Analysis of Protein Biomarkers From Hospitalized COVID-19 Patients Reveals Severity-Specific Signatures and Two Distinct Latent Profiles With Differential Responses to Corticosteroids.

OBJECTIVES: To identify and validate novel COVID-19 subphenotypes with potential heterogenous treatment effects (HTEs) using electronic health record (EHR) data and 33 unique biomarkers. DESIGN: Retrospective cohort study of adults presenting for acute care, with analysis of biomarkers from residual blood collected during routine clinical care. Latent profile analysis (LPA) of biomarker and EHR data identified subphenotypes of COVID-19 inpatients, which were validated using a separate cohort of patients. HTE for glucocorticoid use among subphenotypes was evaluated using both an adjusted logistic regression model and propensity matching analysis for in-hospital mortality. SETTING: Emergency departments from four medical centers. PATIENTS: Patients diagnosed with COVID-19 based on International Classification of Diseases , 10th Revision codes and laboratory test results. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Biomarker levels generally paralleled illness severity, with higher levels among more severely ill patients. LPA of 522 COVID-19 inpatients from three sites identified two profiles: profile 1 ( n = 332), with higher levels of albumin and bicarbonate, and profile 2 ( n = 190), with higher inflammatory markers. Profile 2 patients had higher median length of stay (7.4 vs 4.1 d; p < 0.001) and in-hospital mortality compared with profile 1 patients (25.8% vs 4.8%; p < 0.001). These were validated in a separate, single-site cohort ( n = 192), which demonstrated similar outcome differences. HTE was observed ( p = 0.03), with glucocorticoid treatment associated with increased mortality for profile 1 patients (odds ratio = 4.54). CONCLUSIONS: In this multicenter study combining EHR data with research biomarker analysis of patients with COVID-19, we identified novel profiles with divergent clinical outcomes and differential treatment responses.

State of cancer care in India and opportunities for innovation.

Cancer is one of the leading causes of morbidity and mortality in India. Despite recent medical and technological advances, the cancer burden in India remains high and continues to rise. Moreover, substantial regional disparities in cancer incidence and access to essential medical resources exist throughout the country. While innovative and effective cancer therapies hold promise for improving patient outcomes, several barriers hinder their development and utilization in India. Here we provide an overview of these barriers, including challenges related to patient awareness, inadequate infrastructure, scarcity of trained oncology professionals, and the high cost of cancer care. Furthermore, we discuss the limited availability of cancer clinical trials in the country, along with an examination of potential avenues to enhance cancer care in India. By confronting these hurdles head-on and implementing innovative, pragmatic solutions, we take an indispensable step toward a future where every cancer patient in the country can access quality care.

Cancer is a major cause of illness and death in India. Despite advances in medicine and technology, the number of people with cancer remains high and continues to increase. There are big differences in access to necessary medical resources across different regions of the country. This article focuses on the barriers that hinder the development and use of effective cancer treatments in India. We discuss challenges related to patient awareness, inadequate medical facilities, a shortage of trained cancer specialists and the high cost of cancer treatment. Additionally, we explore the limited availability of cancer clinical trials in India and potential ways to improve cancer care in the country. By finding innovative and practical solutions to these challenges, we can take a crucial step toward a future where all cancer patients in India have access to high-quality care.

Law and Stock Market Development in the UK over Time: An Uneasy Match.

Britain has a reputation for having a stock market-oriented corporate economy and there is an extensive literature maintaining that laws affording substantial protection to outside investors are needed for a thriving stock market. Historically, however, UK equity markets have not always flourished and, when they have, law's contribution has been open to question. This article considers the uneasy match between law and Britain's stock market development from when shares first began to trade publicly through to the present day, offering in so doing insights into the relationship between law and equity markets and current reforms intended to revive a flagging UK stock exchange.

Clinical spectrum of cutaneous melanoma morphology.

BACKGROUND: Melanoma can mimic other cutaneous lesions, but the full spectrum and prevalence of these morphologic variants remain largely unknown. OBJECTIVE: To classify nonacral cutaneous melanomas into distinct morphologic clusters and characterize clusters' clinicopathologic features. METHODS: All pathologic melanoma diagnoses (occurring during 2011-2016) were reviewed for routine prebiopsy digital photographs (n = 400). Six dermatologists independently assigned lesions into 1 of 14 diagnostic classes on the basis of morphology. Image consensus clusters were generated by K-means; clinicopathologic features were compared with analysis of variance and χ2. RESULTS: Five morphologic clusters were identified: typical (n = 136), nevus-like (n = 81), amelanotic/nonmelanoma skin cancer (NMSC)-like (n = 70), seborrheic keratosis (SK)-like (n = 68), and lentigo/lentigo maligna (LM)-like (n = 45) melanomas. Nevus-like melanomas were found in younger patients. Nevus-like and lentigo/LM-like melanomas tended to be thinner and more likely identified on routine dermatologic examinations. NMSC-like melanomas were tender, thicker, more mitotically active, and associated with prior NMSC. Typical and SK-like melanomas had similar clinicopathologic features. LIMITATIONS: Cluster subdivision yielded diminished sample sizes. Visual assignment was performed without clinical context. CONCLUSION: When primary cutaneous melanomas were assigned into diagnostic groups and subjected to novel consensus clustering, recurrent morphologic patterns emerged. The spectrum of these morphologies was unexpectedly diverse, which might have implications for visual training and possibly clinical diagnosis.

Cutaneous Presentation of Mesothelioma With a Sarcomatoid Transformation.

Malignant pleural mesothelioma is a rare neoplasm of mesodermal origin. Cutaneous involvement of malignant pleural mesothelioma is a very rare entity, with only 11 cases reported in the literature. Here, we describe the case of a 75-year-old man with stage IV epithelioid pleural mesothelioma, presenting with a cutaneous eruption 5 months after initial diagnosis, which revealed sarcomatoid features on skin biopsy. Histological analysis of malignancy progression through immunohistochemical staining of the pleural, lymph node, and skin tissue revealed gradual loss of calretinin and gain of desmin, supporting a transformation from epithelioid to sarcomatoid tissue. To our knowledge, this is the first reported case of an epithelioid to sarcomatoid transformation of malignant pleural mesothelioma manifesting in a cutaneous presentation.

Somatic driver mutations in melanoma.

Melanoma has one of the highest somatic mutational burdens among solid malignancies. Although the rapid progress in genomic research has contributed immensely to our understanding of the pathogenesis of melanoma, the clinical significance of the vast array of genomic alterations discovered by next-generation sequencing is far from being fully characterized. Most mutations prevalent in melanoma are simply neutral "passengers," which accompany functionally significant "drivers" under transforming conditions. The delineation of driver mutations from passenger mutations is critical to the development of targeted therapies. Novel advances in genomic data analysis have aided in distinguishing true driver mutations involved in tumor progression. Here, the authors review the current literature on important somatic driver mutations in melanoma, along with the implications for treatment. Cancer 2017;123:2104-17. © 2017 American Cancer Society.

Electrical Chips for Biological Point-of-Care Detection.

As the future of health care diagnostics moves toward more portable and personalized techniques, there is immense potential to harness the power of electrical signals for biological sensing and diagnostic applications at the point of care. Electrical biochips can be used to both manipulate and sense biological entities, as they can have several inherent advantages, including on-chip sample preparation, label-free detection, reduced cost and complexity, decreased sample volumes, increased portability, and large-scale multiplexing. The advantages of fully integrated electrical biochip platforms are particularly attractive for point-of-care systems. This review summarizes these electrical lab-on-a-chip technologies and highlights opportunities to accelerate the transition from academic publications to commercial success.

Ultralocalized thermal reactions in subnanoliter droplets-in-air.

Miniaturized laboratory-on-chip systems promise rapid, sensitive, and multiplexed detection of biological samples for medical diagnostics, drug discovery, and high-throughput screening. Within miniaturized laboratory-on-chips, static and dynamic droplets of fluids in different immiscible media have been used as individual vessels to perform biochemical reactions and confine the products. Approaches to perform localized heating of these individual subnanoliter droplets can allow for new applications that require parallel, time-, and space-multiplex reactions on a single integrated circuit. Our method positions droplets on an array of individual silicon microwave heaters on chip to precisely control the temperature of droplets-in-air, allowing us to perform biochemical reactions, including DNA melting and detection of single base mismatches. We also demonstrate that ssDNA probe molecules can be placed on heaters in solution, dried, and then rehydrated by ssDNA target molecules in droplets for hybridization and detection. This platform enables many applications in droplets including hybridization of low copy number DNA molecules, lysing of single cells, interrogation of ligand-receptor interactions, and rapid temperature cycling for amplification of DNA molecules.

On-chip metal/polypyrrole quasi-reference electrodes for robust ISFET operation.

To operate an ion-sensitive field-effect transistor (ISFETs) it is necessary to set the electrolyte potential using a reference electrode. Conventional reference electrodes are bulky, fragile, and too big for applications where the electrolyte volume is small. Several researchers have proposed tackling this issue using a solid-state planar micro-reference electrode or a reference field-effect transistor. However, these approaches are limited by poor robustness, high cost, or complex integration with other microfabrication processes. Here we report a simple method to create robust on-chip quasi-reference electrodes by electrodepositing polypyrrole on micro-patterned metal leads. The electrodes were fabricated through the polymerization of pyrrole on patterned metals with a cyclic voltammetry process. Open circuit potential measurements were performed to characterize the polypyrrole electrode performance, demonstrating good stability (±1 mV), low drift (∼1 mV h(-1)), and reduced pH response (5 mV per pH). In addition, the polypyrrole deposition was repeated in microelectrodes made of different metals to test compatibility with standard complementary metal-oxide-semiconductor (CMOS) processes. Our results suggest that nickel, a metal commonly used in semiconductor foundries for silicide formation, is a good candidate to form the polypyrrole quasi-reference electrodes. Finally, the polypyrrole microelectrodes were used to operate foundry fabricated ISFETs. These experiments demonstrated that transistors biased with polypyrrole electrodes have pH sensitivity and resolution comparable to ones that are biased with standard reference electrodes. Therefore, the simple fabrication, high compatibility, and robust electrical performance make polypyrrole an ideal choice for the fabrication of outstanding microreference electrodes that enable robust and sensitive operation of multiple ISFET sensors on a chip.

Molecular profiling is not the future: it is now!

Bobby Reddy speaks to Gemma Westcott, Commissioning Editor: Dr Reddy graduated from the UCLA School of Medicine in 1996. Shortly after, he obtained an internship and did his residency in Internal Medicine at Harbor UCLA Medical Center. He then went on to do his fellowship in Hematology and Oncology at City of Hope. Since then, he has been working in private practice (full and part time) for the past 11 years and has had an academic appointment as teaching faculty at Harbor UCLA. Prior to his current role, Dr Reddy worked as a senior medical director as Caris Life Sciences.

Resident Rounds Part III: Case Report: Fatal Cryptococcal Panniculitis in a Lung Transplant Recipient.

Cryptococcal panniculitis is a rare entity previously reported in only 13 solid organ transplant (SOT) recipients. Cutaneous cryptococcosis in SOT recipients warrants extensive systemic workup and treatment as if central nervous system (CNS) disease is present. It should be included in the differential diagnosis of panniculitis in the immunocompromised host, as early diagnosis and treatment are critical. We report a fatal case of cryptococcal panniculitis in a 44-year-old lung transplant recipient.

Electrical detection of nucleic acid amplification using an on-chip quasi-reference electrode and a PVC REFET.

Electrical detection of nucleic acid amplification through pH changes associated with nucleotide addition enables miniaturization, greater portability of testing apparatus, and reduced costs. However, current ion-sensitive field effect transistor methods for sensing nucleic acid amplification rely on establishing the fluid gate potential with a bulky, difficult to microfabricate reference electrode that limits the potential for massively parallel reaction detection. Here we demonstrate a novel method of utilizing a microfabricated solid-state quasi-reference electrode (QRE) paired with a pH-insensitive reference field effect transistor (REFET) for detection of real-time pH changes. The end result is a 0.18 µm, silicon-on-insulator, foundry-fabricated sensor that utilizes a platinum QRE to establish a pH-sensitive fluid gate potential and a PVC membrane REFET to enable pH detection of loop mediated isothermal amplification (LAMP). This technique is highly amendable to commercial scale-up, reduces the packaging and fabrication requirements for ISFET pH detection, and enables massively parallel droplet interrogation for applications, such as monitoring reaction progression in digital PCR.

Enhanced biosensing resolution with foundry fabricated individually addressable dual-gated ISFETs.

The adaptation of semiconductor technologies for biological applications may lead to a new era of inexpensive, sensitive, and portable diagnostics. At the core of these developing technologies is the ion-sensitive field-effect transistor (ISFET), a biochemical to electrical transducer with seamless integration to electronic systems. We present a novel structure for a true dual-gated ISFET that is fabricated with a silicon-on-insulator (SOI) complementary metal-oxide-semiconductor process by Taiwan Semiconductor Manufacturing Company (TSMC). In contrast to conventional SOI ISFETs, each transistor has an individually addressable back-gate and a gate oxide that is directly exposed to the solution. The elimination of the commonly used floating gate architecture reduces the chance of electrostatic discharge and increases the potential achievable transistor density. We show that when operated in a "dual-gate" mode, the transistor response can exhibit sensitivities to pH changes beyond the Nernst limit. This enhancement in sensitivity was shown to increase the sensor's signal-to-noise ratio, allowing the device to resolve smaller pH changes. An improved resolution can be used to enhance small signals and increase the sensor accuracy when monitoring small pH dynamics in biological reactions. As a proof of concept, we demonstrate that the amplified sensitivity and improved resolution result in a shorter detection time and a larger output signal of a loop-mediated isothermal DNA amplification reaction (LAMP) targeting a pathogenic bacteria gene, showing benefits of the new structure for biosensing applications.

Landscape of cancer clinical trials in India - a comprehensive analysis of the Clinical Trial Registry-India.

Background: Cancer is one of the leading causes of morbidity and mortality in India. Clinical trials are critical for driving innovation in cancer therapy, diagnosis, and prevention. This study aims to depict the evolving landscape of cancer clinical trials in India by analysing the clinical trials registered in Clinical Trial Registry-India (CTRI). Methods: We identified cancer trials registered in CTRI (between 2007 and 2021) using search terms adapted from the cancer types defined by the National Cancer Institute (USA). We then collated and analysed the publicly available information from CTRI (cancer subtypes, type of trial, treatment intent, type of intervention, sponsor type, recruitment countries) and used descriptive statistics to illustrate the overall as well as year-to-year trend. Findings: In total, we identified 1988 cancer trials, the majority of which focused on treating cancer (63%) and rest of the trials aimed at optimising the operational aspects of surgery (19%), mitigating treatment-related toxicity (10.6%), or treating cancer-related symptoms (7.8%). Focusing on trials with the intent of treating cancer, we found that most were investigating solid tumours as opposed to haematological malignancies with the most prominent cancer subtypes being breast cancer (17%), head and neck cancer (9.8%), lung cancer (9.6%), and cervical cancer (6.6%). The number of trials conducted in a given cancer subtype from our analysis overall correlated to the incidence, mortality, and 5-year prevalence of the respective cancer subtype in India; however, head and neck cancer and cervical cancer were underrepresented in trials as compared with the disease burden. The most common type of intervention was investigational drugs. The most common sponsor types were global pharmaceutical industry (26%) and research institution and hospital (26%). Despite a relatively high cancer burden, the availability of cancer trials in the Northeastern states of India was limited. Interpretation: There is a pressing need for clinical cancer research in India to be better aligned with the nation's healthcare needs and disease burden, focusing on prevalent and deadly cancers while ensuring the availability of clinical trials across geographic regions and underserved populations. Funding: Pi Health USA, a fully owned subsidiary of BeiGene Ltd.

Effect of biointerfacing linker chemistries on the sensitivity of silicon nanowires for protein detection.

Point-of-care diagnostics show promise in removing reliance on centralized lab testing facilities and may help increase both the survival rate for infectious diseases as well as monitoring of chronic illnesses. CMOS compatible diagnostic platforms are currently being considered as possible solutions as they can be easily miniaturized and can be cost-effective. Top-down fabricated silicon nanowires are a CMOS-compatible technology which have demonstrated high sensitivities in detecting biological analytes, such as proteins, DNA, and RNA. However, the reported response of nanowires to these analytes has varied widely since several different functionalization protocols have been attempted with little characterization and comparison. Here we report protocols for fabrication and functionalization of silicon nanowires which yield highly stable nanowires in aqueous solutions and limits of detection to ∼1 pg/mL of the model protein used in the study. A thorough characterization was done into optimizing the release of the silicon nanowires using combined dry and wet etch techniques, which yielded nanowires that could be directly compared to increase output statistics. Moreover, a range of different linker chemistries were tried for reacting the primary antibody, and its response to target and nonspecific antigens, with polyethylene glycol based linker BS(PEG)5 providing the best response. Consequently, this chemistry was used to characterize different oxide thicknesses and their responses to the mouse IgG antigen, which with the smallest oxide thickness yielded 0.1-1 pg/mL limits of detection and a dynamic range over 3 orders of magnitude.

On-chip parallel detection of foodborne pathogens using loop-mediated isothermal amplification.

According to estimates issued by the Center for Disease Control and Prevention, one out of six Americans will get sick during this year due to consumption of contaminated products and there will be 50,000 related hospitalizations. To control and treat the responsible foodborne diseases, rapid and accurate detection of pathogens is extremely important. A portable device capable of performing nucleic acid amplification will enable the effective detection of infectious agents in multiple settings, leading to better enforcement of food safety regulations. This work demonstrates the multiplexed detection of food pathogens through loop-mediated isothermal amplification on a silicon chip. Silane passivation is used to prevent the adsorption of the polymerase on silicon oxide, which can severely inhibit nucleic acid amplification. We demonstrate the multiplexed screening of virulence genes of Listeria monocytogenes, Escherichia coli, and Salmonella by dehydrating the corresponding primers in oxidized silicon wells. Droplets of 30 nL with reagents for nucleic acid amplification and lysate of suspected pathogens are arrayed on micro-machined wells with an automated microinjection system. We show that dehydrated primers re-suspend when other reagents are microinjected, and the resulting mix can be used to specifically amplify the targeted gene. Results of characterization experiments demonstrate sensitivity down to a few templates per reaction, specificity that enables multiplexed screening, and robustness that allows amplification without DNA extraction.

DRESS syndrome: Part I. Clinical perspectives.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, also referred to as drug-induced hypersensitivity syndrome, is a distinct, potentially life-threatening adverse reaction. It is seen in children and adults most often as a morbilliform cutaneous eruption with fever, lymphadenopathy, hematologic abnormalities, and multiorgan manifestations. Historically, it was most frequently linked with phenytoin and known as phenytoin hypersensitivity syndrome. However, because many other medications were found to produce the same reaction, another name was in order. Anticonvulsants and sulfonamides are the most common offending agents. Its etiology has been linked with lymphocyte activation, drug metabolic enzyme defects, eosinophilia, and human herpesvirus-6 reactivation. DRESS has a later onset and longer duration than other drug reactions, with a latent period of 2 to 6 weeks. It may have significant multisystem involvement, including hematologic, hepatic, renal, pulmonary, cardiac, neurologic, gastrointestinal, and endocrine abnormalities. This syndrome has a 10% mortality rate, most commonly from fulminant hepatitis with hepatic necrosis.

DRESS syndrome: Part II. Management and therapeutics.

The appropriate management of the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is paramount because it is associated with significant morbidity and mortality. This syndrome shares clinical features with other dermatologic conditions, including other severe cutaneous drug reactions, requiring the clinician to carefully examine the proposed criteria to make the appropriate diagnosis. Once the diagnosis of DRESS syndrome has been established, the next step in management is immediate cessation of the causative medication(s). In cases in which the culprit drug is not obvious, clinicians must use their clinical judgment to select which medication to discontinue. They may also utilize patch or lymphocyte transformation tests to aid in identification when appropriate. Topical corticosteroids can be used for symptomatic relief, but systemic steroid therapy is generally required. Other immunosuppressants have also been employed in treatment and show promise in future therapy. Patients with DRESS syndrome should be managed in an intensive care or burn unit for appropriate care and infection control. In addition, appropriate specialists should be consulted based on the affected organ systems. Most patients recover completely after drug withdrawal and appropriate therapy. However, some patients with DRESS syndrome suffer from chronic complications and approximately 10% die, primarily from visceral organ compromise. Controlled clinical trials investigating the most appropriate therapies and their risks, particularly intravenous corticosteroids, are lacking, and would be invaluable in determining the optimal future treatment regimen for DRESS syndrome.

Bioactive oligopeptides in dermatology: Part II.

Peptides are central to the regulation and modulation of the chemical reactions and biological responses that occur in nature. Many physiological processes are affected by the interactions of these peptides, including cell proliferation and migration, inflammation, melanogenesis, angiogenesis and innate immunity. Thus, biologically active peptides offer a great potential medically and therapeutically. Moreover, the ability to generate synthetic peptides with attention to specifically modulating their pharmacokinetics and properties for increased potency, delivery and stability has spurred much interest in this rapidly growing field of research. In this review, we focus on the therapeutic uses of bioactive peptides as antimicrobials and effectors of neurotransmitter release. We also highlight the advantages and challenges associated with this new technology and discuss methods for improving oligopeptide transdermal delivery.