomial infection was higher in the MTP group compared with the DXM group (40.5% vs. 35%, p = 0.653), with a relative risk of 1.16 (95% CI: 0.60-2.23). CONCLUSION: MTP did not demonstrate a significant reduction in intubation or intensive care unit admissions. Although a high dose of MTP improved gas exchange in patients with severe and critical COVID-19, it did not provide an overall mortality benefit compared to standard treatment.

An epistatic interaction between pre-natal smoke exposure and socioeconomic status has a significant impact on bronchodilator drug response in African American youth with asthma.

BACKGROUND: Asthma is one of the leading chronic illnesses among children in the United States. Asthma prevalence is higher among African Americans (11.2%) compared to European Americans (7.7%). Bronchodilator medications are part of the first-line therapy, and the rescue medication, for acute asthma symptoms. Bronchodilator drug response (BDR) varies substantially among different racial/ethnic groups. Asthma prevalence in African Americans is only 3.5% higher than that of European Americans, however, asthma mortality among African Americans is four times that of European Americans; variation in BDR may play an important role in explaining this health disparity. To improve our understanding of disparate health outcomes in complex phenotypes such as BDR, it is important to consider interactions between environmental and biological variables. RESULTS: We evaluated the impact of pairwise and three-variable interactions between environmental, social, and biological variables on BDR in 233 African American youth with asthma using Visualization of Statistical Epistasis Networks (ViSEN). ViSEN is a non-parametric entropy-based approach able to quantify interaction effects using an information-theory metric known as Information Gain (IG). We performed analyses in the full dataset and in sex-stratified subsets. Our analyses identified several interaction models significantly, and suggestively, associated with BDR. The strongest interaction significantly associated with BDR was a pairwise interaction between pre-natal smoke exposure and socioeconomic status (full dataset IG: 2.78%, p = 0.001; female IG: 7.27%, p = 0.004)). Sex-stratified analyses yielded divergent results for females and males, indicating the presence of sex-specific effects. CONCLUSIONS: Our study identified novel interaction effects significantly, and suggestively, associated with BDR in African American children with asthma. Notably, we found that all of the interactions identified by ViSEN were "pure" interaction effects, in that they were not the result of strong main effects on BDR, highlighting the complexity of the network of biological and environmental factors impacting this phenotype. Several associations uncovered by ViSEN would not have been detected using regression-based methods, thus emphasizing the importance of employing statistical methods optimized to detect both additive and non-additive interaction effects when studying complex phenotypes such as BDR. The information gained in this study increases our understanding and appreciation of the complex nature of the interactions between environmental and health-related factors that influence BDR and will be invaluable to biomedical researchers designing future studies.

Cost-effective method for growing three-dimensional cell cultures in extracellular matrix extract.

Three-dimensional (3-D) cell cultures are advantageous for modeling complex cellular behavior. A major issue with 3-D cultures grown in Engelbreth-Holm-Swarm (EHS) extracellular matrix extract, however, is the expense. We describe here a simple method using a rubber gasket laid over a coverslip, which provides sufficient 3-D area filled with a minimal amount of EHS, resulting in cost-effective 3-D cellular cultures that are easy to manipulate.

Referral for cancer genetics consultation: a review and compilation of risk assessment criteria.

BACKGROUND: There have been many papers on the diagnostic criteria for specific hereditary cancer susceptibility syndromes and the likelihood that an individual has a germline mutation in one of the various cancer susceptibility genes. To assist health care professionals in deciding when a cancer genetics consultation is appropriate, available reports were critically reviewed in order to develop a single set of risk assessment criteria. METHODS: The criteria were based on a comprehensive review of publications describing diagnostic criteria for hereditary cancer syndromes and risk to first degree relatives of cancer patients. Priority was given to diagnostic criteria from consensus statements (for example, those from the National Comprehensive Cancer Network). Expert opinion from study personnel was then used to adopt a single set of criteria from other publications whenever guidelines differed. RESULTS: Based on family history, a set of criteria was developed to identify patients at risk for a hereditary cancer susceptibility syndrome, patients with moderate risk who might benefit from increased cancer surveillance, and patients who are at average risk. The criteria were applied to 4360 individuals who provided their cancer family history between July 1999 and April 2002, using a touch screen computer system in the lobby of a comprehensive cancer centre. They categorised an acceptable number of users into each risk level: 14.9% high risk, 13.7% moderate risk, and 59.6% average risk; 11.8% provided insufficient information for risk assessment. CONCLUSIONS: These criteria should improve ease of referral and promote consistency across centres when evaluating patients for referral to cancer genetics specialists.

Strategies for the assessment of matrix effect in quantitative bioanalytical methods based on HPLC-MS/MS.

In recent years, high-performance liquid chromatography (HPLC) with tandem mass spectrometric (MS/MS) detection has been demonstrated to be a powerful technique for the quantitative determination of drugs and metabolites in biological fluids. However, the common and early perception that utilization of HPLC-MS/MS practically guarantees selectivity is being challenged by a number of reported examples of lack of selectivity due to ion suppression or enhancement caused by the sample matrix and interferences from metabolites. In light of these serious method liabilities, questions about how to develop and validate reliable HPLC-MS/MS methods, especially for supporting long-term human pharmacokinetic studies, are being raised. The central issue is what experiments, in addition to the validation data usually provided for the conventional bioanalytical methods, need to be conducted to confirm HPLC-MS/MS assay selectivity and reliability. The current regulatory requirements include the need for the assessment and elimination of the matrix effect in the bioanalytical methods, but the experimental procedures necessary to assess the matrix effect are not detailed. Practical, experimental approaches for studying, identifying, and eliminating the effect of matrix on the results of quantitative analyses by HPLC-MS/MS are described in this paper. Using as an example a set of validation experiments performed for one of our investigational new drug candidates, the concepts of the quantitative assessment of the "absolute" versus "relative" matrix effect are introduced. In addition, experiments for the determination of, the "true" recovery of analytes using HPLC-MS/MS are described eliminating the uncertainty about the effect of matrix on the determination of this commonly measured method parameter. Determination of the matrix effect allows the assessment of the reliability and selectivity of an existing HPLC-MS/MS method. If the results of these studies are not satisfactory, the parameters determined may provide a guide to what changes in the method need to be made to improve assay selectivity. In addition, a direct comparison of the extent of the matrix effect using two different interfaces (a heated nebulizer, HN, and ion spray, ISP) under otherwise the same sample preparation and chromatographic conditions was made. It was demonstrated that, for the investigational drug under study, the matrix effect was clearly observed when ISP interface was utilized but it was absent when the HN interface was employed.

Interpreting epidemiological research: blinded comparison of methods used to estimate the prevalence of inherited mutations in BRCA1.

While sequence analysis is considered by many to be the most sensitive method of detecting unknown mutations in large genes such as BRCA1, most published estimates of the prevalence of mutations in this gene have been derived from studies that have used other methods of gene analysis. In order to determine the relative sensitivity of techniques that are widely used in research on BRCA1, a set of blinded samples containing 58 distinct mutations were analysed by four separate laboratories. Each used one of the following methods: single strand conformational polymorphism analysis (SSCP), conformation sensitive gel electrophoresis (CSGE), two dimensional gene scanning (TDGS), and denaturing high performance liquid chromatography (DHPLC). Only the laboratory using DHPLC correctly identified each of the mutations. The laboratory using TDGS correctly identified 91% of the mutations but produced three apparent false positive results. The laboratories using SSCP and CSGE detected abnormal migration for 72% and 76% of the mutations, respectively, but subsequently confirmed and reported only 65% and 60% of mutations, respectively. False negatives therefore resulted not only from failure of the techniques to distinguish wild type from mutant, but also from failure to confirm the mutation by sequence analysis as well as from human errors leading to misreporting of results. These findings characterise sources of error in commonly used methods of mutation detection that should be addressed by laboratories using these methods. Based upon sources of error identified in this comparison, it is likely that mutations in BRCA1 and BRCA2 are more prevalent than some studies have previously reported. The findings of this comparison provide a basis for interpreting studies of mutations in susceptibility genes across many inherited cancer syndromes.

Genetic testing for cancer predisposition.

Clinical cancer genetics is becoming an integral part of the care of cancer patients. This review describes the clinical aspects, genetics, and clinical genetic management of most of the major hereditary cancer susceptibility syndromes. Multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and familial adenomatous polyposis are examples of syndromes for which genetic testing to identify at-risk family members is considered the standard of care. Genetic testing for these syndromes is sensitive and affordable, and it will change medical management. Cancer genetic counseling and testing is probably beneficial in other syndromes, such as the hereditary breast cancer syndromes, hereditary nonpolyposis colorectal cancer syndrome, Peutz-Jeghers syndrome, and juvenile polyposis. There are also hereditary cancer syndromes for which testing is not yet available and/or is unlikely to change medical management, including Li-Fraumeni syndrome and hereditary malignant melanoma. Thorough medical care requires the identification of families likely to have a hereditary cancer susceptibility syndrome for referral to cancer genetics professionals.

Integrating acute and long-term care for high-cost populations.

The inadequacies of our fragmented acute and long-term care financing and delivery systems have been well recognized for many years. Yet over the past two decades only a very small number of "boutique" initiatives have been able to improve the financing and the delivery of care to chronically ill and disabled populations. These initiatives share most of the following characteristics: prepaid, risk-adjusted financing; integrated Medicare and Medicaid funding streams; a flexible array of acute and long-term benefits; well-organized, redesigned care delivery systems that tailor these benefits to individual need; a mission-driven philosophy; and considerable creativity in engaging government payers. The experience of these "boutiques" illustrates both the obstacles to, and the opportunity for, meaningful, widespread care delivery reform for vulnerable chronically ill populations.

Oral fluoropyrimidine treatment of colorectal cancer.

5-Fluorouracil (5-FU) has been utilized as part of standard chemotherapy for treatment of early-stage and metastatic colorectal cancer for more than 4 decades. The oral fluoropyrimidines have been studied extensively as an alternative to intravenous 5-FU. The goal of such an approach is to simplify drug administration and to improve the toxicity profile while maintaining efficacy that is at least equivalent to intravenous therapy. The goal of this article is to review the features of the main oral 5-FU prodrugs, which include capecitabine, uracil and tegafur (UFT)/leucovorin, S-1, and BOF-A2 and to describe their potential efficacy in treating colorectal cancer.

A highly accurate, low cost test for BRCA1 mutations.

The hereditary breast and ovarian cancer syndrome is associated with a high frequency of BRCA1 mutations. However, the widespread use of BRCA1 testing has been limited to date by three principal concerns: the fear of loss of health and life insurance, the uncertain clinical value of a positive test result, and the current lack of an inexpensive and sensitive screening test for BRCA1 mutations. We have developed an inexpensive system for gene mutational scanning, based on a combination of extensive multiplex PCR amplification and two dimensional electrophoresis. The efficiency of this system, as a screening test for BRCA1 mutations, was evaluated in a panel of 60 samples from high risk women, 14 of which contained a previously identified mutation in BRCA1. All 14 mutations were identified, as well as an additional five that had previously escaped detection. In addition to the 19 mutations, a total of 15 different polymorphic variants were scored, most of which were recurring. All were confirmed by nucleotide sequencing. The cost of screening per sample was calculated to be approximately US$70 for the manual technique used in this study, and may be reduced to approximately US$10 with the introduction of commercially available PCR robotics and fluorescent imaging. Implementation of this method of mutation screening in the research and clinical setting should permit rapid accrual of quantitative data on genotype-phenotype associations for the evaluation of diagnostic testing.

Critical factors in the performance and cost of two-dimensional gene scanning: RB1 as a model.

Two-dimensional (2-D) gene scanning (TDGS) is a method for mutation detection based on the electrophoretic separation of PCR-amplified DNA fragments according to size and base pair sequence. The use of denaturing gradient gel electrophoresis (DGGE) as the second separation step provides virtually 100% sensitivity, while the 2-D format allows the inspection of multiple gene fragments simultaneously. Analysis of many exons in parallel is greatly facilitated by extensive PCR multiplexing based on preamplification by long-distance PCR. Recently, TDGS has been applied to detect mutations in the retinoblastoma tumor suppressor gene RB1. Using RB1 as a model, we have now analyzed each step of the protocol, presenting overall improvements and a detailed cost analysis, where the total cost of the assay is found to be about $40 (US). An overall picture of TDGS cost-performance, as compared to direct sequencing, is provided as a function of the number of target fragments.

PACE: a model for integrated care of frail older patients. Program of All-inclusive Care for the Elderly.

The Program of All-inclusive Care for the Elderly (PACE) is a model of care that pools Medicare and Medicaid funds to provide acute and long-term care services for older patients through the use of interdisciplinary teams. Services include physician visits, prescription drugs, rehabilitation services, personal care workers, hospitalization, and nursing home care, if needed. PACE programs may also offer social services intervention, case management, respite care, or extended home care nursing. The PACE site assumes financial responsibility for all services. Now that PACE programs can become permanent providers under Medicare, their number is expected to grow.

Ethnicity and decision-makers in a group of frail older people.

OBJECTIVE: To assess the relationship between ethnicity and decision-makers expressing healthcare wishes in a group of frail older persons enrolled in the Program of All-inclusive Care for the Elderly (PACE). DESIGN: A retrospective chart review of 1193 participants in the PACE program. SETTING: Program of All-inclusive Care for the Elderly, a comprehensive managed care demonstration program serving frail older participants at 10 sites across the nation. PARTICIPANTS: A total of 1193 older adults, all of whom met state criteria for nursing home level of care. Three hundred were non-Hispanic whites, 364 were black, 156 were Hispanic, and 288 were Asian. MEASUREMENTS: Demographic characteristics of the patients and the presence or absence of an alternative decision-maker; the characteristics of alternative decision-makers included the relationship to the participant as recorded in the patient's medical record. RESULTS: Ninety-one percent of white patients expressed their own healthcare wishes in contrast to only 85% of Hispanic, 83% of Asian, and 67% of black patients. An alternative decision-maker was identified for about 15% of Asians and Hispanics and for one-third of blacks, but only about 8% of whites had an alternative decision-maker. Black and Hispanic patients were most likely to have a daughter as an alternative decision-maker, Asians were most likely to have a son, and whites patients were most likely to have a spouse as an alternative decision-maker. Blacks, particularly black men, were the most likely to have a relative other than a spouse or child as an alternative decision-maker. CONCLUSIONS: In this population, we found significant ethnic variation in the person identified to be the decision-maker in a group of frail older people. Ethnic variation reflected sociodemographic as well as cultural differences. However, there are important limitations to this study, and caution should be used in extrapolating the results to other populations or in attributing the results to ethnicity alone. An awareness of cross-cultural patterns in identified or de facto decision-makers can be significant for healthcare workers when they approach patients and their families about issues surrounding end of life decisions.

Program of All-inclusive Care for the Elderly (PACE): an innovative model of integrated geriatric care and financing.

OBJECTIVES: The Program of All-inclusive Care for the Elderly (PACE) is a long-term care delivery and financing innovation. A major goal of PACE is prevention of unnecessary use of hospital and nursing home care. SETTING: PACE serves enrollees in day centers and clinics, their homes, hospitals and nursing homes. Beginning at On Lok in San Francisco, the PACE model has been successfully replicated across the country. In 1995, PACE was fully operational in 11 cities in nine states. PARTICIPANTS: To enroll in PACE, a person must be 55 years of age or older, be certified by the state as eligible for care in a nursing home and live in the program's defined geographical catchment area. PACE participants are ethnically diverse. In 1995, the average PACE enrollee was 80.0 years old and had an average of 7.8 medical conditions and 2.7 dependencies in Activities of Daily Living. A significant number have bladder incontinence (55%). Many enrollees (39%) live alone in the community, and 14% have no means of informal support. INTERVENTION: Medicare and Medicaid waivers allow delivery of services beyond the usual Medicare and Medicaid benefits. The PACE service delivery system is comprehensive, uses an interdisciplinary team for care management, and integrates primary and specialty medical care. PACE receives monthly capitation payments from Medicare and Medicaid. Patients ineligible for Medicaid pay privately. RESULTS: Outcomes of PACE programs have been positive. There has been steady census growth, good consumer satisfaction, reduction in use of institutional care, controlled utilization of medical services, and cost savings to public and private payers of care, including Medicare and Medicaid. However, starting up a PACE program requires substantial time and capital, and the model has not yet attracted large numbers of older middle income adults. CONCLUSION: The growing number of older people in the United States challenges healthcare providers and policy makers alike to provide high quality care in an environment of shrinking resources. The PACE model's comprehensiveness of health and social services, its cost-effective coordinated system of care delivery, and its method of integrated financing have wide applicability and appeal.

The relationship between ethnicity and advance directives in a frail older population.

OBJECTIVE: To assess the relationship between ethnicity and Health Care wishes, including Advance Directives, in a group of frail older persons in PACE (Program For All Inclusive Care Of The Elderly). DESIGN: Retrospective chart review of 1193 participants in the PACE program. SETTING: Program of All Inclusive Care Of The Elderly (PACE), a comprehensive managed care demonstration program serving frail older participants at 10 sites across the nation. PARTICIPANTS: A total of 1193 older adults, all of whom met state criteria for nursing home level of care. There were 385 non-Hispanic whites, 364 blacks, 156 Hispanics, and 288 Asians. MEASUREMENTS: Presence or absence of advance directives, type of health care wishes selected including living will, durable power of attorney, and health care proxy. RESULTS: Frail older white, black, Hispanic and Asian Americans differ significantly in their health care wishes and how they choose to express them. Blacks were significantly more likely to select aggressive interventions and less likely than non-Hispanic whites and Hispanics to utilize a written instrument for expressing health care wishes. Whites were significantly more likely to utilize written documents for advance directives, whereas Asians were more likely to select less aggressive interventions but were unlikely to use written advance directives. CONCLUSIONS: In this population, we found significant ethnic variations in choice of health care wishes. Although health care wishes are an individual decision, an awareness of cross cultural patterns can assist practitioners in addressing the concerns of their patients, as well as assisting Health Care Policy Development.

Case management in capitated long-term care.

For a very impaired population needing multiple interrelated services, the case management approach used by On Lok Senior Health Services in San Francisco, California, produces a responsive, flexible service system. Case management in On Lok's consolidated model has three key characteristics: (1) a true multidisciplinary team of medical as well as nonmedical personnel who separately assess, then, as a group, plan with the client and/or the family the services to be given; (2) use of the same team to assess needs and deliver services; and (3) team access to a potentially unlimited array of services, with freedom to adapt or create needed services.

Bayesian comparison of cost-effectiveness of different clinical approaches to diagnose coronary artery disease.

The objective of this study was to compare the cost-effectiveness of four clinical policies (policies I to IV) in the diagnosis of the presence or absence of coronary artery disease. A model based on Bayes' theorem and published clinical data was constructed to make these comparisons. Effectiveness was defined as either the number of patients with coronary disease diagnosed or as the number of quality-adjusted life years extended by therapy after the diagnosis of coronary disease. The following conclusions arise strictly from analysis of the model and may not necessarily be applicable to all situations. As prevalence of coronary disease in the population increased, it caused a linear increase in cost per patient tested, but a hyperbolic decrease in cost per effect, that is, increased cost-effectiveness. Thus, cost-effectiveness of all policies (I to IV) was poor in populations with a prevalence of disease below 10%, for example, asymptomatic people with no risk factors. Analysis of the model also indicates that at prevalences less than 80%, exercise thallium scintigraphy alone as a first test (policy II) is a more cost-effective initial test than is exercise electrocardiography alone as a first test (policy I) or exercise electrocardiography first combined with thallium imaging as a second test (policy IV). Exercise electrocardiography before thallium imaging (policy IV) is more cost-effective than exercise electrocardiography alone (policy I) at prevalences less than 80%. 4) Noninvasive exercise testing before angiography (policies I, II and IV) is more cost-effective than using coronary angiography as the first and only test (policy III) at prevalences less than 80%. 5) Above a threshold value of prevalence of 80% (for example patients with typical angina), proceeding to angiography as the first test (policy III) was more cost-effective than initial noninvasive exercise tests (policies I, II and IV). One advantage of this quantitative model is that it estimates a threshold value of prevalence (80%) at which the rank order of policies changes. The model also allows substitution of different values for any variable as a way of accounting for the uncertainty inherent in the data. In conclusion, it is essential to consider the prevalence of disease when selecting the most cost-effective clinical approach to making a diagnosis.