History of the development of isolated heart perfusion experimental model and its pioneering role in understanding heart physiology.

The isolated heart perfusion model, a fundamental tool in cardiovascular research, has evolved significantly since its inception in the late 19th century. This review traces the development of the isolated heart model, from its early adaptations by pioneers such as Langendorff and Starling to modern advancements by researchers like Morgan and Neely. We discuss the various applications of the model in pharmacological testing, disease modeling, and educational settings, emphasizing its crucial role in understanding cardiac function and disease mechanisms. Recent technological enhancements, including high-resolution imaging, integration with bioengineering, and advanced genomic and proteomic analyses, have significantly broadened the capabilities of these models. Looking forward, we explore potential future developments such as the integration of precision medicine, stem cell research, and artificial intelligence, which promise to revolutionize the use of isolated heart perfusion models. This review highlights the model's crucial role in bridging experimental research and clinical applications.

Cardiac implantable electronic devices in pregnancy: A position statement.

The aim of this document is to provide guidance for the management of women and birthing people with a permanent pacemaker (PPM) or implantable cardioverter defibrillator (ICD). Cardiac devices are becoming more common in obstetric practice and a reference document for contemporary evidence-based practice is required. Where evidence is limited, expert consensus has established recommendations. The purpose is to improve safety and reduce the risk of adverse events relating to implanted cardiac devices during pregnancy, birth and the postnatal period.

Corosolic acid attenuates cardiac ischemia/reperfusion injury through the PHB2/PINK1/parkin/mitophagy pathway.

Despite advances in treatment, myocardial infarction remains the leading cause of heart failure and death worldwide, and the restoration of coronary blood flow can also cause heart damage. In this study, we found that corosolic acid (CA), also known as plant insulin, significantly protects the heart from ischemia-reperfusion (I/R) injury. In addition, CA can inhibit oxidative stress and improve mitochondrial structure and function in cardiomyocytes. Subsequently, our study demonstrated that CA improved the expression of the mitophagy-related proteins Prohibitin 2 (PHB2), PTEN-induced putative kinase protein-1 (PINK1), and Parkin. Meanwhile, through molecular docking, we found an excellent binding between CA and PHB2 protein. Finally, the knockdown of PHB2 eliminated the protective effect of CA on hypoxia-reoxygenation in cardiomyocytes. Taken together, our study reveals that CA increases mitophagy in cardiomyocytes via the PHB2/PINK1/Parkin signaling pathway, inhibits oxidative stress response, and maintains mitochondrial function, thereby improving cardiac function after I/R.

The arena or E-games triathlon as a unique real world and virtual mixed-model endurance sports event.

The sport of triathlon has evolved to become a discipline comprising races of different lengths and formats. It has also undergone significant growth in popularity and exposure with several variations in format from the classic swim - bike - run combination attracting significant television and media coverage. Since 2021 an original and unique format called the Arena Games Triathlon (or in 2024 the E-Games) has evolved that involves athletes competing against each other in swimming, cycling and running combining both the real and virtual worlds in one race. This model of endurance sport is currently unique, provides instantaneous data on performance and has the potential to be a tool for performance prediction, talent selection and sport development. The goal of this perspective paper is to provide context around the emergence of the Arena Games Triathlon series, describe the format of this type of racing, outline how it has the potential to drive training and evaluation of triathletes and discuss the attractiveness of its future inclusion as an Olympic discipline.

Fluid and electrolyte pathophysiology in common febrile illness in children and the implications for clinical management.

Achieving fluid homeostasis and the management of fluid and electrolyte complications are constants in the treatment of seriously ill children worldwide. Consensus on the most appropriate fluid strategy for unwell children has been difficult to achieve and has evolved over the last two decades, most notably in high-income countries where adverse events relating to poor fluid management were identified more readily, and official robust inquiries were possible. However, this has not been the situation in many low-income settings where fluids that are prohibited from use in high-income countries may be all that are available, local guidelines and processes to recognise adverse events are not developed, and there has been limited training on safe fluid management for front-line healthcare workers. This narrative review outlines the fluid and electrolyte pathophysiology of common febrile illnesses in children, describes the evolution of this field and concludes with implications and principles of a fluid management strategy for seriously ill children. This review was prepared as a physiological background paper to support evidence presented to the WHO Guideline Development Group for Fluid Guidelines in Children, Geneva, March 2024.

The effect of an acute bout of exercise on circulating vitamin D metabolite concentrations: a randomised crossover study in healthy adults.

The effect of acute exercise on circulating concentrations of vitamin D metabolites is unclear. To address this knowledge gap, we examined the effect of a bout of treadmill-based exercise versus rest on circulating concentrations of 25(OH)D3, 25(OH)D2, 3-epi-25(OH)D3, 24,25(OH)2D3, 1,25(OH)2D3, and vitamin D2 and D3 in healthy men and women. Thirty-three healthy adults (14 females, 41 (15) years, body mass index 26.2 (3.7) kg/m2, V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ 36.2 (9.2) ml/kg/min; mean (SD)) completed two laboratory visits involving 60 min of moderate-intensity treadmill exercise (60% V ̇ O 2 max ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}{\mathrm{max}}}}$ ) versus 60 min of seated rest, both in an overnight fasted-state, as part of a randomised crossover design. Venous blood samples were drawn at baseline, immediately (0 h), 1 h and 24 h after the exercise or rest-period. There was a significant time × trial interaction effect for total circulating 25(OH)D (P = 0.0148), 25(OH)D3 (P = 0.0127) and 1,25(OH)2D3 (P = 0.0226). Immediately post-exercise, 25(OH)D, 25(OH)D3 and 1,25(OH)2D3 concentrations were significantly elevated compared to the control resting condition, and 1,25(OH) 2D3 remained significantly elevated 1 h later. Circulating albumin, vitamin D binding protein, calcium and parathyroid hormone were elevated immediately post-exercise. Thus, an acute bout of moderate intensity exercise transiently increases concentrations of circulating 25(OH)D and 1,25(OH)2D3 compared to resting conditions. KEY POINTS: Observational studies suggest that acute exercise might change circulating concentrations of vitamin D metabolites, but this has not been investigated using randomised crossover studies and using robust analytical procedures. In this study, we used a randomised crossover design to examine the effect of a bout of treadmill-based exercise (vs. rest) on circulating concentrations of a wide range of vitamin D metabolites in healthy humans. We show that an acute bout of moderate intensity exercise transiently increases concentrations of circulating 25(OH)D and 1,25(OH)2D3 compared to resting conditions. These findings indicate that regular exercise could lead to transient but regular windows of enhanced vitamin D biological action.

Physiological and transcriptional changes associated with obligate aestivation in the cabbage stem flea beetle (Psylliodes chrysocephala).

Aestivation is a form of seasonal dormancy observed in various insect species, usually coinciding with the summer season. The cabbage stem flea beetle, Psylliodes chrysocephala (Coleoptera: Chrysomelidae), is a key pest of oilseed rape that obligatorily aestivates as adult in late summer. Since the physiological and transcriptional processes linked to aestivation in P. chrysocephala are still little understood, we analyzed relevant physiological parameters and performed RNA-seq analyses on laboratory-reared beetles in their pre-aestivation, aestivation, and post-aestivation stages. We found that the beetles reached aestivation at 15 days post-eclosion, showing strongly reduced metabolic activity, with less than 50% CO2 production, compared to pre-aestivating individuals. Under constant laboratory conditions, the beetles aestivated for about 25 days. Female beetles reached reproductive maturity at a median of 52 days post-eclosion. Furthermore, aestivating beetles had significantly reduced carbohydrate reserves and increased lipid reserves compared with pre-aestivating beetles, indicating that aestivation is associated with drastic changes in energy metabolism. Aestivating beetles contained 30% less water and their survival rates under high-temperature conditions (30 °C) were 40% higher compared to pre-aestivating beetles. RNA-seq studies showed that, in particular, gene ontology terms related to carbohydrate and lipid metabolism, digestion, and mitochondrial activity were enriched, with clear differences in transcript abundance between beetles in aestivation compared to pre- or post-aestivation. Specifically, mitochondrial transcripts, such as respiratory chain I subunits, and digestion-related transcripts, such as trypsin, were less abundant during aestivation, which supports the idea that aestivation is associated with decreased metabolic activity. This study represents the first exploration of the transcriptomic and physiological processes linked to aestivation in P. chrysocephala.

Response of Elymus nutans Griseb. seedling physiology and endogenous hormones to drought and salt stress.

Elymus nutans Griseb. (E. nutans), a pioneer plant for the restoration of high quality pasture and vegetation, is widely used to establish artificial grasslands and ecologically restore arid and salinized soils. To investigate the effects of drought stress and salt stress on the physiology and endogenous hormones of E. nutans seedlings, this experiment configured the same environmental water potential (0 (CK), - 0.04, - 0.14, - 0.29, - 0.49, - 0.73, and - 1.02 MPa) of PEG-6000 and NaCl stress to investigate the effects of drought stress and salt stress, respectively, on E. nutans seedlings under the same environmental water potential. The results showed that although the physiological indices and endogenous hormones of the E. nutans seedlings responded differently to drought stress and salt stress under the same environmental water potential, the physiological indices of E. nutans shoots and roots were comprehensively evaluated using the genus function method, and the physiological indices of the E. nutans seedlings under the same environmental water potential exhibited better salt tolerance than drought tolerance. The changes in endogenous hormones of the E. nutans seedlings under drought stress were analyzed to find that treatment with gibberellic acid (GA3), gibberellin A7 (GA7), 6-benzyladenine (6-BA), 6-(y,y-dimethylallylaminopurine) (2.IP), trans-zeatin (TZ), kinetin (KT), dihydrozeatin (DHZ), indole acetic acid (IAA), and 2,6-dichloroisonicotininc acid (INA) was more effective than those under drought stress. By analyzing the amplitude of changes in the endogenous hormones in E. nutans seedlings, the amplitude of changes in the contents of GA3, GA7, 6-BA, 2.IP, TZ, KT, DHZ, IAA, isopentenyl adenosine (IPA), indole-3-butyric acid (IBA), naphthalene acetic acid (NAA), and abscisic acid was larger in drought stress compared with salt stress, which could be because the endogenous hormones are important for the drought tolerance of E. nutans itself. The amplitude of the changes in the contents of DHZ, TZR, salicylic acid, and jasmonic acid was larger in salt stress compared with drought stress. Changes in the content of melatonin were larger in salt stress compared with drought stress, which could indicate that endogenous hormones and substances are important for the salt tolerance of E. nutans itself.

Evaluating physiological barriers to oral intake in hospitalized patients: A secondary analysis.

BACKGROUND: Oral intake in hospitalized patients is frequently below estimated targets. Multiple physiological symptoms are proposed to impact oral intake, yet many have not been quantified objectively. AIM: To describe the challenges of objectively measuring physiological nutrition-impacting symptoms in hospitalized patients. METHOD: A secondary analysis of data from a single-center, descriptive cohort study of physiological nutrition-impacting symptoms in intensive care unit (ICU) survivors and general medical patients was conducted. Demographic and clinical characteristics were extracted for patients who completed the original study and collected retrospectively for those who were screened and recruited but did not complete the original study. Reasons for patient exclusion from the original study were quantified from the screening database. Descriptive data are reported as mean ± SD, median [interquartile range], or number (percentage). RESULTS: ICU survivors and general medical patients were screened for inclusion in the original study between March 1 and December 23, 2021. Of the 644 patients screened, 97% did not complete the study, with 93% excluded at screening. Of the 266 ICU survivors and 398 general medical patients screened, 89% and 95% were excluded, respectively. Major exclusion criteria included the inability to follow commands or give informed consent (n = 155, 25%), the inability to consume the easy-to-chew and thin-fluid buffet meal, and imminent discharge (both, n = 120, 19%). CONCLUSION: Understanding physiological factors that drive reduced oral intake in hospitalized patients is challenging. Exclusion criteria required to objectively quantify physiological nutrition-impacting symptoms significantly preclude participation and likely act as independent barriers to oral intake.

Pathophysiology of Chronic Hypercapnic Respiratory Failure.

Chronic hypercapnic respiratory failure occurs in several conditions associated with hypoventilation. The mechanisms underlying the development of chronic hypercapnia include a combination of processes that increase metabolic CO2 production, reduce minute ventilation (V'e), or increase dead space fraction (Vd/Vt). Fundamental to the pathophysiology is a mismatch between increased load and a reduction in the capacity of the respiratory pump to compensate. Though neural respiratory drive may be decreased in a subset of central hypoventilation disorders, it is more commonly increased in attempting to maintain the load-capacity homeostatic balance.

Towards better mortality prediction in cancer patients in the ICU: a comparative analysis of prognostic scales: systematic literature review.

OBJECTIVE: To evaluate the predictive ability of mortality prediction scales in cancer patients admitted to intensive care units (ICUs). DESIGN: A systematic review of the literature was conducted using a search algorithm in October 2022. The following databases were searched: PubMed, Scopus, Virtual Health Library (BVS), and Medrxiv. The risk of bias was assessed using the QUADAS-2 scale. SETTING: ICUs admitting cancer patients. PARTICIPANTS: Studies that included adult patients with an active cancer diagnosis who were admitted to the ICU. INTERVENTIONS: Integrative study without interventions. MAIN VARIABLES OF INTEREST: Mortality prediction, standardized mortality, discrimination, and calibration. RESULTS: Seven mortality risk prediction models were analyzed in cancer patients in the ICU. Most models (APACHE II, APACHE IV, SOFA, SAPS-II, SAPS-III, and MPM II) underestimated mortality, while the ICMM overestimated it. The APACHE II had the SMR (Standardized Mortality Ratio) value closest to 1, suggesting a better prognostic ability compared to the other models. CONCLUSIONS: Predicting mortality in ICU cancer patients remains an intricate challenge due to the lack of a definitive superior model and the inherent limitations of available prediction tools. For evidence-based informed clinical decision-making, it is crucial to consider the healthcare team's familiarity with each tool and its inherent limitations. Developing novel instruments or conducting large-scale validation studies is essential to enhance prediction accuracy and optimize patient care in this population.

Cardiac Fibroblasts: Answering the Call.

Cardiac fibroblasts play a pivotal role in maintaining heart homeostasis by depositing extracellular matrix (ECM) to provide structural support for the myocardium, vasculature, and neuronal network and by contributing to essential physiological processes. In response to injury such as myocardial infarction or pressure overload, fibroblasts become activated, leading to increased ECM production that can ultimately drive left ventricular remodeling and progress to heart failure. Recently, the AJP-Heart and Circulatory Physiology issued a call for papers on cardiac fibroblasts that yielded articles with topics spanning fibroblast physiology, technical considerations, signaling pathways, and interactions with other cell types. This mini-review summarizes those articles and places the new findings in the context of what is currently known for cardiac fibroblasts and what future directions remain.

Ecological momentary assessment of the unique effects of trait worry on daily negative emotionality: does arousal matter?

Worry proneness is a transdiagnostic trait that predicts increased negative affect (NA), potentially in the service of preventing negative emotional contrasts. Although discrete types of NA vary along the dimension of arousal, the extent to which trait worry predicts high vs. low arousal forms of NA in daily life is unclear. This distinction has important implications for conceptualising how worry may perturb adaptive emotionality in various disorders. The present study (not pre-registered) aimed to isolate the effects of trait worry on high (N = 88) and low (N = 122) arousal NA in daily life using ecological momentary assessment while controlling for potential physical and psychological confounds. Participants were assessed for trait worry and depressive symptoms at baseline then reported their affect, heart rate, and exercise three times per day for one week. Multilevel models revealed that trait worry predicted both increased high and low arousal NA after controlling for momentary heart rate, daily exercise, and depression. In contrast, baseline depressive symptoms only predicted low arousal NA in daily life. Findings support the contrast avoidance model of worry and suggest that worry is linked to increased state NA in daily life, independent of arousal.

Diuresis-led volume replacement strategy in extremely low birth weight infants.

AIM: In extremely low birth weight infants, fluid overload has been associated with bronchopulmonary dysplasia and death. Excessive weight loss may increase the risk of meconium obstruction and intestinal perforation. As these infants display oliguria followed by polyuria, we embarked on a diuresis-led volume replacement strategy as of January 2020. METHODS: This single-centre analysis presents data of infants <1000 g birth weight surviving for more than 3 days admitted 2017-2019 (n = 217, daily volume increase) versus 2020-2022 (n = 2022, diuresis-led volume replacement). RESULTS: The second cohort had lower gestational age (median [interquartile range]: 253/7 [243/7-264/7] vs. 263/7 [251/7-282/7] weeks), less antenatal steroids (58% vs. 69%), more indomethacin (66% vs. 47%) and higher initial diuresis (5.6 [4.9-6.8] vs. 4.8 [4.2-5.5] mL/kg/h) but did not differ by relative weight loss at Day 7 of life. Employing binary logistic regression with gestational age, antenatal steroids and indomethacin as covariates, the cohorts did not differ by rates of patent ductus arteriosus, abdominal surgery or severe retinopathy of prematurity, while there were significant declines in sepsis (from 32% to 19%), bronchopulmonary dysplasia (from 26% to 23%) and mortality (from 13% to 7%). CONCLUSION: Diuresis-led volume replacement appears to be safe and maybe beneficial.

Building Digital Twins for Cardiovascular Health: From Principles to Clinical Impact.

The past several decades have seen rapid advances in diagnosis and treatment of cardiovascular diseases and stroke, enabled by technological breakthroughs in imaging, genomics, and physiological monitoring, coupled with therapeutic interventions. We now face the challenge of how to (1) rapidly process large, complex multimodal and multiscale medical measurements; (2) map all available data streams to the trajectories of disease states over the patient's lifetime; and (3) apply this information for optimal clinical interventions and outcomes. Here we review new advances that may address these challenges using digital twin technology to fulfill the promise of personalized cardiovascular medical practice. Rooted in engineering mechanics and manufacturing, the digital twin is a virtual representation engineered to model and simulate its physical counterpart. Recent breakthroughs in scientific computation, artificial intelligence, and sensor technology have enabled rapid bidirectional interactions between the virtual-physical counterparts with measurements of the physical twin that inform and improve its virtual twin, which in turn provide updated virtual projections of disease trajectories and anticipated clinical outcomes. Verification, validation, and uncertainty quantification builds confidence and trust by clinicians and patients in the digital twin and establishes boundaries for the use of simulations in cardiovascular medicine. Mechanistic physiological models form the fundamental building blocks of the personalized digital twin that continuously forecast optimal management of cardiovascular health using individualized data streams. We present exemplars from the existing body of literature pertaining to mechanistic model development for cardiovascular dynamics and summarize existing technical challenges and opportunities pertaining to the foundation of a digital twin.

Implications of chronic hypoxia during development in red drum.

Respiratory plasticity is a beneficial response to chronic hypoxia in fish. Red drum, a teleost that commonly experiences hypoxia in the Gulf of Mexico, have shown respiratory plasticity following sublethal hypoxia exposure as juveniles, but implications of hypoxic exposure during development are unknown. We exposed red drum embryos to hypoxia (40% air saturation) or normoxia (100% air saturation) for 3 days post fertilization (dpf). This time frame encompasses hatch and exogenous feeding. At 3 dpf, there was no difference in survival and no change in size. After the 3-day hypoxia exposure, all larvae were moved and reared in common normoxic conditions. Fish were reared for ∼3 months and measured for implications of the developmental hypoxia exposure on swim performance and whole-animal aerobic metabolism. We used a cross design wherein fish from normoxia (N=24) were swam in Blazka swim tunnels in both hypoxia (40%, n=12) and normoxia (100%, n=12), and likewise for hypoxia-exposed fish (N=20, n=10 each group). Oxygen consumption, critical swim speed (Ucrit), critical oxygen threshold (Pcrit), and mitochondrial respiration were measured. Hypoxia-exposed fish had higher aerobic scope, maximum metabolic rate, and higher liver mitochondrial efficiency relative to control fish in normoxia. Interestingly, hypoxia-exposed fish showed increased hypoxia sensitivity (higher Pcrit), and recruit burst swimming at lower swim speeds relative to control fish. These data provide evidence that hypoxia exposure leads to a complex response in later life.

Inopinatus corneliae sp. nov. gen. nov. isolated from human skin: A newly discovered keratinophilic hyphomycete, order Onygenales.

BACKGROUND: Fungi clinically relevant to human skin comprise prevalent commensals and well-known pathogens. Only rarely human skin harbours fungi that evade identification. OBJECTIVE: To characterise an enigmatic specimen isolated from a skin lesion. METHODS: A comprehensive clinical and mycological workup including conventional methods for phenotypic characterisation and sequencing based on internal transcribed spacer (ITS) and large subunit (LSU) regions to infer a phylogenetic tree. RESULTS: Cultures on common solid media were macroscopically inconspicuous initially until mycelial tufts developed on the surface, notably on potato dextrose agar. Polymorphous chlamydospores were detected but no aleurospores and ascomata. At 26°C, the isolate grew on standard agars, plant materials and garden soil and utilised peptone, keratins, lipids, inulin, erythrocytes and cellulose. It also grew at 5°C and at 37°C. Nucleotide sequences of its ITS region showed 93% similarity to sequences of different Malbranchea species. The closest matches among LSU rRNA sequences were obtained with the genera Amauroascus, Arthroderma, Auxarthronopsis and Malbranchea (93%-95%). A combined phylogenetic analysis placed the fungus in a sister clade to Neogymnomycetaceae, classified as incertae sedis in Onygenales, on a large distance to either Diploospora rosea or 'Amauroascus' aureus. CONCLUSIONS: The genus Inopinatus gen. nov. (MB854685) with the species Inopinatus corneliae sp. nov. (MB854687) is introduced to accommodate our isolate (holotype: DSM 116806; isotypes: CBS 151104, IHEM 29063). Probably Inopinatus corneliae is a geophilic species that, although potentially harmful, was no relevant pathogen in our case. Its ecology, epidemiology and pathogenicity need to be further clarified.

Heterozygous Gnaq deficiency enhances Ifi202b/IFI16 and NF-κB activation in endothelial cells and exacerbates lupus nephritis pathology.

Lupus nephritis (LN), a severe complication of systemic lupus erythematosus (SLE), exhibits significant heterogeneity. Recent evidence suggests that non-immune factors contribute to end-organ damage, challenging the traditional view of LN solely arising from immune dysregulation. To investigate this, we employed autoimmune-prone Gnaq +/- mice receiving intraperitoneal pristane injections. Bone marrow transfer (BMT) distinguished the roles of immune versus non-immune cells. We observed that: (1) BMT from wild-type (WT) mice to Gnaq +/- recipients resulted in severe proteinuria and diffuse proliferative nephritis after pristane exposure; (2) GNAQ knockdown increased the expression of IFI16/Ifi202b and activated the NF-κB pathway in endothelial cells; and (3) increased IFI16 expression in human kidney biopsies correlated with proliferative LN. Taken together, these findings suggest that GNAQ acts as an inflammatory regulator in kidney endothelial cells via the IFI16/NF-κB pathway, potentially linking it to the development of LN in humans.

Comparison of Critical Illness Score in Patients Admitted to Intermediate Care Units of a Tertiary Care Hospital: A Comparative Cross-Sectional Study from Karachi, Pakistan.

Introduction: Intermediate care units (IMCUs) serve as step-up units for emergency department patients and as step-down units for critically ill patients transferred from intensive care units. This study compares four critical illness scores for assessment of acutely ill patients and their accuracy in predicting mortality in patients admitted to IMCU. Methods: A comparative cross-sectional study on patients aged ≥18 admitted to IMCU of Aga Khan University Hospital from 2017 to 2019. All patients admitted to IMCU from the emergency room were included in the study. Patient's record were reviewed for demographic data, physiological and laboratory parameters. Critical illness scores were calculated from these variables for each patient. Results: A total of 1192 patients were admitted to the IMCU, of which 923 (77.4%) medical records were finally analyzed. The mean (SD) age of participants was 62 years (± 16.5) and 469 (50.8%) were women. The overall hospital mortality rate of patients managed in IMCU was 6.4% (59/923 patients). The median scores of APACHE II, SOFA, SAPS II and MEWS were 16 (IQR 11-21), 4 (IQR 2-6), 36 (IQR 30-53) and 3 (IQR 2-4) points respectively. AUC for SAPS II was 0.763 (95% CI: 0.71-0.81), SOFA score was 0.735 (95% CI: 0.68-0.79) and MEWS score was 0.714 (95% CI: 0.66-0.77). The lowest ROC curve was 0.584 (95% CI: 0.52-0.64) for APACHE II. Conclusion: In conclusion, our study found that SAPS II, followed by SOFA and MEWS scores, provided better discrimination in stratifying critical illness in patients admitted to IMCU of a tertiary care hospital in Pakistan.