Sampling the skin surface chemistry for diagnosis and prognosis.

Skin and wound blotting are non-invasive techniques used to sample the skin and wound surface chemistry, whereby a nitrocellulose membrane is applied to an intact or broken cutaneous surface to detect biomarkers. However, there has been no comprehensive review of the evidence for the techniques used and data obtained to date. The primary aim of this study was to review the utilities of surface blotting for the diagnosis and prognosis of physiological, pre-disease, and pathological states. The secondary aim was to summarise the procedural steps. A systematic literature search was conducted on 9 July 2021 using Medline, Embase, and Google Scholar databases. Investigators used McMaster's Critical Review Form for Quantitative Studies to assess quality, then performed a narrative synthesis reporting according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Twenty-five studies were reviewed. Eighteen studies were of good quality, and seven were of moderate quality. These studies conducted skin and wound blotting on 176 animals and 1546 humans. Studies reported physiological and pathological states for diagnosis and prediction of conditions, including skin tears, wound healing, biofilm detection, and skin barrier function. The four steps for blotting are surface preparation, blot preparation, application and removal of blot, and analysis. This review demonstrates that blotting can determine the skin and wound surface chemistry using a versatile and reproducible technique. However, future research is needed to validate the technique and skin biomarkers identified.

A New Approach to Disease, Risk, and Boundaries Based on Emergent Probability.

The status of risk factors and disease remains a disputed question in the theory and practice of medicine and healthcare, and so does the related question of delineating disease boundaries. I present a framework based on Bernard Lonergan's account of emergent probability for differentiating (1) generically distinct levels of systematic function within organisms and between organisms and their environments and (2) the methods of functional, genetic, and statistical investigation. I then argue on this basis that it is possible to understand disease in terms of biological or higher intra-level dysfunction, risk factors-including genetic risk factors-in terms of statistical inter-level conditioning of a given stage or developmental sequence of systematic functioning, and the empirical boundaries of disease in terms of the limits of both functional categorization (from an epistemic standpoint) and upper-level integration of lower-level processes and events (from an ontological standpoint).

A Gaussian Process Model of Human Electrocorticographic Data.

We present a model-based method for inferring full-brain neural activity at millimeter-scale spatial resolutions and millisecond-scale temporal resolutions using standard human intracranial recordings. Our approach makes the simplifying assumptions that different people's brains exhibit similar correlational structure, and that activity and correlation patterns vary smoothly over space. One can then ask, for an arbitrary individual's brain: given recordings from a limited set of locations in that individual's brain, along with the observed spatial correlations learned from other people's recordings, how much can be inferred about ongoing activity at other locations throughout that individual's brain? We show that our approach generalizes across people and tasks, thereby providing a person- and task-general means of inferring high spatiotemporal resolution full-brain neural dynamics from standard low-density intracranial recordings.

Feasibility and safety of exercise stress testing using an anti-gravity treadmill with Tc-99m tetrofosmin single-photon emission computed tomography (SPECT) myocardial perfusion imaging: A pilot non-randomized controlled study.

BACKGROUND: Exercise is the AHA/ACC guideline-recommended stress modality for myocardial perfusion imaging, but many patients are unable to exercise to target heart rate on a conventional treadmill. We examined the feasibility and safety of stress imaging using an anti-gravity treadmill in patients with perceived poor exercise capacity. METHODS AND RESULTS: 49 patients were recruited for stress testing by anti-gravity treadmill (n = 29) or to a regadenoson control group (n = 20). Seventeen anti-gravity test patients (59%) reached target heart rate obviating the need for a pharmacologic stress agent. Adverse effects of the anti-gravity treadmill were limited to minor muscle aches in 5 subjects. Stress myocardial perfusion image quality judged by 3 blinded readers on a 5-point scale was comparable for the anti-gravity treadmill (4.30 ± SD 0.87) vs pharmacologic stress (4.28 ± SD 0.66). CONCLUSION: Stress testing using an anti-gravity treadmill is feasible and may help some patients safely achieve target heart rate.

Embedded wisdom or rooted problems? Aid workers' perspectives on local social and political infrastructure in post-tsunami Aceh.

This paper analyses the role of local social, cultural, and political institutions in post-disaster reconstruction projects. It contends that such institutions are important considerations within community-driven reconstruction initiatives, but are often viewed with ambivalence by external aid organisations. This paper draws upon in-depth qualitative interviews with aid workers involved in the post-tsunami reconstruction in Aceh, Indonesia, to establish: (i) what roles community institutions were suited to play in the reconstruction; (ii) what were the limitations of community institutions when engaging with external aid agencies; (iii) how did external aid agencies engage with local community institutions; and (iv) how did external aid agencies perceive community institutions.

Pharmacogenetics of antiplatelet therapy.

There has been substantial progress toward understanding and investigating the specific genetic factors that influence interindividual variations in platelet-directed therapy. There has also been substantial progress toward better understanding of the pharmacogenetics of drug metabolism and phamacodynamic response to platelet antagonists. We summarize the relationship between genetic polymorphisms, response to platelet antagonists, and clinical impact on patient treatment for the commonly used antiplatelet drugs. The challenge faced in translating genotype identification into improved clinical outcomes reflects the complexity involved in the genomic influence on drug metabolism and activation.

Transcriptomic signature, bioactivity and safety of a non-hepatotoxic analgesic generating AM404 in the midbrain PAG region.

Safe and effective pain management is a critical healthcare and societal need. The potential for acute liver injury from paracetamol (ApAP) overdose; nephrotoxicity and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use; and opioids' addiction are unresolved challenges. We developed SRP-001, a non-opioid and non-hepatotoxic small molecule that, unlike ApAP, does not produce the hepatotoxic metabolite N-acetyl-p-benzoquinone-imine (NAPQI) and preserves hepatic tight junction integrity at high doses. CD-1 mice exposed to SRP-001 showed no mortality, unlike a 70% mortality observed with increasing equimolar doses of ApAP within 72 h. SRP-001 and ApAP have comparable antinociceptive effects, including the complete Freund's adjuvant-induced inflammatory von Frey model. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception region, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways/networks, including endocannabinoid signaling, genes pertaining to mechanical nociception, and fatty acid amide hydrolase (FAAH). Both regulate the expression of key genes encoding FAAH, 2-arachidonoylglycerol (2-AG), cannabinoid receptor 1 (CNR1), CNR2, transient receptor potential vanilloid type 4 (TRPV4), and voltage-gated Ca2+ channel. Phase 1 trial (NCT05484414) (02/08/2022) demonstrates SRP-001's safety, tolerability, and favorable pharmacokinetics, including a half-life from 4.9 to 9.8 h. Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.

Detecting Rickettsia parkeri infection from eschar swab specimens.

The typical clinical presentation of several spotted fever group Rickettsia infections includes eschars. Clinical diagnosis of the condition is usually made by analysis of blood samples. We describe a more sensitive, noninvasive means of obtaining a sample for diagnosis by using an eschar swab specimen from patients infected with Rickettsia parkeri.

Free tissue reconstruction of a liquid nitrogen burn: a case report and literature review.

Due to its boiling point of -196°C, liquid nitrogen is a cryogenic substance which is commonly used in many industries for its cooling properties. However, this extreme cooling capability means it also has the potential to inflict severe full-thickness burns. Despite its widespread use in the workplace, very little has been described in the literature regarding complex reconstruction of liquid nitrogen burns. We present a case that is unique, not only in its unusual mechanism of injury, but also in that it is the first described case of free tissue reconstruction of cryogenic burns.

A retrospective, cross-sectional analysis of delirium in burn injury compared to other surgical specialities.

BACKGROUND: Delirium is an acute cerebral disorder characterised by a disturbance in cognition, attention, and awareness. Often, it's undiagnosed and associated with increased morbidity and mortality. For burn patients, the reported prevalence ranges from 16% to 39%, with a multifactorial aetiology, increasing when intensive care is required. A direct comparison of delirium between surgical specialities has not been made. AIM: 1. To audit the use of the 4AT for those who become delirious during their stay. 2. Assess the proportion of patients diagnosed with delirium during hospitalisation by surgical specialities. 3. Identification of the factors associated with delirium in surgical patients. METHODS: Investigators at a single centre conducted a two-phase study. An initial retrospective audit of delirious patients under burns, general, and orthopaedic specialities over 16months, as defined by ICD-10 coding, identified compliance screening with the 4 A's Test. This informed the design of a retrospective, observational cohort study to compare factors associated with delirium and statistical comparison between four specialities to identify delirium-associated factor, where an analysis corrects for age. RESULTS: 37% of patients with an ICD-10 code indicating delirium had a 4AT test completed. Speciality, number of operations, LOS, ICU hours, age, and discharge destination were all statistically significant independent variables. When all other variables were equal, burns had the highest predicted probability of delirium diagnosis. CONCLUSIONS: Further analysis to identify and diagnose across the specialties is required. From a patient viewpoint, their LOS, ICU hours, and operations are increased for patients coded as delirious compared to non-delirious across the specialities. On a hospital level, the mean difference in cost for a delirious compared to a non-delirious patient is AU$9317. Despite the low incidence of delirium amongst the observed specialities, burns patients were most likely to develop delirium when demographic and clinical profiles were the same, and were more likely to develop delirium at a younger age and if in ICU.

Transcriptomic signature, bioactivity and safety of a non-hepatoxic analgesic generating AM404 in the mid-brain PAG region.

The safe and effective management of pain is a critical healthcare and societal need. The potential for misuse and addiction associated with opioids, nephrotoxicity, and gastrointestinal damage from chronic non-steroidal anti-inflammatory drug (NSAID) use, as well as acute liver injury from paracetamol (ApAP) overdose, are unresolved challenges. To address them, we developed a non-opioid and non-hepatotoxic small molecule, SRP-001. Compared to ApAP, SRP-001 is not hepatotoxic as it does not produce N-acetyl-p-benzoquinone-imine (NAPQI) and maintains hepatic tight junction integrity at high doses. SRP-001 has comparable analgesia in pain models, including the complete Freund's adjuvant (CFA) inflammatory von Frey. Both induce analgesia via N-arachidonoylphenolamine (AM404) formation in the midbrain periaqueductal grey (PAG) nociception area, with SRP-001 generating higher amounts of AM404 than ApAP. Single-cell transcriptomics of PAG uncovered that SRP-001 and ApAP also share modulation of pain-related gene expression and cell signaling pathways, including the endocannabinoid, mechanical nociception, and fatty acid amide hydrolase (FAAH) pathways. Both regulate the expression of key genes encoding FAAH, 2-AG, CNR1, CNR2, TRPV4, and voltage-gated Ca2+ channel. Interim Phase 1 trial results demonstrate SRP-001's safety, tolerability, and favorable pharmacokinetics (NCT05484414). Given its non-hepatotoxicity and clinically validated analgesic mechanisms, SRP-001 offers a promising alternative to ApAP, NSAIDs, and opioids for safer pain treatment.

Hypertensive Conditions: Essential (Primary) Hypertension in Adults.

Blood pressure (BP) screening using an office-based measurement is recommended for adults 18 years and older without a history of hypertension. If abnormal, the BP measurement should be repeated twice with the average of those final two readings used to determine the BP category. Home BP monitoring and ambulatory BP monitoring are beneficial in patients for whom there is a concern for masked or white-coat hypertension. Guidelines differ regarding the BP cutoff used for the diagnosis of hypertension. Lifestyle modifications are the foundation of hypertension management with the Dietary Approaches to Stop Hypertension (DASH) diet being the most effective dietary modification. First-line pharmacotherapy should include one or more of the following: an angiotensin-converting enzyme inhibitor, an angiotensin receptor blocker, a dihydropyridine calcium channel blocker, and a thiazide or thiazidelike diuretic. Compared with standard BP control, intensive BP control (ie, systolic BP less than 120 mm Hg) leads to a decrease in atherosclerotic cardiovascular disease and all-cause mortality in patients with elevated risk but increases adverse effects, including hypotension, electrolyte abnormalities, acute kidney injury, and syncope.

Hypertensive Conditions: Secondary Causes of Hypertension in Adults.

Secondary hypertension (HTN) refers to high blood pressure (BP) caused by an identifiable and potentially correctable condition or disease. Common causes of secondary HTN include renovascular disease, renal parenchymal disease, primary hyperaldosteronism, drug and substance use, and obstructive sleep apnea; less common etiologies include pheochromocytoma/paraganglioma, Cushing syndrome, thyroid and parathyroid conditions, congenital adrenal hyperplasia, and aortic coarctation. An identifiable secondary cause of HTN is present in approximately 10% of adult patients with HTN. Early recognition of suggestive clinical findings and laboratory results enables the timely diagnosis of specific secondary causes of HTN. Correct diagnosis of a causative underlying condition can lead to more effective, even curative management and subsequent cardiovascular risk reduction. Management involves treating the underlying condition. Some patients may benefit from referral to a specialist with specific expertise in treating the causative condition.

Hypertensive Conditions: Hypertension in Children and Adolescents.

Hypertension (HTN) in children and adolescents is a spectrum of disease, ranging from elevated blood pressure (BP) to stage 1 and 2 HTN. The prevalence of elevated BP and HTN in this age group has increased significantly over the past 20 years, particularly in girls. Screening for HTN in asymptomatic children and adolescents is controversial. Primary HTN is now the predominant cause of HTN among the pediatric population in the United States, especially among adolescents. Secondary pediatric HTN is high BP due to an underlying medical condition and is more common among children 6 years and younger. Ambulatory BP monitoring should be considered in pediatric patients with repeatedly elevated office BP measurements. All children with BP greater than the 90th percentile should be encouraged to adopt lifestyle changes, but those with persistent or severe elevations in BP may benefit from pharmacotherapy.

Hypertensive Conditions: Hypertensive Disorders in Pregnancy.

Hypertensive disorders in pregnancy (HDP) represent a spectrum of disease that affect women through pregnancy and the immediate postpartum period. These conditions are associated with significant morbidity and mortality during and after pregnancy and have been linked to cardiovascular disease later in life. The HDP spectrum includes gestational hypertension (HTN), preeclampsia, eclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, chronic HTN, and chronic HTN with superimposed preeclampsia. Low-dose aspirin is recommended as a preventive drug after 12 weeks' gestation in women who are at high risk of preeclampsia. In HDP, close blood pressure (BP) monitoring, laboratory evaluation, and fetal assessment are warranted. Labetalol and nifedipine extended release are first-line oral antihypertensives for outpatient BP management of chronic HTN; labetalol, hydralazine, and nifedipine immediate release are used for hospitalized patients. HDP may develop or progress in the postpartum period; continued vigilance is important in the puerperium.

Distributed Subnetworks of Depression Defined by Direct Intracranial Neurophysiology.

Major depressive disorder is a common and disabling disorder with high rates of treatment resistance. Evidence suggests it is characterized by distributed network dysfunction that may be variable across patients, challenging the identification of quantitative biological substrates. We carried out this study to determine whether application of a novel computational approach to a large sample of high spatiotemporal resolution direct neural recordings in humans could unlock the functional organization and coordinated activity patterns of depression networks. This group level analysis of depression networks from heterogenous intracranial recordings was possible due to application of a correlational model-based method for inferring whole-brain neural activity. We then applied a network framework to discover brain dynamics across this model that could classify depression. We found a highly distributed pattern of neural activity and connectivity across cortical and subcortical structures that was present in the majority of depressed subjects. Furthermore, we found that this depression signature consisted of two subnetworks across individuals. The first was characterized by left temporal lobe hypoconnectivity and pathological beta activity. The second was characterized by a hypoactive, but hyperconnected left frontal cortex. These findings have applications toward personalization of therapy.

Closed-loop neuromodulation in an individual with treatment-resistant depression.

Deep brain stimulation is a promising treatment for neuropsychiatric conditions such as major depression. It could be optimized by identifying neural biomarkers that trigger therapy selectively when symptom severity is elevated. We developed an approach that first used multi-day intracranial electrophysiology and focal electrical stimulation to identify a personalized symptom-specific biomarker and a treatment location where stimulation improved symptoms. We then implanted a chronic deep brain sensing and stimulation device and implemented a biomarker-driven closed-loop therapy in an individual with depression. Closed-loop therapy resulted in a rapid and sustained improvement in depression. Future work is required to determine if the results and approach of this n-of-1 study generalize to a broader population.

Grounding medical ethics in philosophy of medicine: problematic and potential.

After considering two of Pellegrino's papers that address the relation between philosophy of medicine and medical ethics, I identify several overarching problems in his account that revolve around his self-described essentialism and the lack of a systematic attempt to relate clinical medicine to biomedicine and public health. I address these from the critical realist position of Bernard Lonergan, who grounds both metaphysics and ethics on the normative structure of human inquiry and seeks to understand historical development, such as we are witnessing in health science and health care, in terms of the dynamic structure of the human good. I conclude that Lonergan's generalized empirical method and hierarchical account of world order provide a potentially dynamic framework on which to build a more comprehensive philosophy of medicine than one whose foundations rest primarily on a phenomenology of the clinical encounter and the telos of medicine.

A concise guide to clinical reasoning.

What constitutes clinical reasoning is a disputed subject regarding the processes underlying accurate diagnosis, the importance of patient-specific versus population-based data, and the relation between virtue and expertise in clinical practice. In this paper, I present a model of clinical reasoning that identifies and integrates the processes of diagnosis, prognosis, and therapeutic decision making. The model is based on the generalized empirical method of Bernard Lonergan, which approaches inquiry with equal attention to the subject who investigates and the object under investigation. After identifying the structured operations of knowing and doing and relating these to a self-correcting cycle of learning, I correlate levels of inquiry regarding what-is-going-on and what-to-do to the practical and theoretical elements of clinical reasoning. I conclude that this model provides a methodical way to study questions regarding the operations of clinical reasoning as well as what constitute significant clinical data, clinical expertise, and virtuous health care practice.

Probenecid Improves Cardiac Function in Patients With Heart Failure With Reduced Ejection Fraction In Vivo and Cardiomyocyte Calcium Sensitivity In Vitro.

BACKGROUND: Transient receptor potential vanilloid 2 is a calcium channel activated by probenecid. Probenecid is a Food and Drug Administration-approved uricosuric drug that has recently been shown to induce positive lusitropic and inotropic effects in animal models through cardiomyocyte transient receptor potential vanilloid 2 activation. The aim of this study was to test the hypothesis that oral probenecid can improve cardiac function and symptomatology in patients with heart failure with reduced ejection fraction and to further elucidate its calcium-dependent effects on myocyte contractility. METHODS AND RESULTS: The clinical trial recruited stable outpatients with heart failure with reduced ejection fraction randomized in a single-center, double-blind, crossover design. Clinical data were collected including a dyspnea assessment, physical examination, ECG, echocardiogram to assess systolic and diastolic function, a 6-minute walk test, and laboratory studies. In vitro force generation studies were performed on cardiomyocytes isolated from murine tissue exposed to probenecid or control treatments. The clinical trial recruited 20 subjects (mean age 57 years, mean baseline fractional shortening of 13.6±1.0%). Probenecid therapy increased fractional shortening by 2.1±1.0% compared with placebo -1.7±1.0% (P=0.007). Additionally, probenecid improved diastolic function compared with placebo by decreasing the E/E' by -2.95±1.21 versus 1.32±1.21 in comparison to placebo (P=0.03). In vitro probenecid increased myofilament force generation (92.36 versus 80.82 mN/mm2, P<0.05) and calcium sensitivity (pCa 5.67 versus 5.60, P<0.01) compared with control. CONCLUSIONS: Probenecid improves cardiac function with minimal effects on symptomatology and no significant adverse effects after 1 week in patients with heart failure with reduced ejection fraction and increases force development and calcium sensitivity at the cardiomyocyte level. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01814319.