Understanding clinical complexity in organ and organizational systems: Challenges local and global.

INTRODUCTION: Complexity in healthcare systems has been arbitrarily defined as tasks or systems ranging from complicated to intractable, with a general view of these not being 'simple'. Complexity in healthcare systems in first-world countries has been well elucidated, however, data from third-world countries is still scant. MATERIALS AND METHODS: We present four cases each from three different organ systems-chronic kidney disease, alcohol use disorder, and heart failure-in the backdrop of our healthcare organization. We present our analysis of the complexities faced clinically and, in our local healthcare system which led to these events. RESULTS: Analysis of these cases showed that patients with chronic kidney disease had vertebral-spinal pathologies due to poor infection control measures during haemodialysis. All these patients were young with a long history of secondary hypertension. In patients with alcohol use disorder, a common theme of how government regulations and peer pressure promote alcohol use is analysed. In the four patients with unexplained heart failure, vascular health is viewed as a fractal dimension and the various factors affecting vascular health are elaborated. CONCLUSION: Complexities exist clinically in making a diagnosis, and organizationally, in the variables and nodes dictating patient outcomes. Clinical complexities cannot be simplified but have to be navigated in an optimized way to improve clinical outcomes.

ATP-Enhanced Multistimuli-Responsive Förster Resonance Energy Transfer in Organic Coassemblies.

In recent years, ATP has emerged as an anionic biocomponent for the design of dynamic and stimuli-responsive supramolecular assemblies. Herein, we present ATP-enhanced Förster resonance energy transfer (FRET) in the coassemblies of pyrene-imidazolium amphiphiles with pyrene acting as an excellent donor for the coembedded acceptor dyes to generate tunable multiluminescent materials in aqueous solutions and in polymer and solid films. We achieved high energy transfer efficiency up to 95% even at a donor/acceptor (D/A) ratio of 100:1. By a simple variation of the D/A ratio, emission covering almost the whole range of the visible spectrum from blue to red including white light was obtained in solution and in solid and polymer films. Furthermore, the systems exhibited FRET ON/OFF features controlled by various stimuli such as temperature, pH, and metal ions. Most notably, a ratiometric and linear luminescence response to temperature and pH was observed. The stimuli-responsive tunable solid-state emission was further exploited in encryption-decryption applications.

Stroke Strikes in Bangladesh: Current Insights and Future Directions.

Stroke is a neurological condition attributable to vascular injury (e.g., infarction, hemorrhage) of the central nervous system. Globally, it ranks high among the leading causes of death. The poor stroke management system in Bangladesh is contributing to the country's rapid rise in stroke incidence. Stroke-related mortality and disability can be decreased by being aware of and taking steps to address potential risk factors. The population in this area has a generally poor understanding of strokes. Important avenues for preventing stroke in this population may include an effective public awareness campaign which includes spreading knowledge regarding early signs of stroke (facial drooping, arm weakness, speech difficulties, and time), the golden hour of stroke, cardiopulmonary resuscitation, the development of structured emergency medical care, appropriate rehabilitation, control of blood pressure and blood glucose, and cessation of smoking.

Cascade Energy Transfer in Biopolymer-Templated Multi-Chromophoric Assemblies: Ratiometric Temperature Sensing.

Natural light-harvesting complexes collect energy from sunlight and transfer it to the reaction center through a cascade of energy and electron transfer steps. Artificial light-harvesting systems functioning in aqueous media mimic natural photosynthetic systems. However, their design remains a challenging task as closely packed antenna chromophores often undergo severe self-quenching. Herein, we report luminescent co-assemblies between cationic pyrene-appended imidazolium amphiphiles and two anionic biopolymeric scaffolds, heparin and DNA in aqueous media. These co-assemblies served as excellent platforms for constructing artificial light-harvesting systems as upon co-embedding of multiple external dyes, highly efficient single-step and cascade energy transfer was observed from the pyrene donors to the acceptor dyes. Most notably, the efficiency of the energy transfer process was possible to modulate by employing multiple stimuli such as pH and temperature, and this resulted in the generation of multi-color luminescent materials in solution and film states, and they were also exploited in ratiometric temperature sensing. Their stimuli-responsive luminescence in the solid state was found to be advantageous for encryption studies.

The role of switch maintenance therapy in urothelial cancers.

Maintenance therapy with immune checkpoint inhibitors (ICIs) has changed the treatment paradigm of metastatic urothelial carcinoma (mUC). The JAVELIN Bladder 100 trial established avelumab, one of several ICIs in use today, as a life-prolonging maintenance therapy for patients with advanced urothelial carcinoma. Platinum-based chemotherapy is most often used in the first-line treatment of mUC, and while response rates approach about 50%, disease control is usually short-lived upon completion of the standard three to six cycles of chemotherapy. Much progress has been made in recent years in the second-line space and beyond with the use of ICIs, antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs) in eligible patients at the time of disease progression post-platinum-based chemotherapy. However, many patients with progressive mUC after first-line chemotherapy suffer from rapid progression of disease, treatment toxicity with subsequent lines of therapy, and a limited life expectancy. Until the results of the JAVELIN Bladder 100 trial were presented in 2020, there were no maintenance strategies proven to be beneficial over best supportive care after disease control is achieved with first-line platinum-based chemotherapy. To date, standard of care frontline treatment of metastatic urothelial cancer remains to be four to six cycles of platinum-based chemotherapy followed by maintenance avelumab. This review summarizes the current evidence available on maintenance therapies in mUC, as well as several highly anticipated clinical trials that we hope will result in further progress in the management of this aggressive cancer and improve patient outcomes.

Heparin-Induced Dual Mode Luminescence Modulation of Organic Nanoparticles and Efficient Energy Transfer.

Amphiphilic di-cationic fumaronitrile derivatives with peripheral n-alkyl chains formed organic nanoparticles (NPs) through self-assembly in aqueous media. The NPs exhibited enhanced luminescence in both steady-state and delayed mode in comparison to their molecularly dissolved state. Due to the presence of the multivalent array of positive charges on their surface, they were found to bind heparin, a bio-polyanion which is routinely employed during surgery as an anticoagulant. The electrostatically driven co-assemblies resulted in a significant enhancement in the steady-state and delayed luminescence of the NPs. This provided a highly sensitive detection of the polyanion in aqueous buffer as well as in highly competitive serum and plasma media. Furthermore, and most notably, the heparin based co-assemblies were found to act as efficient donors exhibiting fluorescence resonance energy transfer (FRET) to acceptor dyes with the energy transfer efficiency reaching up to 88%.

MLH1-methylated endometrial cancer under 60 years of age as the "sentinel" cancer in female carriers of high-risk constitutional MLH1 epimutation.

OBJECTIVE: Universal screening of endometrial carcinoma (EC) for mismatch repair deficiency (MMRd) and Lynch syndrome uses presence of MLH1 methylation to omit common sporadic cases from follow-up germline testing. However, this overlooks rare cases with high-risk constitutional MLH1 methylation (epimutation), a poorly-recognized mechanism that predisposes to Lynch-type cancers with MLH1 methylation. We aimed to determine the role and frequency of constitutional MLH1 methylation among EC cases with MMRd, MLH1-methylated tumors. METHODS: We screened blood for constitutional MLH1 methylation using pyrosequencing and real-time methylation-specific PCR in patients with MMRd, MLH1-methylated EC ascertained from (i) cancer clinics (n = 4, <60 years), and (ii) two population-based cohorts; "Columbus-area" (n = 68, all ages) and "Ohio Colorectal Cancer Prevention Initiative (OCCPI)" (n = 24, <60 years). RESULTS: Constitutional MLH1 methylation was identified in three out of four patients diagnosed between 36 and 59 years from cancer clinics. Two had mono-/hemiallelic epimutation (∼50% alleles methylated). One with multiple primaries had low-level mosaicism in normal tissues and somatic "second-hits" affecting the unmethylated allele in all tumors, demonstrating causation. In the population-based cohorts, all 68 cases from the Columbus-area cohort were negative and low-level mosaic constitutional MLH1 methylation was identified in one patient aged 36 years out of 24 from the OCCPI cohort, representing one of six (∼17%) patients <50 years and one of 45 patients (∼2%) <60 years in the combined cohorts. EC was the first/dual-first cancer in three patients with underlying constitutional MLH1 methylation. CONCLUSIONS: A correct diagnosis at first presentation of cancer is important as it will significantly alter clinical management. Screening for constitutional MLH1 methylation is warranted in patients with early-onset EC or synchronous/metachronous tumors (any age) displaying MLH1 methylation.

Luminescence Sensing of Biomacromolecules Heparin and Protamine in 100% Human Serum and Plasma by Supramolecular Polymeric Assemblies.

Heparin, an anionic biomacromolecule, is routinely used as an anticoagulant during medical surgery to prevent blood clot formation and in the treatment of several heart, lung, and circulatory disorders having a higher risk of blood clotting. We herein report supramolecular polymeric nanoassemblies of cationic pyrene-tagged bis-imidazolium amphiphiles for heparin detection with high sensitivity and selectivity in aqueous buffer, plasma, and serum media. The nano-assemblies exhibited cyan-green excimeric emission in aqueous media, and their multivalent array of positive surface charges allowed them to form co-assemblies with heparin, resulting in significantly enhanced emission. This provided a convenient method for heparin detection in buffer at nanomolar concentrations, and most notably, a ratiometric fluorescence response was obtained even in highly competitive 100% human serum and 100% human plasma in a clinically relevant concentration range. Moreover, using the heparin-based luminescent co-assemblies, protamine sulfate, a clinically administered antidote to heparin, was also detected in 100% human serum and 100% human plasma at sub-micromolar concentrations.

Autoimmune haemolytic anaemia due to immunodeficiency.

Autoimmune disorders are common presenting manifestations of immunodeficiency syndromes. We present a case of a woman in her late teens, with a history of frequent sinopulmonary tract infections during her childhood, who presented to our hospital with anaemia, jaundice and fatigue. She also had significant physical growth retardation for her age and sex. With this case report, we intend to present the diagnostic and therapeutic challenges faced by the patient and our healthcare system and propose a few feasible solutions to tackle these challenges.

Integrated case-based clinical approach in understanding pathways, complexities, pitfalls and challenges in neurodegenerative disorders.

INTRODUCTION: This paper presents 5 cases of neurodegenerative disorders from our tertiary care rural hospital in south India. The purpose of this paper is to generate an emerging common theme by thematic analysis of clinical data from each of these patients. A theme emerged, we identified that there was a common clinical ground in patients with movement disorders and psychiatric symptoms. From this common theme, these patients eventually went on to develop different courses of illnesses. METHODOLOGY: Clinical analysis of a case series of 5 patients with neurodegenerative disorders attending the Medicine or Psychiatry services of our hospital. CONCLUSION: A clear & consistent association between movement disorders and psychiatric symptoms was found. Although our data is limited, we conclude that movement disorders can be early clinical markers of organic psychopathology. However, we are aware that this association can be confounded by substance abuse, stress, sleep disruption and even therapeutic interventions, and thus these factors were accounted for and yet we conclude that movement disorders can be early clinical indictors of organic psychopathology.

Nontubercular mycobacterial cough.

SummaryHabitual cough suppression leading to non-tuberculous mycobacteria infections and bronchiectasis has been reported. We present a case of a 55-year-old woman with a chronic history of cough with mild expectoration and frequent lower respiratory tract infections, remitting with antibiotic therapy and other supportive measures. She also reported habitual cough suppression for several years. She was eventually diagnosed with Mycobacterium avium complex (MAC) positive right middle lobe bronchiectasis-Lady Windermere syndrome and obstructive sleep apnoea (OSA), causing disabling symptoms limiting her daily activities. We aim to highlight two key issues-diagnosing MAC infections in a tuberculosis endemic country, and OSA and its long-term clinical implications.

Diseasomics: Actionable machine interpretable disease knowledge at the point-of-care.

Physicians establish diagnosis by assessing a patient's signs, symptoms, age, sex, laboratory test findings and the disease history. All this must be done in limited time and against the backdrop of an increasing overall workload. In the era of evidence-based medicine it is utmost important for a clinician to be abreast of the latest guidelines and treatment protocols which are changing rapidly. In resource limited settings, the updated knowledge often does not reach the point-of-care. This paper presents an artificial intelligence (AI)-based approach for integrating comprehensive disease knowledge, to support physicians and healthcare workers in arriving at accurate diagnoses at the point-of-care. We integrated different disease-related knowledge bodies to construct a comprehensive, machine interpretable diseasomics knowledge-graph that includes the Disease Ontology, disease symptoms, SNOMED CT, DisGeNET, and PharmGKB data. The resulting disease-symptom network comprises knowledge from the Symptom Ontology, electronic health records (EHR), human symptom disease network, Disease Ontology, Wikipedia, PubMed, textbooks, and symptomology knowledge sources with 84.56% accuracy. We also integrated spatial and temporal comorbidity knowledge obtained from EHR for two population data sets from Spain and Sweden respectively. The knowledge graph is stored in a graph database as a digital twin of the disease knowledge. We use node2vec (node embedding) as digital triplet for link prediction in disease-symptom networks to identify missing associations. This diseasomics knowledge graph is expected to democratize the medical knowledge and empower non-specialist health workers to make evidence based informed decisions and help achieve the goal of universal health coverage (UHC). The machine interpretable knowledge graphs presented in this paper are associations between various entities and do not imply causation. Our differential diagnostic tool focusses on signs and symptoms and does not include a complete assessment of patient's lifestyle and health history which would typically be necessary to rule out conditions and to arrive at a final diagnosis. The predicted diseases are ordered according to the specific disease burden in South Asia. The knowledge graphs and the tools presented here can be used as a guide.

Concurrent Waldenstrom Macroglobulinemia and Mutant Transthyretin Cardiac Amyloidosis.

Cardiac amyloidosis is caused by abnormal deposit of amyloid in the myocardium and can be divided into light chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis. ATTR amyloidosis can be further divided into wild-type and mutant type based on genetic mutation. Differentiation between AL, wild-type, and mutant type ATTR amyloidosis has significant prognostic and therapeutic implications.

Nonalcoholic Fatty Liver Disease Prevalence Trends Among Adolescents and Young Adults in the United States, 2007-2016.

Understanding the burden of NAFLD among adolescents and young adults has become increasingly relevant. Our aim was to estimate the prevalence of NAFLD among adolescents and young adults in the United States. Data were obtained from National Health and Nutrition Examination Survey from 2007-2016. Adolescents and young adults aged 12 to 29 years were included. NAFLD was determined by the U.S. Fatty Liver Index in the absence of secondary causes of liver disease, and the differences in prevalence trends were analyzed based on age, gender, and race. Complete data were available for 4,654 adolescents and young adults (mean age 21 years; 50.9% male; 56.8% White, 20.9% Hispanic, and 13.3% Black). The overall prevalence of NAFLD among adolescents and young adults was 18.5%, ranging from 13.2% among early and middle adolescents (12-17 years) to 18.7% among late adolescents and young adults (18-24 years), to 24.0% among older young adults (25-30 years) (trend P < 0.001). The prevalence of NAFLD was higher for boys than for girls (aged 12-17: 15.1% vs. 11.3%; aged 18-24: 21.1% vs. 16.2%; aged 25-30: 28.7% vs. 19.2%, all P < 0.030). Among all age groups, Hispanics had a higher prevalence of NAFLD than Whites and Blacks (pairwise P < 0.001). Over the study time period, the prevalence of NAFLD among early and middle adolescents and young adults did not change (trend P > 0.80). In contrast, NAFLD prevalence among late adolescents increased (trend P = 0.018). In fact, White and Hispanic late adolescents were the drivers behind this increase in the prevalence of NAFLD. Conclusion: These data indicate an increasing trend in NAFLD prevalence among 18-24-year-olds. These data have important public health and policy implications.

Poor Awareness of Liver Disease Among Adults With NAFLD in the United States.

Population-based studies that estimate awareness of nonalcoholic fatty liver disease (NAFLD) in the United States are scant. We aimed to understand public awareness of NAFLD and its temporal trends. Our study included 11,700 adults (18+ years old) from five National Health and Nutrition Examination Surveys (2007-2016). NAFLD was determined by the improved Fatty Liver Index for the multiethnic U.S. population (US-FLI) in the absence of secondary causes of liver disease. Overall prevalence of NAFLD, hepatitis C virus, and hepatitis B virus were 36.6%, 1.02% and 0.35%, respectively. From 2007-2008 to 2015-2016, awareness of liver disease among adults with NAFLD improved from 4.4% to 6.3% (trend P = 0.026) but 4 to 10 times lower than awareness about viral hepatitis. In 2015-2016, among adults with NAFLD, awareness of liver disease was lower among young adults (aged 18-29 years) compared with those aged ≥ 30 years (0% vs. 6.9%) and lower among non-Hispanic Blacks compared with other races (0.7% vs. 6.6%) (all P < 0.001). In multivariable analysis, young adults (adjusted odds ratio [aOR] = 0.29; confidence interval [CI] 0.10-0.87) and non-Hispanic Blacks (aOR = 0.43; CI 0.20-0.96) were negatively associated with awareness of liver disease among adults with NAFLD, whereas diabetes (aOR = 2.22; CI 1.37-3.58), advanced fibrosis (aOR = 2.34; CI 1.17-4.68), and a higher number of health care visits (aOR = 1.33; CI 1.15-1.50) were positively associated with awareness of liver disease. Nearly 96% of adults with NAFLD in the United States were unaware they had liver disease, especially among young adults and non-Hispanic Blacks. Findings indicate efforts are needed to improve awareness of NAFLD.

Cucurbituril Based Luminescent Materials in Aqueous Media and Solid State.

Cucurbit[n]urils, the pumpkin shaped macrocyclic host molecules possessing a hydrophobic cavity and two identical carbonyl portals, have drawn a lot of attention in recent years due to their high-affinity yet dynamic molecular recognition properties in water. The reversible and stimuli-responsive nature of their host-guest complexes imparts "smart" features leading to materials with intriguing optical, mechanical and morphological properties. In this review, we focus on the design of cucurbituril based luminescent materials in aqueous media as well in solid or film state. The design principles of fluorescent complexes, small assemblies as well as supramolecular polymers along with their stimuli-responsive properties and applications in diverse areas such as optoelectronic devices, light harvesting, anti-counterfeiting and information technology, cell imaging, etc are highlighted with selected examples from recent literature. We also discuss examples of room temperature phosphorescent materials derived from purely organic luminogens in the presence of cucurbiturils.

Selective recognition of ATP by multivalent nano-assemblies of bisimidazolium amphiphiles through "turn-on" fluorescence response.

Bisimidazolium receptors, tagged with chromophoric pyrene at one end and linked to an n-alkyl chain at the other, underwent self-assembly in aqueous media depending on the length of the alkyl segment. The amphiphilic derivatives having n-decyl or longer chains, formed nano-assemblies with cyanic-green emission resulting from the stacked pyrene chromophores in the aggregates. The presence of positive surface charges on the multivalent aggregates led to ATP binding which was accompanied by a significant increase in the excimeric emission intensity. This provided a convenient way of monitoring ATP binding in a "turn-on" mode and an efficient detection of ATP was achieved in aqueous buffer and also in buffer containing 150 mM NaCl at physiological pH value. Furthermore, the multivalent aggregates demonstrated a significant selectivity in ATP detection over ADP, AMP and pyrophosphate.

Traumatic subdural haematoma: integrating case-based clinical judgement with guidelines.

Traumatic brain injury (TBI) is one of the leading causes of mortality and morbidity with a significant loss of functional capacity and a huge socioeconomic burden. Road traffic accidents are the most common (60%) cause followed by falls and violence in India and worldwide. This case discusses the story of a 23-year-old man with severe TBI-subdural haematoma, who presented in a comatose state. The patient was a purported candidate for emergency decompressive surgery as per Brain Trauma Foundation (BTF) guidelines but was managed conservatively. This case questions the plausibility of the BTF guidelines for severe TBI, particularly in rural hospitals in India and how such cases are often managed with clinical judgement based on the review of literature. The patient recovered well with a perfect 8/8 on Glasgow Outcome Scale Extended Score.

A Remarkable Fluorescence Quenching Based Amplification in ATP Detection through Signal Transduction in Self-Assembled Multivalent Aggregates.

Signal transduction is essential for the survival of living organisms, because it allows them to respond to the changes in external environments. In artificial systems, signal transduction has been exploited for the highly sensitive detection of analytes. Herein, a remarkable signal transduction, upon ATP binding, in the multivalent fibrillar nanoaggregates of anthracene conjugated imidazolium receptors is reported. The aggregates of one particular amphiphilic receptor sensed ATP in high pm concentrations with one ATP molecule essentially quenching the emission of thousands of receptors. A cooperative merging of the multivalent binding and signal transduction led to this superquenching and translated to an outstanding enhancement of more than a millionfold in the sensitivity of ATP detection by the nanoaggregates; in comparison to the "molecular" imidazolium receptors. Furthermore, an exceptional selectivity to ATP over other nucleotides was demonstrated.

Nonalcoholic Fatty Liver Disease and Alcoholic Liver Disease are Major Drivers of Liver Mortality in the United States.

In the United States, chronic viral hepatitis B and C (CHB and CHC), nonalcoholic fatty liver disease (NAFLD), and alcohol-related liver disease (ALD) are the main causes of liver deaths attributable to hepatocellular carcinoma (HCC) and cirrhosis. Our aim was to assess the changes in the rates of mortality and years of potential life lost (YLL) for HCC and cirrhosis due to different liver diseases. We used multiple-cause mortality data (2007-2017) from the National Center for Health Statistics. Annual percentage change (APC) in age-standardized death rate per 100,000 (ASDR) and age-standardized years of life lost per 100,000 (ASYLLR) were calculated. In the United States in 2017, there were 2,797,265 deaths with 73,424 liver deaths, contributing to 1,467,742 of YLL. Of the liver deaths, HCC was noted in 12,169 (16.6%) and cirrhosis in 60,111 (82.0%). CHC was responsible for 50.4% of HCC deaths; NAFLD, 35.4%; HBV, 6.0%; ALD, 5.4%; and others, 2.8%. NAFLD was responsible for 48.9% of cirrhosis deaths; ALD, 34.7%; CHC, 12.3%; CHB, 0.9%; and others, 3.2%. Between 2007 and 2017, the increase in ASDR for HCC due to ALD and NAFLD accelerated after 2014 (APC, 11.38% and 6.55%, respectively) whereas CHC stabilized (APC, 0.63%; P = 0.272) after 2011. The increase in ASYLLR of HCC escalated after 2014 for ALD and NAFLD (APC, 12.12% and 6.15%, respectively) and leveled out for CHC after 2012 (APC, -1.05%; P = 0.056). Furthermore, the highest annual increase in ASDR and ASYLLR for cirrhosis was due to ALD (APC, 3.24% and 3.34%, respectively) followed by NAFLD (APC, 1.23% and 0.49%, respectively). Conclusion: Over the past decade, ASDR and ASYLLR due to ALD and NAFLD have been increasing in the United States. The rising burden of HCC and cirrhosis are primarily driven by NAFLD and ALD.