Interferon beta produces only small benefits in multiple sclerosis.
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Adjuvants, Immunologic↗
Biomedical subjects
L McKee
Publications and source records attributed to L McKee.
When is the 'right' time to initiate an assessment of a health technology?
There is currently no generally accepted formula for the optimal timing of health technology assessments (HTAs). This paper presents some of the relevant issues and then reviews the existing literature on timing of HTAs. It finds that the literature that specifically addresses these issues is limited. There is a consensus that HTAs should be initiated at an early stage of the development of a new health technology, and repeated during the life cycle of the technology. However, the questions of reliably identifying new technologies at an early stage in their development and of deciding on a detectable critical point for starting evaluation are not resolved. It is proposed that a system of categorization and prioritization of health technologies should be developed to allow decisions to be made as to when a strongly precautionary approach is required and how the limited resources available for HTA could be optimally deployed.
Diffusion of Innovation↗
When and how to assess fast-changing technologies: a comparative study of medical applications of four generic technologies.
OBJECTIVES. To try to identify the optimal time at which to start assessing new and fast-evolving health technologies. To provide insight into factors influencing the timing of assessments and the choice of methods for assessing new and fast-changing technologies. HOW THE RESEARCH WAS CONDUCTED. A series of literature reviews were undertaken covering the general principles involved in the timing of health technology assessments (HTAs). Additionally, the reported assessments of laparoscopic cholecystectomy, chorionic villus sampling (CVS), teleradiology, teledermatology, genetic screening for predisposition to breast cancer, and gene therapy for cystic fibrosis were reviewed to try to identify the factors that influenced the timing of these assessments. Key individuals in each field were also interviewed. The selected technologies allowed comparison between those that were new and evolving and those that were relatively well-established. A bibliometric study of publication trends was also undertaken to see whether these trends would suggest points in the development of a technology that could be used as indicators that assessment should be started. RESEARCH FINDINGS. TIMING. The precise point at which assessment should start was not identified but the bibliometric study suggested that extending this approach might give useful results. For all health technologies, more regular reporting of outcomes and side-effects should be encouraged during the period after initial assessment and, where the technology is fast-changing, reassessment should take place from time to time. The precise intervals were not identified and the problem remains of deciding when a technology has changed enough to warrant reassessment. FACTORS INFLUENCING TIMING. Published reports of assessments did not generally specify the reasons for their timing, but a number of factors appear to have influenced the timing of those assessments, directly or indirectly. Product champions and opinion leaders pioneer the introduction of new technologies into clinical practice, and their reports may lead to the rapid diffusion of such technologies before they have been adequately evaluated, as was the case with laparoscopic cholecystectomy; this diffusion may limit the methods of evaluation that can then be used. It is therefore important to assess new health technologies before diffusion takes place. The extent to which regulatory control is imposed on the introduction of new health technologies can also influence the timing of assessments. Such controls might have helped to restrict the diffusion of laparoscopic cholecystectomy, making a large and widely generalisable randomised controlled trial (RCT) feasible. The source and availability of funding for studies may influence the nature and timing of trials. Many telemedicine evaluations were funded by commercial telecommunications organisations and were thus restricted in their timing (and biased towards the technological aspects of the applications) by the availability of funds. Media coverage undoubtedly has an influence although this influence is not always predictable; it may generate 'favourable' publicity about new health technologies, which can lead to immediate demands for the new technique, as was the case with laparosocpic cholecystectomy with its apparent benefits. Thus assessments should be made before media coverage exerts popular pressure on purchasers to adopt the technology and dissuades patients from participating in RCTs (because of fear they may be randomised to the standard treatment as occurred in a US trial of CVS). Innovators should also be cautious in the claims that they make to the media.(ABSTRACT TRUNCATED)
Breast Neoplasms↗
Factors associated with intention to undergo annual prostate cancer screening among African American men in Philadelphia.
BACKGROUND: This study assesses whether African American men in Philadelphia are receptive to annual prostate cancer screening. Factors associated with intention to undergo prostate cancer screening are also identified. METHODS: The authors randomly selected 218 African American men from the patient population of a large primary care practice in Philadelphia. The men were 40 to 70 years of age and were available for a telephone survey. Responses to survey items defined by the Preventive Health Model were collected from 154 respondents (71%). Univariate and multivariate analyses of screening intention were performed using survey data on sociodemographic background and medical history; knowledge, attitudes, and beliefs about prostate cancer and screening; social support and influence; and, intention to undergo a screening examination. RESULTS: Overall, 69% of subjects reported that they intended to have annual prostate cancer screening. Logistic regression analyses showed that subject belief in screening efficacy (P=0.0002) were positively and significantly associated with intention to screen. CONCLUSIONS: Findings reported here show that African American men in an urban primary care practice setting are receptive to annual prostate cancer screening and that psychologic and social influence factors are associated with screening intention. The data highlight the need for health care professionals to provide education and advice regarding prostate cancer care to men in this population.
Adult↗
An economic evaluation of short-term inpatient rehabilitation for children with severe asthma.
BACKGROUND: The cost of asthma care in the United States in 1990 has been estimated to be 6.2 billion dollars. The greatest proportion is due to hospital care. OBJECTIVE: We report changes in estimated medical charges of 59 children with severe asthma 1 year before inpatient rehabilitation and over a 4-year follow-up period. METHODS: Asthma resource use (e.g., hospital, physician, medication) was identified before and after inpatient rehabilitation. Estimated charges were assigned. This was done retrospectively for the 1-year period before rehabilitation, prospectively during rehabilitation, and over a 4-year follow-up period. Patients served as their own controls. There was no control group. RESULTS: When median asthma resource use 1 year before rehabilitation was compared with that during the first, second, third, and fourth years of follow-up, there was a reduction in median hospitalization and median emergency care. Compared with mean total medical charges the year before rehabilitation, reductions in mean total medical charges were 56.7% at the completion of the first year (excluding charges for rehabilitation), 70.5% at second year, 74.6% at third year, and 77.5% at fourth year. Over the 4-year postrehabilitation period, the discounted cumulative net savings was $29,605. The discounted cumulative net savings surpassed the mean rehabilitation charge during the early months of the fourth year of the postrehabilitation period. CONCLUSION: Inpatient rehabilitation was significantly associated with a reduction in estimated total medical charges over a 4-year follow-up period.
Adolescent↗
Effects of hypocarbia on the development of cystic periventricular leukomalacia in premature infants treated with high-frequency jet ventilation.
BACKGROUND AND OBJECTIVE: Previous data from our institution indicate that mechanically ventilated premature infants are at increased risk for cystic periventricular leukomalacia (CPVL), particularly if hypocapnia occurs. High-frequency jet ventilation (HFJV) may produce substantial hypocapnia. We sought to investigate whether hypocapnia during HFJV is associated with the development of CPVL. METHODS: Sixty-seven premature infants (mean gestational age, 27.2 weeks; mean birth weight, 1001 g) underwent HFJV for a mean of 44 (range, 8 to 70) hours during the first 3 days of life. All infants were followed with serial neurosonograms at least weekly until 6 to 8 weeks of age and every 2 to 4 weeks thereafter until discharge. To assess the cumulative effects of hypotension, acidosis, hypoxemia, and hypocarbia during the first 3 days of life on the development of PVL, we developed a quantitative assessment in which we assigned threshold levels at particular critical values of these parameters (such as a mean PaCO2 of 20 mm Hg) and calculated an area above the curve between longitudinally connected values of these parameters and the threshold levels. RESULTS: Nine of the 67 infants died before 21 days of life. Of the 58 who survived beyond 21 days, large CPVL (> 5 mm in size) developed in 18 infants. Infants with cysts were similar in birth weight, gestational age, and virtually all other antepartum, intrapartum, and postpartum parameters compared with the 40 neonates in whom CPVL did not develop. However, infants with CPVL were significantly more likely to have moderate or severe periventricular echodensities preceding development of CPVL and periventricular echodensities that persisted for a longer period. We did not find an effect of hypotension, acidosis, or hypoxemia on the development of CPVL. There were no differences in the mean PaCO2, the absolute low PaCO2 values, the ranges of low PaCO2 between groups, or area above the curve measurements at threshold levels of 15 and 20 mm Hg, respectively. However, logistic regression analysis revealed that infants with CPVL were independently significantly more likely to have greater cumulative hypocarbia below a threshold level of 25 mm Hg during the first day of life (odds ratio, 5.43; 95% confidence interval, 1.33 to 22.2). CONCLUSIONS: Hypocarbia produced by treatment with HFJV during the first 3 days of life is associated with the subsequent development of CPVL. The mechanisms for the development of CPVL among premature infants treated with HFJV need to be established.
Carbon Dioxide↗
High-frequency jet ventilation in the early management of respiratory distress syndrome is associated with a greater risk for adverse outcomes.
OBJECTIVE: The objective of this investigation was to determine if high-frequency jet ventilation (HFJV) used early in the treatment of premature infants with respiratory distress syndrome was effective in reducing pulmonary morbidity without increasing the occurrence of adverse neurologic outcomes. STUDY DESIGN: A total of 73 premature infants who met the inclusion criteria (gestational age of less than 33 weeks, birth weight of more than 500 g, age of less than 24 hours, need for assisted ventilation with peak inspiratory pressure of more than 16 and FIO2 more than 0.30, and roentgenographic evidence of respiratory distress syndrome) were randomized to either conventional (n = 36) or to high-frequency jet (n = 37) ventilation. Our goals were to maintain the infants on the assigned ventilator for at least 7 days unless they could either be extubated or meet crossover criteria. Univariate analyses were initially used to compare the two groups. Stepwise logistic regression was subsequently used to assess whether various factors independently influenced adverse outcomes. RESULTS: The two groups of infants were similar in all obstetrical, perinatal, and neonatal demographic characteristics. The mean birth weight and gestational age in the conventional group were 930 g and 26.6 weeks and in the HFJV group, 961 g and 26.9 weeks. The infants were randomized at similar ages (7.1 and 7.3 hours of life, respectively). Their prerandomization ventilator settings and arterial blood gases were nearly identical. There were no differences in pulmonary outcomes (occurrence of air leaks, need for oxygen or ventilation at 36 weeks postconception), and there were no differences in the mean number of days oxygen was required, number of days ventilated, or length of hospital stay. Infants ventilated with HFJV were significantly more likely to develop cystic periventricular leukomalacia (10 vs 2, P = .022) or to have a poor outcome (grade IV hemorrhage, cystic periventricular leukomalacia, or death) (17 vs 7, P = .016). Logistic regression analysis revealed HFJV to be a significant independent predictor of both cystic periventricular leukomalacia and a poor outcome. The presence of hypocarbia was not an independently significant predictor of adverse outcomes. CONCLUSIONS: With the HFJV treatment strategy that we used, use of the high-frequency jet ventilator in the early management of premature infants with respiratory distress syndrome resulted in significantly more adverse outcomes than in those treated with conventional mechanical ventilation.
Blood Pressure↗
Electroencephalographic, neuroradiologic, and neurodevelopmental studies in infants with subclavian steal during ECMO.
Color Doppler imaging revealed a subclavian steal--retrograde flow in the right vertebral artery which shunted blood from the brain's posterior circulation to the right arm via the subclavian artery--in 17 of 54 infants (31%) during extracorporeal membrane oxygenation (ECMO); right vertebral artery flow returned to antegrade after ECMO and removal of the right common carotid arterial cannula. When subjects with and without a subclavian steal were compared, there were no statistically significant differences in mortality; in the results of neonatal electroencephalograms, cranial ultrasound studies, or computed tomography studies; or in early neurological development. Blood flow patterns and peak systolic velocities in the circle of Willis, middle cerebral arteries, internal carotid arteries, and basilar artery were similar in both groups during ECMO; blood flow velocity in the middle cerebral arteries was slightly but significantly lower on the right than the left in both groups. Our results indicate that increased flow in the left vertebral artery adequately compensated for the effect of a subclavian steal on the basilar and cerebral circulation. The moderate to marked neonatal electroencephalographic abnormalities commonly occurring during ECMO and the approximately 20% incidence of neurodevelopmental deficits among ECMO survivors remain largely unexplained.
Blood Flow Velocity↗
AIDS specialist versus generalist ambulatory care for advanced HIV infection and impact on hospital use.
We examined patterns of ambulatory care in the year before diagnosis of acquired immune deficiency syndrome (AIDS) for 5,720 persons infected with human immunodeficiency virus (HIV) who were continuously enrolled in the New York State Medicaid program and diagnosed in 1984-90. For 3,175 persons followed > or = 6 months after AIDS, we also examined the change between the year before AIDS diagnosis and the 6 months afterward in the predominant provider who was seen most frequently and at least twice. Approximately 75% of the population had a predominant provider identified. Of this group, 43% of the patients had a generalist as their predominant provider before AIDS diagnosis, falling to only 25% after diagnosis. The proportion with an AIDS specialist predominant provider increased from 22% before AIDS diagnosis to 39% afterward (P < 0.001). Patients with a generalist predominant provider before AIDS diagnosis had higher odds of switching providers and of hospitalization after AIDS diagnosis than patients with an AIDS specialist predominant provider. If generalists are to be encouraged to manage patients with advanced HIV disease, a better understanding of factors contributing to these outcomes is needed.
Acquired Immunodeficiency Syndrome↗
Patterns of ambulatory care for AIDS patients, and association with emergency room use.
OBJECTIVE: We examined the association of patterns of ambulatory care for AIDS patients with any use of the emergency room (ER) and the monthly rate of ER visits in the six months after AIDS diagnosis. DATA SOURCES/STUDY SETTING: The study population was obtained from the New York State Medicaid HIV/AIDS Research Data Base and includes patients diagnosed with AIDS from 1983 to 1990. DATA COLLECTION/EXTRACTION METHODS: To examine patterns of care and ER use not leading to hospitalization, we studied patients who survived at least six months after their first AIDS-defining diagnosis. The data base included person level information on visits to different provider sites and patient demographic and clinical characteristics. STUDY DESIGN: We defined the dominant provider as the site delivering the majority of ambulatory care for patients with a minimum of four ambulatory visits in the six months after AIDS diagnosis. Dominant providers were classified by specialty and setting: generalist physician; general medicine clinic; AIDS specialty clinic; and other specialty clinic or physician (e.g., cardiology). Patients without a dominant provider were grouped into those with four or more visits and those with fewer than four visits. Regression analysis was used to estimate relationships between ER use and patterns of ambulatory care and patient demographic and severity of illness characteristics. PRINCIPAL RESULTS: The study population included 9,155 AIDS patients aged 13 to 60 years at diagnosis, continuously Medicaid-enrolled, and surviving at least six months after AIDS diagnosis. Among those with four or more visits (56 percent), over 70 percent had a dominant provider. Overall, 39 percent of the study population visited the ER while, in the group with four or more visits, 53 percent of those without a dominant provider had an ER visit. Patients without a dominant provider were estimated to have 32 percent higher odds of ER use than patients with a dominant provider. Among patients with a dominant provider, patients with a generalist or primary care clinic dominant site of care were estimated respectively to have 18 percent and 23 percent lower odds than patients with an AIDS specialty clinic as the dominant site of care. Drug users had higher odds of ER use, as did women. CONCLUSIONS: In this Medicaid AIDS population, a dominant provider delivering the majority of a patient's care was associated with less use of the ER by the patient. Among patients with a dominant provider, ER use was lowest for those with a primary care provider. Further examination of the type and availability of ambulatory services in AIDS specialty clinics and primary care settings, as well as more detailed information on patient characteristics, may reveal reasons for these patterns of ER use.
Acquired Immunodeficiency Syndrome↗
Outcome of short-term hospitalization for children with severe asthma.
This study presents results of a family-centered, short-term residential program in which medical, behavioral, and treatment assessments were provided to the child with severe asthma and the family. After a median stay of 15 days, forty-four consecutively admitted children with severe asthma achieved a 93% reduction in hospital days (median, 7 hospital days for the year before treatment versus median 0 hospital days per patient per year at 20 1/2-month follow-up; p less than 0.001) and an 81% reduction in emergency care (median, 4 visits for the year previously versus median, 0.4 visits per patient per year at follow-up; p less than 0.01). There was also a significant reduction in corticosteroid bursts and improvement in FEV1. Unique to this program was mandatory family participation focusing on the child's and family's adaptation to severe asthma and development of family-specific interventions to promote compliance with the treatment regimen. Child and family functioning was assessed at admission and follow-up. Hospital use at follow-up was greater for children from dysfunctional families. Families demonstrating difficulties in disciplining the child with asthma required more hospital days both before admission and at follow-up. Short-term hospitalization for children with severe asthma is associated with significant improvement in pulmonary morbidity when the family of the child is included in assessment and treatment.
Acute Disease↗
Neurodevelopment of preterm infants: neonatal neurosonographic and serum bilirubin studies.
In this study of 249 preterm infants of less than 34 weeks' gestation, the relationships between maximal serum total bilirubin concentrations during the neonatal period, neonatal cranial ultrasonographic abnormalities, and severe neurodevelopmental sequelae are described. The subjects, who were selected on the basis of serial cranial ultrasonographic findings, had repeated neurologic and developmental examinations during late infancy and early childhood that established the presence (n = 45) or absence (n = 204) of spastic forms of cerebral palsy. Of the 204 subjects without cerebral palsy, 23 scored abnormally low on standardized developmental testing during early childhood. All but seven of the subjects with cerebral palsy had grade III/IV intracranial hemorrhage or moderate to severe periventricular echogenicity or both, ultrasonographic abnormalities that probably reflect a disruption in the blood-brain barrier as well as extravasation of blood into brain tissue; however, analysis of the data did not suggest that these cranial ultrasonographic abnormalities increased either the maximum serum bilirubin concentration during the neonatal period or the susceptibility of the subjects to neurologic damage from hyperbilirubinemia. Also, there was no evidence to suggest that bilirubinemia in the range studied (2.3 to 22.5 mg/100 mL total serum bilirubin) was causally related to cerebral palsy, early developmental delay, or the development of periventricular cysts in this population of preterm infants.(ABSTRACT TRUNCATED AT 250 WORDS)
Apgar Score↗
Mechanical ventilation in preterm infants: neurosonographic and developmental studies.
Surviving preterm infants of less than 34 weeks' gestation who were selected on the basis of serial cranial ultrasonographic findings during their nursery course had repeated neurologic and developmental examinations during late infancy and early childhood that established the presence (n = 46) or absence (n = 205) of spastic forms of cerebral palsy. Of the 205 infants without cerebral palsy, 22 scored abnormally low on standardized developmental testing during early childhood. The need for mechanical ventilation beginning on the first day of life (n = 92) was significantly related to gestational age, birth weight, Apgar scores, patent ductus arteriosus, grade III/IV intracranial hemorrhage, large periventricular cysts, and the development of cerebral palsy. In the 192 mechanically ventilated infants, vaginal bleeding during the third trimester, low Apgar scores, and maximally low PCO2 values during the first 3 days of life were significantly related to large periventricular cysts (n = 41) and cerebral palsy (n = 43), but not to developmental delay in the absence of cerebral palsy (n = 18). The severity of intracranial hemorrhage in mechanically ventilated infants was significantly associated with gestational age and maximally low measurements of PCO2 and pH, but not with Apgar scores or maximally low measurements of PO2. Logistic regression analyses controlling for possible confounding variables disclosed that PCO2 values of less than 17 mm Hg during the first 3 days of life in mechanically ventilated infants were associated with a significantly increased risk of moderate to severe periventricular echodensity, large periventricular cysts, grade III/IV intracranial hemorrhage, and cerebral palsy. Neurosonographic abnormalities were highly predictive of cerebral palsy independent of PCO2 measurements.(ABSTRACT TRUNCATED AT 250 WORDS)
Brain Diseases↗
The AIDS-defining diagnosis and subsequent complications: a survival-based severity index.
To define a survival-based severity measure for AIDS, we convened a panel of AIDS experts who identified factors influencing AIDS prognosis and estimated the impact of prognostic factors on survival time. The resulting conceptual model included 19 AIDS-defining conditions and 80 subsequent AIDS-related complications. This model was tested on longitudinal disease histories of 3,937 AIDS patients in the New York State Medicaid Program diagnosed between 1983 and 1986 and followed through 1988. The initial AIDS diagnosis and complications within 3 months of AIDS onset were identified from coded diagnoses recorded on inpatient and outpatient claims. Three AIDS-defining diagnosis groups were created; survival times from least to most severe group were 25, 10, and 7 months. To determine the influence of subsequent complications on risk of death, the survival times associated with combinations of defining diagnosis groups and four severity levels of subsequent complications were determined. Median survival ranged from 43 months for the least severe defining diagnosis group without early complications to 12 months for the group with severe defining diagnoses and serious complications. The matrix of AIDS-defining diagnoses and complications was divided into four severity categories with significantly different survival curves. This severity measure uses longitudinal data commonly available to clinicians and researchers to create distinct AIDS prognostic categories.
Acquired Immunodeficiency Syndrome↗
Psychosocial status of young adult survivors of childhood cancer: a survey.
The majority of childhood cancer patients now can expect to survive into early adulthood, cured of their cancer. Current adult survivors are a diverse group in terms of diagnosis, age at diagnosis, and types of treatment. It is estimated that by 1990, 1 in every 1,000 twenty-year-olds will have had cancer, making it important to describe the long-term psychosocial adjustment of this population. Patients who were diagnosed between 1948 and 1975 while less than 16 years of age, who were currently 18 years or older, had been off therapy for at least 5 years, and had no known brain damage were eligible for this survey and were identified through the tumor registry at the Children's Hospital of Philadelphia (CHP). Initially, the parents were contacted by letter. Ninety-five (57%) of the 167 eligible patients participated in a telephone interview, which covered educational achievement, occupational status, interpersonal relationships, marital status, pregnancies, employee benefits and insurance, and medical and health behaviors. Respondents were not different from nonrespondents in terms of sex, year of diagnosis, age at diagnosis, diagnoses, stage of illness, or type of treatments. There were no differences in terms of education, marital status, fertility issues, or occupational status by diagnosis group, age at diagnosis, or treatments. The patients were compared to siblings over 18 years of age in terms of education and marital status. No significant differences in sex distribution or years of education between patients and siblings were found. The siblings were, as a group, older than the patients and were more likely to be married. In general, these patients were functioning normally, but there are many unexplored areas of interpersonal relationships and productivity that need further study before conclusions regarding psychosocial adjustment of childhood cancer survivors can be drawn.
Adolescent↗
Dystrophin analysis in clonal myoblasts derived from a Duchenne muscular dystrophy carrier.
Clonal myogenic cell cultures were established from a potential heterozygote for a mutant Duchenne muscular dystrophy (DMD) gene who was also heterozygous for isozymes of the X-linked enzyme glucose-6-phosphate dehydrogenase. Previous tissue culture studies of this muscle donor demonstrated equal proliferative capacity of myoblasts that had lyonized either the paternal or maternal X-chromosome, indicating that mutation of the DMD gene does not affect growth of myoblasts. If this muscle donor were a gonadal mosaic, this conclusion would be incorrect. In the present study, only those myogenic colonies expressing the glucose-6-phosphate dehydrogenase-A isozyme were found to express dystrophin, indicating that this woman was indeed a heterozygote for DMD. By documenting dystrophin deficiency in a specific population of myogenic cells from this woman, we verify our previous conclusion regarding the normal proliferative capacity of DMD myoblasts. Somatic cell testing of dystrophin expression may offer an alternative to established genetic carrier tests for those women in whom deletions of the DMD are not detectable, whose pedigree structure does not permit linkage analysis, or in whom standard phenotypic analyses are ambiguous.
Blotting, Western↗
Ethnomedical treatment of children's diarrheal illnesses in the highlands of Ecuador.
In rural communities in the Ecuadorian Highlands, gastrointestinal disease is the leading cause of death. This paper proposes a model of the world view that specifies the factors that condition illness or health and a traditional taxonomy that relies on certain criteria to categorize three classes of diarrhea. These determine whether ethnomedical or medical treatment will be used to 'cure' a child. The three illness classes: diarrhea produced by supernatural forces, by humoral imbalances, and by 'infection' differ etiologically. The ambient air and its temperatures, the constitution, humoral state and overt personality characteristics (character) of the individual, and the predelictions of the evil spirits that seek to sap their vital essence all figure in the origins of illness. The model of the world view is related to a folk taxonomy, which, it is asserted, provides a charter for families' responses to child illness, that more often than not, are appropriate under the economic conditions they suffer.
Adult↗
Comparison of Duchenne and normal myoblasts from a heterozygote.
To test the hypothesis that the Duchenne muscular dystrophy gene limits the proliferation of myoblasts, we studied myoblasts from a woman who was a carrier of the Duchenne gene and also heterozygous for glucose-6-phosphate dehydrogenase (G6PD), an X-linked enzyme. G6PD-A and G6PD-B cells did not differ in proliferative capacity, implying no difference in proliferative capacity of cells bearing the Duchenne gene or the normal allele.
Cell Separation↗