Home-based intensive nutrition therapy improves frailty and sarcopenia in patients with decompensated cirrhosis: A randomized clinical trial.

BACKGROUND AND AIM: The majority of patients with decompensated cirrhosis suffer from malnutrition, a potentially modifiable contributor to frailty and sarcopenia. The present study investigated the impact of a 6-month dietician-supported home-based intensive nutrition therapy (HINT) intervention on objective frailty and sarcopenia metrics in patients with decompensated cirrhosis. METHODS: One hundred adult patients with decompensated cirrhosis, frailty, and sarcopenia at baseline were randomized 1:1 to receive standard medical therapy (SMT) plus HINT (intervention) versus SMT (control) alone. The primary outcome was an improvement in frailty as measured by the liver frailty index (LFI). Secondary outcome measures included sarcopenia metrics, liver disease severity scores, hospitalization, and death. RESULTS: The LFI improved more in the intervention arm as compared with controls (0.8 vs 0.4; P < 0.001). Baseline and end-of-study skeletal muscle index (SMI) was available in a subset of 32 male patients, with greater improvements seen in the intervention arm compared with controls (6.36 vs 0.80; P = 0.02). Patients in the intervention arm had less hospitalizations over the 6-month follow-up (19 [38%] vs 29 [58%]; P = 0.04). On subgroup analysis, in the 64% of patients who were adherent to calorie and protein intake targets at 6 months, significant improvement was seen in liver disease severity scores and survival (P < 0.05). CONCLUSION: In patients with decompensated cirrhosis, frailty, and sarcopenia, a 6-month dietitian-supported home-based intensive outpatient nutrition therapy was associated with statistically and clinically relevant improvement in frailty. The subgroup of adherent patients showed improvement in their liver disease scores and reduction in mortality. These findings support the key role of food as medicine in the management of cirrhosis.

Physiological response of diverse halophytes to high salinity through ionic accumulation and ROS scavenging.

Salt stress induced modulations in different ionic ratios and ROS system were studied in ten halophytic species, namely Atriplex lentiformis, Tamarix aphylla, Sporobolus marginatus, Suaeda nudiflora, Urochondra setulosa, Arundo donax, Aeluropus lagopoides, Heliotropium ramossimum, Atriplex nummularia, Leptachloa fusca at salinity level of ECe ∼ 30 dSm-1 (≈300 mM NaCl) to explore their possible role in salt tolerance ability of these halophytes. These halophytes were categorized for their salt tolerance levels based on the ratios of Na+/K+, Na+/Ca2+, Na+/Cl- and Na + Cl/K + Ca. Variable responses were observed among all halophytes where Atriplex lentiformis had lowest leaf Na+/K+ (0.44) which is one of the best indicator of salt tolerance, Heliotropium ramossimum had lowest Na+/Ca2+ and Na+/Cl- (0.97 and 0.18), whereas Sporobolus marginatus had lowest Na + Cl/K + Ca (0.79). Specific enzymes activities of ascorbate peroxidase (APX), superoxide dismutase (SOD), catalase (CAT) and peroxidase (POX) were also assessed to get better comprehension of the ROS scavenging system under salinity in these halophytes. Urochondra setulosa showed highest APX and SOD activity followed by Atriplex lentiformis. Most efficient enzyme in degrading hydrogen peroxide i.e. CAT showed highest activity in Suaeda nudiflora followed by Atriplex nummularia and Urochondra setulosa, whereas Atriplex nummularia and Atriplex lentiformis showed higher POX activity. Significant variability in H2O2 and MDA content was also observed. These results possibly suggest higher inbuilt genetic potential of these halophytes to combat high salinity induced oxidative stress via higher antioxidant activities. Novelty statement: Halophytic plant adopt different strategies to cope up with the toxic ions and our studies show that the induction of antioxidant defense system to scavenge ROS, alongwith structural modifications in terms of lipid peroxidation and compartmentalization of toxic ions are the main strategies for tighter control of ion fluxes in the studied halophytes.

Bile duct paucity in childhood-spectrum, profile, and outcome.

We studied the etiological spectrum, clinicolaboratory and histological profile, and outcome of infants and children under 18 years of age presenting between December 2010 and May 2016 with histological evidence of paucity of intralobular bile ducts (PILBD, bile ducts to portal tract ratio < 0.6) Post-transplant PILBD was excluded. Of 632 pediatric liver biopsies screened, 70 had PILBD-44 were infants. PILBD was classified histologically into destructive (n = 50) and non-destructive PILBD (n = 20). Presentations were jaundice (98%), organomegaly (94%), pale stools (50%), and pruritus (43%). Infants had more cholestasis but less fibrosis on histology. Overall, 29 required liver transplantation (LT) for portal hypertension (n = 26), decompensation (n = 25), growth failure (n = 20), intractable pruritus (n = 5), and recurrent cholangitis (n = 2). Destructive PILBD has an odds for poor outcome (decompensation or need for LT within 1 year) of 1.53 (95% CI = 1.15-2.04). On binary logistic regression analysis, poor outcome was related to advanced fibrosis on liver biopsy [Exp (B) = 5.46, 95% CI = 1.56-19.04]. CONCLUSION: PILBD was present in 11% of pediatric liver biopsies and has a varied etiological spectrum. Destructive PILBD has poor outcome. Need for LT is guided by the presence of advanced fibrosis. What is Known: • Natural history of syndromic ductal paucity (Alagille syndrome) is complex. • Duct loss is commonly seen with late presentation of biliary atresia. What is New: • The study classifies the etiological spectrum of ductal paucity histologically into destructive and non-destructive. • Destructive duct loss carries poor prognosis regardless of the etiology of liver disease with subsequent need for liver transplantation.

Unlocking growth potential: Synergistic potassium fertilization for enhanced yield, nutrient uptake, and energy fractions in Chinese cabbage.

The implementation of integrated potassium management presents a viable approach for augmenting plant growth, yield, and nutrient uptake while enhancing soil nutrient availability. A field experiment was executed during the rabi season of 2020, employing a randomized complete block design encompassing eight treatments involving standard (100%) and reduced (75% and 50%) rates of the recommended dose of potassium (RDK) administered through muriate of potash (MOP). Treatments included variations in the incorporation/exclusion of plant growth-promoting rhizobacteria (PGPR), farmyard manure (FYM) at 25% of potassium recommendation, and foliar application of nano potash. The use of 100% RDK +25% K augmentation through FYM + PGPR and nano K fertilizer spray at 25 and 40 DAS (T8) exhibited significant enhancements in green fodder yield (64.0 ± 2.2 t ha-1) over control with no potassium application (47.3 ± 3.7 t ha-1) and found at par with and 75% RDK + 25% K augmentation through FYM + PGPR and nano K fertilizer spray at 25 and 40 DAS (T7). These treatments yielded maximum percent increase for plant height (34.9%), leaf count (38.5%), leaf dimensions (28.8-31.5%), stem girth (25.84%), root volume (27.0%), and root length (37.64%), observed at the harvest stage compared to control (T1-no potassium application). The treatment T8 was on par with T7 and recorded highest uptake of macro (N, P, and K) and micro (Zn, Fe, Cu, and Mn) nutrients. While soil parameters such as available nitrogen and potassium levels were notably increased through the application of treatment T7 across various treatment combinations and found significantly superiority over treatment T8. Multivariate analysis also highlighted treatment T7 is more efficient in maintaining sustainability. Hence, based on the present findings it can be concluded that application of 75% RDK +25% K augmentation through FYM + PGPR and nano K fertilizer spray at 25 and 40 DAS (T7) can be recommended for achieving enhanced productivity and soil fertility improvement within agricultural systems.

Optimizing agricultural sustainability: enriched organic formulations for growth, yield, and soil quality in a multi-crop system.

Utilizing agricultural and industrial wastes, potent reservoirs of nutrients, for nourishing the soil and crops through composting embodies a sustainable approach to waste management and organic agriculture. To investigate this, a 2-year field experiment was conducted at ICAR-IARI, New Delhi, focusing on a pigeon pea-vegetable mustard-okra cropping system. Seven nutrient sources were tested, including a control (T1), 100% recommended dose of nitrogen (RDN) through farmyard manure (T2), 100% RDN through improved rice residue compost (T3), 100% RDN through a paddy husk ash (PHA)-based formulation (T4), 75% RDN through PHA-based formulation (T5), 100% RDN through a potato peel compost (PPC)-based formulation (T6), and 75% RDN through PPC-based formulation (T7). Employing a randomized block design with three replications, the results revealed that treatment T4 exhibited the significantly highest seed (1.89 ± 0.09 and 1.97 ± 0.12 t ha-1) and stover (7.83 ± 0.41 and 8.03 ± 0.58 t ha-1) yield of pigeon pea, leaf yield (81.57 ± 4.69 and 82.97 ± 4.17 t ha-1) of vegetable mustard, and fruit (13.54 ± 0.82 and 13.78 ± 0.81 t ha-1) and stover (21.64 ± 1.31 and 22.03 ± 1.30 t ha-1) yield of okra during both study years compared to the control (T1). Treatment T4 was on par with T2 and T6 for seed and stover yield in pigeon pea, as well as okra, and leaf yield in vegetable mustard over both years. Moreover, T4 demonstrated notable increase of 124.1% and 158.2% in NH4-N and NO3-N levels in the soil, respectively, over the control. The enhanced status of available nitrogen (N) and phosphorus (P) in the soil, coupled with increased soil organic carbon (0.41%), total bacteria population (21.1%), fungi (37.2%), actinomycetes (44.6%), and microbial biomass carbon (28.5%), further emphasized the positive impact of T4 compared to the control. Treatments T2 and T6 exhibited comparable outcomes to T4 concerning changes in available N, P, soil organic carbon, total bacteria population, fungi, actinomycetes, and microbial biomass carbon. In conclusion, treatments T4 and T6 emerge as viable sources of organic fertilizer, particularly in regions confronting farmyard manure shortages. These formulations offer substantial advantages, including enhanced yield, soil quality improvement, and efficient fertilizer utilization, thus contributing significantly to sustainable agricultural practices.

A study of rhino-orbito-cerebral mucormycosis with COVID-19: A new challenge in North West of Rajasthan.

Background: Mucormycosis is a life-threatening fungal disease in immunocompromised patients. There has been increase in the number of mucormycosis associated with COVID-19 patients in second wave. Now country battle with both COVID-19 and mucormycosis. An invasive mucormycosis infection has been a significant burden in India after COVID-19. It has been recently emerged a notifiable disease by the Rajasthan government. Our aim is to develop awareness regarding the importance of early detection and treatment of mucormycosis with COVID-19 and reduce the morbidity and mortality. Materials and Methods: This is a Prospective longitudinal study including 34 patients diagnosed with acute invasive fungal infection by contrast enhancement magnetic resonance imaging studies of paranasal, orbit and brain or nasal biopsy for KOH/culture. Diagnosis is made through routine blood tests, biopsy, and radiological imaging. The patients taken for the study were COVID-19 reverse transcription-polymerase chain reaction positive or recent post COVID-19 (within 15 days) or symptoms of COVID-19 with bilateral pneumonitis. The study was conducted with 34 patients admitted to the department of medicine with mucormycosis within a month may 2021. Results: A total of 34 patients with a mean age of 50.92 years old and male female ratio 24/10 (70.5/29.41) were included in this study. The most common comorbidity was diabetes mellitus (23 patients 67.64%). Nine patients were newly diagnosed or recent onset of diabetes with or after COVID-19 infection. Twenty-four (70.58%) patients were COVID-19 positive or recent (within 15 days) history of COVID-19 positive. Seven (20.58) patients had the history of steroid as a treatment during COVID-19 and 5 (14.70) patients was on oxygen inhalation. One (2.94%) patient was fully vaccinated, and 5 (14.70) patients had the history of steam inhalation. The most common involvement was naso-orbital mucormycosis found in 28 patients (82.35%) followed by nasal-and orbital 26 (76.47) and 18 (52.94), respectively. Naso-Orbito-Cerebral was seen in 16 (47.05) patients. The more common reported symptoms and signs were headache (76.47), facial numbness (64.70), Nasal discharge (52.94), and ophthalmoplegia (52.94). Cranial nerve involvement was seen in 10 patients (facial palsy in 8 patients and bulbar palsy in 2 patients). Total mortality was 7 (7/34 20.58%). Conclusion: COVID-19 infection associated with the wide range of invasive mucormycosis. Early diagnosis and Clinical suspicion of acute invasive fungal sinusitis among COVID-19 patients is essential for better outcomes and higher survival.

Résumé Contexte: La mucormycose est une maladie fongique mortelle chez les patients immunodéprimés. Il y a eu une augmentation du nombre de mucormycose associée aux patients Covid - 19 en deuxième vague. Maintenant, le pays se bat contre le Covid-19 et la mucormycose. Une infection invasive en mucormycose a été une charge significative en Inde après Covid - 19. Il a récemment émergé une maladie notifiable du gouvernement du Rajasthan. Notre objectif est de sensibiliser à l'importance de la détection et du traitement précoce de la mucormycose avec Covid-19 et de réduire la morbidité et la mortalité. Matériaux et méthodes: Il s'agit d'une étude longitudinale prospective comprenant 34 patients diagnostiqués avec une infection fongique invasive aiguë par un contraste d'imagerie magnétique des études d'imagerie par résonance magnétique de biopsie paranasale, en orbite et au cerveau ou nasale pour le KOH / la culture. Le diagnostic est posé par des tests sanguins de routine, une biopsie et une imagerie radiologique. Les patients pris pour l'étude ont été la réaction en chaîne de la transcription inverse de Covid-19, la réaction en chaîne de polymérase positive ou le post-COVID-19 récent (dans les 15 jours) ou les symptômes de Covid-19 avec une pneumonite bilatérale. L'étude a été menée avec 34 patients admis au Département de médecine avec mucormycose dans un mois en mai 2021. Résultats: Un total de 34 patients avec un âge moyen de 50,92 ans et un rapport féminine masculin 24/10 (70,5 / 29,41) ont été inclus dans cette étude. La comorbidité la plus courante était le diabète sucré (23 patients 67,64%). Neuf patients ont été récemment diagnostiqués ou un début récent du diabète avec ou après l'infection à Covid - 19. Vingt-quatre (70,58%) patients étaient des antécédents de Covid - 19 positifs ou récents (dans les 15 jours) de Covid - 19 positifs. Sept (20,58) patients avaient des antécédents de stéroïde comme traitement pendant les patients COVID-19 et 5 (14,70) étaient sous inhalation d'oxygène. Un patient (2,94%) a été entièrement vacciné et 5 (14,70) patients avaient des antécédents d'inhalation de vapeur. L'atteinte la plus courante était la mucormycose naso-orbitale trouvée chez 28 patients (82,35%), suivie respectivement par l'orbital nasal et orbital 26 (76,47) et 18 (52,94). Le naso - orbito-cervebral a été observé chez 16 (47,05) patients. Les symptômes et les signes rapportés les plus courants étaient des maux de tête (76,47), un engourdissement facial (64,70), une décharge nasale (52,94) et une ophtalmoplégie (52,94). Une atteinte du nerf crânien a été observée chez 10 patients (paralysie faciale chez 8 patients et paralysie bulbaire chez 2 patients). La mortalité totale était de 7 (7/34 20,58%). Conclusion: Infection Covid - 19 associée à la large gamme de mucormycose invasive. Le diagnostic précoce et la suspicion clinique de sinusite fongique invasive aiguë chez les patients COVID-19 sont essentiels pour de meilleurs résultats et une survie plus élevée. Mots-clés: Covid - 19, fongique, invasive, nasal, rhinocéros orbital cerebral.

Salinity Stress Tolerance in Potato Cultivars: Evidence from Physiological and Biochemical Traits.

Salinity stress is a major constraint to sustainable crop production due to its adverse impact on crop growth, physiology, and productivity. As potato is the fourth most important staple food crop, enhancing its productivity is necessary to ensure food security for the ever-increasing population. Identification and cultivation of salt-tolerant potato genotypes are imperative mitigating strategies to cope with stress conditions. For this purpose, fifty-three varieties of potato were screened under control and salt stress conditions for growth and yield-related traits during 2020. Salt stress caused a mean reduction of 14.49%, 8.88%, and 38.75% in plant height, stem numbers, and tuber yield, respectively in comparison to control. Based on percent yield reduction, the genotypes were classified as salt-tolerant (seven genotypes), moderately tolerant (thirty-seven genotypes), and salt-sensitive genotypes (nine genotypes). Seven salt-tolerant and nine salt-sensitive genotypes were further evaluated to study their responses to salinity on targeted physiological, biochemical, and ionic traits during 2021. Salt stress significantly reduced the relative water content (RWC), membrane stability index (MSI), photosynthesis rate (Pn), transpiration rate (E), stomatal conductance, and K+/Na+ ratio in all the sixteen genotypes; however, this reduction was more pronounced in salt-sensitive genotypes compared to salt-tolerant ones. The better performance of salt-tolerant genotypes under salt stress was due to the strong antioxidant defense system as evidenced by greater activity of super oxide dismutase (SOD), peroxidase (POX), catalase (CAT), and ascorbate peroxidase (APX) and better osmotic adjustment (accumulation of proline). The stepwise regression approach identified plant height, stem numbers, relative water content, proline content, H2O2, POX, tuber K+/Na+, and membrane stability index as predominant traits for tuber yield, suggesting their significant role in alleviating salt stress. The identified salt-tolerant genotypes could be used in hybridization programs for the development of new high-yielding and salt-tolerant breeding lines. Further, these genotypes can be used to understand the genetic and molecular mechanism of salt tolerance in potato.

de novo transcriptomic profiling of differentially expressed genes in grass halophyte Urochondra setulosa under high salinity.

Soil salinity is one of the major limiting factors for crop productivity across the world. Halophytes have recently been a source of attraction for exploring the survival and tolerance mechanisms at extreme saline conditions. Urochondra setulosa is one of the obligate grass halophyte that can survive in up to 1000 mM NaCl. The de novo transcriptome of Urochondra leaves at different salt concentrations of 300-500 mM NaCl was generated on Illumina HiSeq. Approximately 352.78 million high quality reads with an average contig length of 1259 bp were assembled de novo. A total of 120,231 unigenes were identified. On an average, 65% unigenes were functionally annotated to known proteins. Approximately 35% unigenes were specific to Urochondra. Differential expression revealed significant enrichment (P < 0.05) of transcription factors, transporters and metabolites suggesting the transcriptional regulation of ion homeostasis and signalling at high salt concentrations in this grass. Also, about 143 unigenes were biologically related to salt stress responsive genes. Randomly selected genes of important pathways were validated for functional characterization. This study provides useful information to understand the gene regulation at extremely saline levels. The study offers the first comprehensive evaluation of Urochondra setulosa leaf transcriptome. Examining non-model organisms that can survive in harsh environment can provide novel insights into the stress coping mechanisms which can be useful to develop improved agricultural crops.

Paraquat Poisoning: A Case Report.

Paraquat is commonly used herbicide by farmers in North West Rajasthan. Despite its easy availability, poisoning of its not common. Fatal dose of paraquat is so small that >10 ml poison can damage lungs permanently. Diagnosis is often difficult without proper history, absence of specific clinical feature and lack of diagnostic test. Inhalation exposures represent one of the most important routes of poisoning. We are reporting a case of inhaled paraquat poisoning with complication of irreversible acute kidney, liver and lung injury.

Zoledronate for Osteogenesis imperfecta: evaluation of safety profile in children.

BACKGROUND: The advent of bisphosphonates (BPs) has revolutionised the outcome of Osteogenesis imperfecta (OI) in the last few years. There has always been a safety concern regarding zoledronate's use due to a paucity of studies. The current study is a retrospective evaluation of children with OI on the short- and long-term side effects of zoledronate and the frequency of fractures per year after the drug was introduced. METHODS: A total of 26 children diagnosed with OI, with a median age of 84 (45-121) months were enrolled in the study. They received cyclical zoledronate for a median duration of 36 (11-61) months at quarterly intervals between January 2008 and December 2014. Safety evaluation involved assessment of its short- and long-term effects in addition to the frequency of fractures after its usage. RESULTS: One (3%) neonate had symptomatic hypocalcemia 15 days after the infusion. Three children (11%) had acute phase reactions. None had long-term side effects, including osteonecrosis of the jaw, in our 7-year experience. OI of types III and IV (total of 22) had significant reductions in the number of fractures (p<0.05). CONCLUSIONS: Further long-duration studies are necessary to evaluate the longterm safety of zoledronate.

Neuropsychiatric Profile in Malaria: An Overview.

INTRODUCTION: Malaria is the most important parasitic disease of humans causes clinical illness over 300-500 million people globally and over one million death every year globally. The involvement of the nervous system in malaria is studied in this paper, to help formulate a strategy for better malaria management. AIM: To study the Neuropsychiatric manifestation in malaria. MATERIALS AND METHODS: This was a prospective observational study in 170 patients with a clinical diagnosis of malaria admitted in various medical wards of medicine department of PBM Hospital, Bikaner during epidemic of malaria. It included both sexes of all age groups except the paediatric range. The diagnosis of malaria was confirmed by examination of thick and thin smear/optimal test/strip test. Only those cases that had asexual form of parasite of malaria in the blood by smear examination or optimal test were included in the study. RESULTS: Out of total 170 patients 104 (62%) reported Plasmodium falciparum (PF), Plasmodium vivax (PV) were 57 (33.5%) followed by mixed (PF+PV) 9 (5.3%) cases. The total PBF-MP test positivity was 84.5%. Maximum patients were belonging to the age range of 21-40 year with male predominance. Neuropsychiatric manifestation seen in falciparum malaria (n=111) as follow: altered consciousness 20 (18.01%), headache 17 (15.32%), neck rigidity 5 (4.5%), convulsion 5 (4.55%), extra pyramidal rigidity 2 (1.8%), decorticate rigidity 1 (0.90%), decerebrate rigidity 1 (0.90%), cerebellar ataxia 3 (2.7%), subarachnoid haemorrhage 1 (0.90%), aphasia 2 (1.8%), subconjunctival haemorrhage 1 (0.90%), conjugate deviation of eye 1 (0.90%) and psychosis 6 (5.40%). Twenty one patients presented with cerebral malaria out of 111 patients. Most patients of cerebral malaria presented with altered level of consciousness followed by headache and psychosis. Acute confusional state with clouding of consciousness was the most common presentation of psychosis (50%). CONCLUSION: Neuropsychiatric manifestations are not an uncommon presentation of malaria. Most commonly caused by PF malaria. Malaria should be thought as a differential diagnosis in pyrexia with neuropsychiatric manifestation. Observation obtained in the study will be highly useful for the diagnosis and management of patients suffering from malaria.

Pulmonary cryptosporidiosis in an immunocompetent host treated successfully with nitazoxanide.

Cryptosporidium parvum is an intracellular spore-forming protozoa which predominantly causes intestinal diseases. It causes severe and life-threatening diarrheal diseases in immunocompromised hosts and usually self-limiting disease in immunocompetent hosts. Extra-intestinal manifestations of cryptosporidium infection are very rare. Herein, we report a case of pulmonary cryptosporidiosis in a 35-yrs-old immunocompetent host, who presented with fever, cough and breathlessness which was soon followed by diarrhea and vomiting, had lung consolidation, and treated successfully with nitazoxanide.

Association between erectile dysfunction and cardiovascular risk in individuals with type-2 diabetes without overt cardiovascular disease.

BACKGROUND: Erectile dysfunction in type-2 diabetes may be an independent marker for coronary artery disease. Present study was undertaken to investigate whether type-2 diabetic patients with erectile dysfunction without having overt cardiovascular disease had increased cardiovascular risk. AIM: To find out correlation between ED and cardiovascular risk in diabetic patients. METHODS: Fifty type-2 diabetic patients were assessed for erectile dysfunction using international index of erectile dysfunction (IIEF-5), which include questionnaire and cardiovascular risk assessment by multiparameter cardiovascular analysis device (periscope). RESULTS: The prevalence of erectile dysfunction in type-2 diabetics was very high (78%), mild, moderate and severe ED was present in 6, 36 and 36%, respectively. The total cardiovascular risk was more in patients with ED in comparison to patients without ED (34.87 +/- 18.82 vs 20.91 +/- 11.03 p = 0.002). The mean 10-years coronary risk and cardiac risk was 12.00 + 9.60 and 22.23 + 14.14 (p = 0.029) and 13.36 +/- 1.22 and 28.85 +/- 4.13 (p 0.002) in patients without ED and with ED respectively. The mean vascular and atherosclerosis risk was 28.73 +/- 13.94 and 39.38 +/- 19.51 (p > 0.05) and 26.18 +/- 10.31 and 33.92 +/- 13.40 (p > 0.05) in patients without ED and with ED, respectively. Total cardiovascular risk was found to increase with age, duration of diabetes and HbA1c levels. CONCLUSION: The total cardiovascular risk increases with increasing severity of erectile dysfunction in type-2 diabetic patients without having overt cardiovascular disease.