The Nexus Between Telomere Length and Lymphocyte Count in Seniors Hospitalized With COVID-19.

Profound T-cell lymphopenia is the hallmark of severe coronavirus disease 2019 (COVID-19). T-cell proliferation is telomere length (TL) dependent and telomeres shorten with age. Older COVID-19 patients, we hypothesize, are, therefore, at a higher risk of having TL-dependent lymphopenia. We measured TL by the novel Telomere Shortest Length Assay (TeSLA), and by Southern blotting (SB) of the terminal restriction fragments in peripheral blood mononuclear cells of 17 COVID-19 and 21 non-COVID-19 patients, aged 87 ± 8 (mean ± SD) and 87 ± 9 years, respectively. TeSLA tallies and measures single telomeres, including short telomeres undetected by SB. Such telomeres are relevant to TL-mediated biological processes, including cell viability and senescence. TeSLA yields 2 key metrics: the proportions of telomeres with different lengths (expressed in %) and their mean (TeSLA mTL), (expressed in kb). Lymphocyte count (109/L) was 0.91 ± 0.42 in COVID-19 patients and 1.50 ± 0.50 in non-COVID-19 patients (p < .001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kb (p = .005) and positively correlated with TeSLA mTL (p = .03). Lymphocyte count was not significantly correlated with SB mTL in either COVID-19 or non-COVID-19 patients. We propose that compromised TL-dependent T-cell proliferative response, driven by short telomere in the TL distribution, contributes to COVID-19 lymphopenia among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons. Clinical Trials Registration Number: NCT04325646.

A Mechanism for Severity of Disease in Older Patients with COVID-19: The Nexus between Telomere Length and Lymphopenia.

BACKGROUND: Lymphopenia due to a plummeting T-cell count is a major feature of severe COVID-19. T-cell proliferation is telomere length (TL)-dependent and TL shortens with age. Older persons are disproportionally affected by severe COVID-19, and we hypothesized that those with short TL have less capacity to mount an adequate T-cell proliferative response to SARS-CoV-2. This hypothesis predicts that among older patients with COVID-19, shorter telomeres of peripheral blood mononuclear cells (PBMCs) will be associated with a lower lymphocyte count. METHODS: Our sample comprised 17 COVID-19 and 21 non-COVID-19 patients, aged 87(8) (mean(SD)) and 87 (9) years, respectively. We measured TL by the Telomere Shortest Length Assay, a novel method that measures and tallies the short telomeres directly relevant to telomere-mediated biological processes. The primary analysis quantified TL as the proportion of telomeres shorter than 2 kilobases. For comparison, we also quantified TL by Southern blotting, which measures the mean length of telomeres. RESULTS: Lymphocyte count (109/L) was 0.91 (0.42) in COVID-19 patients and 1.50(0.50) in non-COVID-19 patients (P < 0.001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kilobases (P = 0.005) and positively correlated with the mean of telomeres measured by TeSLA (P = 0.03). Lymphocyte counts showed no statistically significant correlations with Southern blotting results in COVID-19 or non-COVID-19 patients. CONCLUSIONS: These results support the hypothesis that a compromised TL-dependent T-cell proliferative response contributes to lymphopenia and the resulting disproportionate severity of COVID-19 among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.

Improvement of decision-making criteria for the care of elderly cancer patients by general practitioners (Lorraine, France).

OBJECTIVE: The objective of this study was to identify changes in the decision-making criteria of general practitioners (GPs) concerning the care of elderly cancer patients after 1 year of corrective measures for care practices in the Lorraine region, France. MATERIALS AND METHODS: In 2014, a postal mail questionnaire was sent to all GPs in the Lorraine region. This questionnaire was designed to identify GPs' decision-making criteria. It was based on the results of a literature review and on existing guidelines. During 1 year, corrective measures were implemented to improve practices, especially training sessions for physicians and production of specific tools, including a guide to the accepted ideas in geriatric oncology. In 2015, the same questionnaire was resent to all GPs to compare the answers. RESULTS: In 2014, 430 questionnaires were returned out of 2,048 sent, and in 2015, 378 questionnaires were returned out of 2,066 sent. Our results show for the first time that there exists a significant difference in the overall decision criteria between the two survey periods. This difference mainly concerns criteria related to the cancerous diseases. Physicians tend to consider the principal decision criteria to be less important after the training period. GPs express the importance of accessibility to specialists for additional advice in both 2014 and 2015; the distance between the patient's home and an adapted care facility and the interval before care begins are viewed as similarly important. CONCLUSION: Training and information sessions for physicians remain the most important tool for improving care practices. Such training strategies are more effective when carried out at the geographical scale at which the cancer professionals practice, allowing them to exploit their local organizational structure. The analysis of our data makes it possible to further integrate the patient into the care path, which remains a public health issue in terms of cost and organization.

Decision making affecting care of older people with cancer: a comparison between general practitioners and oncologists in Lorraine.

The main objective of this study is to identify the decision criteria of general practitioners and oncologists in the management of older patients with cancer in Lorraine. The secondary objectives are to identify the difficulties encountered and to propose solutions to improve health path of these patients. 2,995 post mail questionnaires were sent to all general practitioners and oncologists in Lorraine. Some decision criteria differ between general practitioners and oncologists: civilian age and accessibility to a specialized advice for general practitioners; type of cancer, nutritional status, application of best practice recommendations, and multidisciplinary discussion for oncologists. The main difficulties reported are organizational and relate to time interval before specific care beginning, accessibility to a medical specialist, and post-diagnosis such link between primary care and hospital. General practitioners and oncologists mainly agree with the difficulties encountered and the solutions to find, even if some decision criteria differences are highlighted. The training of professionals remains the major lever for improvement of medical practices.

Effect of Multimorbidity on Health-Related Quality of Life in Adults Aged 55 Years or Older: Results from the SU.VI.MAX 2 Cohort.

INTRODUCTION: Multimorbid chronic diseases are usually considered separately in trials. Here, we aimed to describe overall multimorbidity patterns in adults aged 55 years or older and assess their effect on health-related quality of life (HRQoL). METHODS: We used data for 5,647 participants included in the SUpplémentation en VItamines et Minéraux AntioXydants 2 (SU.VI.MAX 2) population-based trial. HRQoL was assessed by the French versions of the Medical Outcome Study Short Form 36 and the Duke Health Profile. An exploratory factor analysis was used to determine multimorbidity patterns, and a multimorbidity score for each resulting pattern was calculated. Adjusted multiple linear regression was used to examine the association between the identified multimorbidity and HRQoL scores by gender and for each age group (55-59, 60-64, 65-69, ≥ 70 years). RESULTS: More than 63% of the sample reported two or more chronic conditions (from 55.8% for those 55-59 years to 74.4% for those ≥ 70 years). Multimorbidity was more common among women than men (67.3% vs 60%). Two different multimorbidity patterns were identified. Pattern A was represented mainly by mental illness and bone impairments. Pattern B was represented mainly by cardiovascular and metabolic disorders. After adjusting for covariates, a high pattern A score was associated with reduced HRQoL for the physical and mental components of each HRQoL questionnaire, and a high pattern B score was associated with reduced HRQoL for only the physical component of each questionnaire. These multimorbidity scores affected HRQoL differently by age group. CONCLUSION: Our study used a novel methodological approach to account for multimorbidity patterns in determining the link with chronic conditions. These multimorbidity scores (counted and weighted) can be used in clinical research to control for the effect of multimorbidity on patients' HRQoL and may be useful for clinical practice. CLINICAL TRIAL REGISTRATION: Clinicaltrial.gov (number NCT00272428).

[Antiphospholipid syndrome in nephrology. Kidney damage and practical aspects of the management]. / Le syndrome des antiphospholipides en néphrologie. Atteinte rénale et aspects pratiques de la prise en charge.

The antiphospholipid syndrome is a thrombophilia characterized by the combination of arterial and/or venous thrombotic events or obstetric clinical events, associated with persistent presence of antiphospholipid antibodies. In this syndrome, thromboses may affect all of the vascular tree, renal damage is frequently associated with a specific antiphospholipid syndrome nephropathy. We propose in this review to provide updated recommendations on the management of antiphospholipid syndrome in nephrology. Treatment is based on long-term anticoagulant therapy with or without antiplatelet agents according to clinical events. The use of a conventional nephroprotection must not be forgotten (strict control of blood pressure with drugs blocking the renin-angiotensin-aldosterone system). Catastrophic antiphospholipid syndrome is an extremely severe complication which can threaten the vital prognosis of the patient. This justifies particular surveillance, as well as prevention in high-risk situations. We also illustrate the difficulties of long-term management in these patients, both in dialysis or kidney transplantation.

[What use general practitioners do they tests and scales referred to geriatric?]. / Quelle utilisation les médecins généralistes font-ils des tests et échelles à visée gériatrique ?

JUSTIFICATION: the complexity of the elderly's cares justifies to set up tools of screening, diagnosis and follow-up of multiple pathologies. Numerous tests and scales were elaborated and validated, and are recommended by the Haute autorité de santé (HAS). Are these tools useful and are they adapted to the consultation of general medicine? What are the obstacles to their appropriation by the general practitioners? OBJECTIVE: to determine the frequency of use of a series of twelve tests and scales to geriatric aim by the general practitioners. SECONDARY OBJECTIVE: interests of these tests and obstacles to their use in practice. METHOD: transverse survey by mail way, with a representative sampling of general practitioners of Meurthe-et-Moselle concerning the use of 12 tests or scales validated. RESULTS: 84 general practitioners on 145 requested participated in the survey (rate of answers 58%). The most used tests are the MMSE, the AGGIR, the test of the clock and the test of five words of Dubois (respectively 48, 43, 38 and 36% of regular users). Thirty five percent of the general practitioners never use tests or scales, while 37% use them at least once a month. 85.5% of the trained practitioners use it more frequently. A practitioner on two (51%) considers that these tools are unsuitable for his practice while almost totality of the general practitioners (90%) admits an interest about these tools in the screening, the diagnosis and the follow-up of the geriatric pathologies. The obstacles are essentially connected to the very time-consuming character, to the absence of specific quotation and to the lack of training. CONCLUSION: in the absence of tests and scales conceived by geriatricians and general practitioners, the existing tests although recognized useful are underused by the general practitioners of Meurthe-et-Moselle.

Correlation between peripheral blood pressure and pulse-wave velocity values in the institutionalized elderly persons 80 years of age and older: the PARTAGE study.

BACKGROUND: Carotid-femoral pulse-wave velocity (PWV) provides a comprehensive noninvasive indication of arterial stiffness, and is now established as a strong marker of cardiovascular disease (CVD). The correlation between peripheral blood pressure (BP) and PWV and their respective influences on mortality have been poorly studied in the elderly. Our objective was to analyze this correlation in nursing-home residents over 80 years of age, with the view that the results of this could ultimately be helpful in implementing strategies for the diagnosis and long-term follow-up of CVD and mortality in the very elderly population. METHODS: The Predictive Value of Blood Pressure and Arterial Stiffness in Institutionalized Very Aged Population (PARTAGE) study is a 2-year cohort study of 1,130 subjects living in 72 nursing homes in France and Italy. The correlation between baseline systolic and diastolic blood pressure (SBP and DBP, respectively) and baseline PWV (measured with a PulsePen® tonometer) was studied in 1,071 subjects for whom PWV measurements were available. RESULTS: Correlations between peripheral BP and PWV were significant but weak, with r = 0.24 for self-measured SBP, r = 0.30 for casual SBP, r = 0.11 for self-measured DBP, r = 0.14 for casual DBP, and r = 0.26 for casual pulse pressure (PP). A trend toward a weaker correlation was observed in the older age group for self-measured SBP and in the group with a lower level of activities of daily living (ADL) for self-measured SBP and DBP. CONCLUSIONS: These findings suggest that SBP, DBP, and PWV provide different information in the very elderly. The results of the prospective, longitudinal, long-term PARTAGE study will allow further insight into this and provide additional in-depth information about the respective prognostic value of the measurement of peripheral BP and PWV.

[Place and characteristics of patients older than 85 managed by mobile palliative care team; a retrospective study]. / Place et caractéristiques des patients âgés de 85 ans et plus suivis en équipe mobile de soins palliatifs ; étude rétrospective.

The objectives of this study was to specify the place of the patients older than 85 in the activity of the Mobile health unit of the Hospital of Metz-Thionville, to determine their characteristics and to show possible care differences as compared with younger patients. This is a retrospective study concerning all the patients seen by the Mobile health unit in 2006 and 2007. The patients older than 85 represent 11% of the 652 patients followed by the Unit and 7.8% of the 2.436 consultations on the study period. The older patients have a WHO mean score significantly higher and a Karnofsky mean score significantly lower than the younger subjects. Their survival rate tends to be lower but not significantly. Cancers are less frequent in older patients and they have fewer consultations than younger ones. The older patients present fewer communication problems and less often pain than the younger patients. The prescriptions of non-opioid and opioid analgesics, steroïds or antiepileptic drugs (used as analgesics) are less frequent in the older patients. The results of this study showed some specificities of palliative care in the older patients: we observed a great variety of pathologies and a lower frequency of cancers than in younger patients, various places of care, difficulties to evaluate the symptoms or to treat them due to communication problems especially. If these specificities are real, they do not seem to have important repercussions on following since the group of the patients older than 85 and the one of the younger patients differ only little in terms of survival rate or mean number of consultations.

Mortality and cardiovascular events are best predicted by low central/peripheral pulse pressure amplification but not by high blood pressure levels in elderly nursing home subjects: the PARTAGE (Predictive Values of Blood Pressure and Arterial Stiffness in Institutionalized Very Aged Population) study.

OBJECTIVES: The aim of the longitudinal PARTAGE study was to determine the predictive value of blood pressure (BP) and pulse pressure amplification, a marker of arterial function, for overall mortality (primary endpoint) and major cardiovascular (CV) events, in subjects older than 80 years of age living in a nursing home. BACKGROUND: Assessment of pulse indexes may be important in the evaluation of the CV risk in very elderly frail subjects. METHODS: A total of 1,126 subjects (874 women) who were living in French and Italian nursing homes were enrolled (mean age, 88 ± 5 years). Central (carotid) to peripheral (brachial) pulse pressure amplification (PPA) was calculated with the help of an arterial tonometer. Clinical and 3-day self-measurements of BP were conducted. RESULTS: During the 2-year follow-up, 247 subjects died, and 228 experienced major CV events. The PPA was a predictor of total mortality and major CV events in this population. A 10% increase in PPA was associated with a 24% (p < 0.0003) decrease in total mortality and a 17% (p < 0.01) decrease in major CV events. Systolic BP, diastolic BP, or pulse pressure were either not associated or inversely correlated with total mortality and major CV events. CONCLUSIONS: In very elderly individuals living in nursing homes, low PPA from central to peripheral arteries strongly predicts mortality and adverse effects. Assessment of this parameter could help in risk estimation and improve diagnostic and therapeutic strategies in very old, polymedicated persons. In contrast, high BP is not associated with higher risk of mortality or major CV events in this population. (Predictive Values of Blood Pressure and Arterial Stiffness in Institutionalized Very Aged Population [PARTAGE]; NCT00901355).

[Home delivered meals: impasse or solution?]. / Portage des repas à domicile: impasse ou solution?

Undernutrition is common in elderly people living at home. A loss of autonomy can lead them to use home help services, such as home delivered meals. However this solution is not always effective and having meals brought to the home seems to aggravate their isolation, as the results of a survey of twenty people showed.

[Frailty in older population: a brief position paper from the French society of geriatrics and gerontology]. / La fragilité de la personne âgée: un consensus bref de la Société française de gériatrie et gérontologie.

Frailty in the older population is a clinical syndrome which evaluate a risk level. The Frailty syndrome defines a reduction of the adaptation capacity to a stress. It can be modulated by physical, psychological and social factors. The screening of the frailty syndrome is relevant for older people without disability for basic activities of daily living. The clinical criteria of frailty must be predictive of the risk of functional decline and adverse outcomes, consensual at the international level, and easy to perform in primary care as well as in the clinical researches.

Health-related quality of life in French adolescents and adults: norms for the DUKE Health Profile.

BACKGROUND: The continual monitoring of population health-related quality of life (HRQoL) with validated instruments helps public health agencies assess, protect, and promote population health. This study aimed to determine norms for the French adolescent and adult general population for the Duke Health Profile (DUKE) questionnaire in a large representative community sample. METHODS: We randomly selected 17,733 French people aged 12 to 75 years old in 2 steps, by households and individuals, from the National Health Barometer 2005, a periodic population study by the French National Institute for Prevention and Health Education. Quality of life and other data were collected by computer-assisted telephone interview. RESULTS: Normative data for the French population were analyzed by age, gender and self-reported chronic disease. Globally, function scores (best HRQoL=100) for physical, mental, social, and general health, as well as perceived health and self-esteem, were 72.3 (SEM 0.2), 74.6 (0.2), 66.8 (0.1), 71.3 (0.1), 71.3 (0.3), 76.5 (0.1), respectively. Dysfunction scores (worst HRQoL=100) for anxiety, depression, pain and disability domains were 30.9 (0.1), 27.6 (0.2), 34.3 (0.3), 3.1 (0.1), respectively. CONCLUSION: The French norms for adolescents and adults for the DUKE could be used as a reference for other studies assessing HRQoL, for specific illnesses, in France and for international comparisons.

Tissue factor pathway inhibitor: a new link among arterial stiffness, pulse pressure, and coagulation in postmenopausal women.

OBJECTIVE: To investigate in women older than 60 whether aortic stiffness or pulse pressure (PP) is associated with selected procoagulant or anticoagulant factors and to examine whether pulsatile stretch influences these factors in human vascular smooth muscle cells (VSMCs) in vitro. METHODS AND RESULTS: Aortic pulse wave velocity (PWV) and carotid PP were studied in 123 apparently healthy postmenopausal women. PWV, PP, von Willebrand factor, and free tissue factor pathway inhibitor (TFPI), but not mean arterial pressure, increased with age. Free TFPI and PWV were positively correlated, even after adjustment for age and PP and other confounding parameters. In vitro, 5% or 10% pulsatile stretch (at 1 Hz) enhanced TFPI synthesis and secretion by VSMCs in a time-independent manner (1 to 48 hours) without changes in protein level of smooth muscle myosin heavy chain. Application of 5% static stretch had no effect. CONCLUSIONS: In postmenopausal women, free TFPI increases as vascular wall function deteriorates and PP increases. These findings are supported by the increase in TFPI synthesized by VSMCs in response to cyclic stress in vitro. They suggest that VSMCs require pulsatility to interfere with the coagulation process and highlight the relevance of plasma free TFPI levels to cardiovascular diseases.

Attitudes and approaches to decision making about antihypertensive treatment in elderly patients.

OBJECTIVE: Optimal antihypertensive therapy in very old subjects requires their understanding and acceptance. We investigated elderly patients' willingness to accept antihypertensive therapy and their desire for information and for participation in medical decisions. METHODS: After standardized explanations about hypertension and its treatment, 120 patients (mean age 83.8 ± 7.4 years) were asked whether they would accept hypertension treatment in 15 hypothetical scenarios with different outcomes (myocardial infarction/heart failure, stroke, and death), absolute risks/risk reductions, and risk of side effects. RESULTS: Fifty percent to 60% of patients accepted treatment in all scenarios; only 4% to 7% clearly refused it, and 30% to 40% were unsure. Paradoxically, the Autonomy Preference Index (API) indicated a variable, overall low desire for participation in medical decisions (mean score 58.9 ± 13.9 mean ± SD, on 100), including about hypertension, but patients wanted to receive extensive medical information (mean score 69.6 ± 17.2). CONCLUSIONS: Our data indicate that many patients prefer to delegate the final decision to their physician, although most want to receive extensive information. Although the decision to treat belongs to the physician, initial acceptance of antihypertensive therapy does not imply that patients really understand and adhere to it. True understanding and acceptance of treatment requires attention to patients' preferences and repeated explanations during follow-up.

A simple clinical scale to stratify risk of recurrent falls in community-dwelling adults aged 65 years and older.

BACKGROUND: Correct identification of people at risk for recurrent falls facilitates the establishment of preventive and rehabilitative strategies in older adults. OBJECTIVE: The purposes of this study were: (1) to develop and validate a simple clinical scale to stratify risk for recurrent falls in community-dwelling elderly people based on easily obtained social and clinical items and (2) to evaluate the added value of 3 clinical balance tests in predicting this risk. DESIGN: This was a prospective measurement study. METHODS: A population of 1,618 community-dwelling people over 65 years of age underwent a health checkup, including performance of 3 clinical balance tests: the One-Leg-Balance Test, the Timed "Up & Go" Test, and the Five-Times-Sit-to-Stand Test. Falls were recorded using a self-administered questionnaire that was completed a mean (SD) of 25+/-5 months after the visit. Participants were randomly divided into either group A (n=999), which was used to develop the scale, or group B (n=619), which was used to prospectively validate the scale. RESULTS: Logistic regression analysis identified 4 variables that independently predicted recurrent falls in group A: history of falls, living alone, taking >or=4 medications per day, and female sex. Thereafter, 3 risk categories of recurrent falls (low, moderate, and high) were determined. Predicted probability of recurrent falls increased from 4.1% to 30.1% between the first and third categories. This scale subsequently was validated with great accuracy in group B. Only the Five-Times-Sit-to-Stand Test provided added value in the estimation of risk for recurrent falls, especially for the participants who were at moderate risk, in whom failure on the test (duration of >15 seconds) doubled the risk. LIMITATIONS: Falls were assessed only once, and length of follow-up was heterogeneous (18-36 months). CONCLUSIONS: Clinicians could easily classify older patients in low-, moderate-, or high-risk groups of recurrent falls by using 4 easy-to-obtain items. The Five-Times-Sit-to-Stand Test provides added value to stratify risk for falls in people at moderate risk.

Blood pressure and pulse wave velocity values in the institutionalized elderly aged 80 and over: baseline of the PARTAGE study.

OBJECTIVE: The aim of the longitudinal study PARTAGE (predictive values of blood pressure and arterial stiffness in institutionalized very aged population) was to determine the predictive value of blood pressure (BP) and arterial stiffness for overall mortality, major cardiovascular events and cognitive decline in a large population of institutionalized patients aged 80 and over. In the study herein, we present the baseline data values of this study. METHODS: A total of 1130 patients were recruited (878 women), living in French and Italian nursing homes. Clinical and 3-day self-measurements of BP were conducted. Aortic and upper limb pulse wave velocity were obtained using a PulsePen tonometer. RESULTS: Of this population, 76% of women and 60% of men had a known hypertension and over 91% of the patients were under antihypertensive treatment; 51% of the treated hypertensive patients were well controlled (systolic BP <140 mmHg). No significant differences were found between clinical and self-measured BP. With age, there was an increase in pulse pressure (P < 0.001) due to a decrease in diastolic BP (P < 0.001), without any increase in systolic BP. Aortic but not peripheral pulse wave velocity significantly increased with age (P < 0.005). CONCLUSION: Baseline values obtained herein demonstrate that elderly patients living in nursing homes present hemodynamic characteristics which are different to those described in community-living elderly populations, and indicate the interest of assessing, in longitudinal studies, the role of BP and arterial stiffness in morbidity and mortality in this population.

Heart rate as a risk factor for cardiovascular disease.

Almost all the epidemiological studies that aimed to answer the question of the relationship between heart rate and all-cause or cardiovascular morbidity and mortality reported that a high heart rate was associated with a higher risk of all-cause mortality and cardiovascular events. This relationship has been found to be generally stronger in men than among women. The increase in the cardiovascular risk, associated with the acceleration of heart rate, was comparable to the increase in risk observed with high blood pressure. It has been shown that an increase in heart rate by 10 beats per minute was associated with an increase in the risk of cardiac death by at least 20%, and this increase in the risk is similar to the one observed with an increase in systolic blood pressure by 10 mm Hg. It has also been shown that heart rate recorded in elderly men has a strong predictive value in survival to a very old age. Taken together, these results indicate that the risk associated with accelerated heart rate is not only statistical significant but also clinically relevant and that it should be taken into account in the evaluation of the patients. Although the association between elevated heart rate and cardiovascular morbidity and mortality has been demonstrated in a large number of epidemiological studies, tachycardia has remained a neglected cardiovascular risk factor until very recently. For the first time, the recent guidelines of the European Society of Cardiology and the European Society of Hypertension indicate than an accelerated heart rate is considered as an independent risk factor and potentially as a target for pharmacologic therapies, especially in high-risk patients.