What diagnostic tests are available for respiratory infections or pulmonary exacerbations in cystic fibrosis: A scoping literature review.

A scoping review methodological framework formed the basis of this review. A search of two electronic databases captured relevant literature published from 2013. 1184 articles were screened, 200 of which met inclusion criteria. Included studies were categorised as tests for either respiratory infections OR pulmonary exacerbations. Data were extracted to ascertain test type, sample type, and indication of use for each test type. For infection, culture is the most common testing method, particularly for bacterial infections, whereas PCR is utilised more for the diagnosis of viral infections. Spirometry tests, indicating lung function, facilitate respiratory infection diagnoses. There is no clear definition of what an exacerbation is in persons with CF. A clinical checklist with risk criteria can determine if a patient is experiencing an exacerbation event, however the diagnosis is clinician-led and will vary between individuals. Fuchs criteria are one of the most frequently used tests to assess signs and symptoms of exacerbation in persons with CF. This scoping review highlights the development of home monitoring tests to facilitate earlier and easier diagnoses, and the identification of novel biomarkers for indication of infections/exacerbations as areas of current research and development. Research is particularly prevalent regarding exhaled breath condensate and volatile organic compounds as an alternative sampling/biomarker respectively for infection diagnosis. Whilst there are a wide range of tests available for diagnosing respiratory infections and/or exacerbations, these are typically used clinically in combination to ensure a rapid, accurate diagnosis which will ultimately benefit both the patient and clinician.

Assessment of Safety of a Fully Implanted Endovascular Brain-Computer Interface for Severe Paralysis in 4 Patients: The Stentrode With Thought-Controlled Digital Switch (SWITCH) Study.

Importance: Brain-computer interface (BCI) implants have previously required craniotomy to deliver penetrating or surface electrodes to the brain. Whether a minimally invasive endovascular technique to deliver recording electrodes through the jugular vein to superior sagittal sinus is safe and feasible is unknown. Objective: To assess the safety of an endovascular BCI and feasibility of using the system to control a computer by thought. Design, Setting, and Participants: The Stentrode With Thought-Controlled Digital Switch (SWITCH) study, a single-center, prospective, first in-human study, evaluated 5 patients with severe bilateral upper-limb paralysis, with a follow-up of 12 months. From a referred sample, 4 patients with amyotrophic lateral sclerosis and 1 with primary lateral sclerosis met inclusion criteria and were enrolled in the study. Surgical procedures and follow-up visits were performed at the Royal Melbourne Hospital, Parkville, Australia. Training sessions were performed at patients' homes and at a university clinic. The study start date was May 27, 2019, and final follow-up was completed January 9, 2022. Interventions: Recording devices were delivered via catheter and connected to subcutaneous electronic units. Devices communicated wirelessly to an external device for personal computer control. Main Outcomes and Measures: The primary safety end point was device-related serious adverse events resulting in death or permanent increased disability. Secondary end points were blood vessel occlusion and device migration. Exploratory end points were signal fidelity and stability over 12 months, number of distinct commands created by neuronal activity, and use of system for digital device control. Results: Of 4 patients included in analyses, all were male, and the mean (SD) age was 61 (17) years. Patients with preserved motor cortex activity and suitable venous anatomy were implanted. Each completed 12-month follow-up with no serious adverse events and no vessel occlusion or device migration. Mean (SD) signal bandwidth was 233 (16) Hz and was stable throughout study in all 4 patients (SD range across all sessions, 7-32 Hz). At least 5 attempted movement types were decoded offline, and each patient successfully controlled a computer with the BCI. Conclusions and Relevance: Endovascular access to the sensorimotor cortex is an alternative to placing BCI electrodes in or on the dura by open-brain surgery. These final safety and feasibility data from the first in-human SWITCH study indicate that it is possible to record neural signals from a blood vessel. The favorable safety profile could promote wider and more rapid translation of BCI to people with paralysis. Trial Registration: ClinicalTrials.gov Identifier: NCT03834857.

An introduction to spatial transcriptomics for biomedical research.

Single-cell transcriptomics (scRNA-seq) has become essential for biomedical research over the past decade, particularly in developmental biology, cancer, immunology, and neuroscience. Most commercially available scRNA-seq protocols require cells to be recovered intact and viable from tissue. This has precluded many cell types from study and largely destroys the spatial context that could otherwise inform analyses of cell identity and function. An increasing number of commercially available platforms now facilitate spatially resolved, high-dimensional assessment of gene transcription, known as 'spatial transcriptomics'. Here, we introduce different classes of method, which either record the locations of hybridized mRNA molecules in tissue, image the positions of cells themselves prior to assessment, or employ spatial arrays of mRNA probes of pre-determined location. We review sizes of tissue area that can be assessed, their spatial resolution, and the number and types of genes that can be profiled. We discuss if tissue preservation influences choice of platform, and provide guidance on whether specific platforms may be better suited to discovery screens or hypothesis testing. Finally, we introduce bioinformatic methods for analysing spatial transcriptomic data, including pre-processing, integration with existing scRNA-seq data, and inference of cell-cell interactions. Spatial -omics methods are already improving our understanding of human tissues in research, diagnostic, and therapeutic settings. To build upon these recent advancements, we provide entry-level guidance for those seeking to employ spatial transcriptomics in their own biomedical research.

Phase I Trial Characterizing the Pharmacokinetic Profile of N-803, a Chimeric IL-15 Superagonist, in Healthy Volunteers.

The oncotherapeutic promise of IL-15, a potent immunostimulant, is limited by a short serum t 1/2 The fusion protein N-803 is a chimeric IL-15 superagonist that has a >20-fold longer in vivo t 1/2 versus IL-15. This phase 1 study characterized the pharmacokinetic (PK) profile and safety of N-803 after s.c. administration to healthy human volunteers. Volunteers received two doses of N-803, and after each dose, PK and safety were assessed for 9 d. The primary endpoint was the N-803 PK profile, the secondary endpoint was safety, and immune cell levels and immunogenicity were measures of interest. Serum N-803 concentrations peaked 4 h after administration and declined with a t 1/2 of ∼20 h. N-803 did not cause treatment-emergent serious adverse events (AEs) or grade ≥3 AEs. Injection site reactions, chills, and pyrexia were the most common AEs. Administration of N-803 was well tolerated and accompanied by proliferation of NK cells and CD8+ T cells and sustained increases in the number of NK cells. Our results suggest that N-803 administration can potentiate antitumor immunity.

Motor neuroprosthesis implanted with neurointerventional surgery improves capacity for activities of daily living tasks in severe paralysis: first in-human experience.

BACKGROUND: Implantable brain-computer interfaces (BCIs), functioning as motor neuroprostheses, have the potential to restore voluntary motor impulses to control digital devices and improve functional independence in patients with severe paralysis due to brain, spinal cord, peripheral nerve or muscle dysfunction. However, reports to date have had limited clinical translation. METHODS: Two participants with amyotrophic lateral sclerosis (ALS) underwent implant in a single-arm, open-label, prospective, early feasibility study. Using a minimally invasive neurointervention procedure, a novel endovascular Stentrode BCI was implanted in the superior sagittal sinus adjacent to primary motor cortex. The participants undertook machine-learning-assisted training to use wirelessly transmitted electrocorticography signal associated with attempted movements to control multiple mouse-click actions, including zoom and left-click. Used in combination with an eye-tracker for cursor navigation, participants achieved Windows 10 operating system control to conduct instrumental activities of daily living (IADL) tasks. RESULTS: Unsupervised home use commenced from day 86 onwards for participant 1, and day 71 for participant 2. Participant 1 achieved a typing task average click selection accuracy of 92.63% (100.00%, 87.50%-100.00%) (trial mean (median, Q1-Q3)) at a rate of 13.81 (13.44, 10.96-16.09) correct characters per minute (CCPM) with predictive text disabled. Participant 2 achieved an average click selection accuracy of 93.18% (100.00%, 88.19%-100.00%) at 20.10 (17.73, 12.27-26.50) CCPM. Completion of IADL tasks including text messaging, online shopping and managing finances independently was demonstrated in both participants. CONCLUSION: We describe the first-in-human experience of a minimally invasive, fully implanted, wireless, ambulatory motor neuroprosthesis using an endovascular stent-electrode array to transmit electrocorticography signals from the motor cortex for multiple command control of digital devices in two participants with flaccid upper limb paralysis.

Utility of Severity-Based Prehospital Triage for Endovascular Thrombectomy: ACT-FAST Validation Study.

BACKGROUND AND PURPOSE: Severity-based assessment tools may assist in prehospital triage of patients to comprehensive stroke centers (CSCs) for endovascular thrombectomy (EVT), but criticisms regarding diagnostic inaccuracy have not been adequately addressed. This study aimed to quantify the benefits and disadvantages of severity-based triage in a large real-world paramedic validation of the Ambulance Clinical Triage for Acute Stroke Treatment (ACT-FAST) algorithm. METHODS: Ambulance Victoria paramedics assessed the prehospital ACT-FAST algorithm in patients with suspected stroke from November 2017 to July 2019 following an 8-minute training video. All patients were transported to the nearest stroke center as per current guidelines. ACT-FAST diagnostic accuracy was compared with hospital imaging for the presence of large vessel occlusion (LVO) and need for CSC-level care (LVO, intracranial hemorrhage, and tumor). Patient-level time saving to EVT was modeled using a validated Google Maps algorithm. Disadvantages of CSC bypass examined potential thrombolysis delays in non-LVO infarcts, proportion of patients with false-negative EVT, and CSC overburdening. RESULTS: Of 517 prehospital assessments, 168/517 (32.5%) were ACT-FAST positive and 132/517 (25.5%) had LVO. ACT-FAST sensitivity and specificity for LVO was 75.8% and 81.8%, respectively. Positive predictive value was 58.8% for LVO and 80.0% when intracranial hemorrhage and tumor (CSC-level care) were included. Within the metropolitan region, 29/55 (52.7%) of ACT-FAST-positive patients requiring EVT underwent a secondary interhospital transfer. Prehospital bypass with avoidance of secondary transfers was modeled to save 52 minutes (95% CI, 40.0-61.5) to EVT commencement. ACT-FAST was false-positive in 8 patients receiving thrombolysis (8.1% of 99 non-LVO infarcts) and false-negative in 4 patients with EVT requiring secondary transfer (5.4% of 74 EVT cases). CSC bypass was estimated to over-triage 1.1 patients-per-CSC-per-week in our region. CONCLUSIONS: The overall benefits of an ACT-FAST algorithm bypass strategy in expediting EVT and avoiding secondary transfers are estimated to substantially outweigh the disadvantages of potentially delayed thrombolysis and over-triage, with only a small proportion of EVT patients missed.

Transcriptome dynamics of CD4+ T cells during malaria maps gradual transit from effector to memory.

The dynamics of CD4+ T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4+ T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (TH1) and follicular helper T (TFH) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated TH1 and TFH trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between TFH and central memory were revealed, with antimalarials modulating these responses and boosting TH1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4+ T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene-gene correlations ( http://haquelab.mdhs.unimelb.edu.au/cd4_memory/ ).

Single-cell transcriptomics of alloreactive CD4+ T cells over time reveals divergent fates during gut graft-versus-host disease.

Acute gastrointestinal (GI) graft-versus-host disease (GVHD) is a primary determinant of mortality after allogeneic hematopoietic stem cell transplantation (alloSCT). The condition is mediated by alloreactive donor CD4+ T cells that differentiate into pathogenic subsets expressing IFN-γ, IL-17A, or GM-CSF and is regulated by subsets expressing IL-10 and/or Foxp3. Developmental relationships between Th cell states during priming in mesenteric lymph nodes (mLNs) and effector function in the GI tract remain undefined at genome scale. We applied scRNA-Seq and computational modeling to a mouse model of donor DC-mediated GVHD exacerbation, creating an atlas of putative CD4+ T cell differentiation pathways in vivo. Computational trajectory inference suggested emergence of pathogenic and regulatory states along a single developmental trajectory in mLNs. Importantly, we inferred an unexpected second trajectory, categorized by little proliferation or cytokine expression, reduced glycolysis, and high tcf7 expression. TCF1hi cells upregulated α4ß7 before gut migration and failed to express cytokines. These cells exhibited recall potential and plasticity following secondary transplantation, including cytokine or Foxp3 expression, but reduced T cell factor 1 (TCF1). Thus, scRNA-Seq suggested divergence of alloreactive CD4+ T cells into quiescent and effector states during gut GVHD exacerbation by donor DC, reflecting putative heterogeneous priming in vivo. These findings, which are potentially the first at a single-cell level during GVHD over time, may assist in examination of T cell differentiation in patients undergoing alloSCT.

The Cdc48 unfoldase prepares well-folded protein substrates for degradation by the 26S proteasome.

Cdc48/p97 is an essential and highly conserved AAA+ ATPase that uses its protein-unfoldase activity to extract ubiquitinated polypeptides from macromolecular complexes and membranes. This motor has also been implicated in protein-degradation pathways, yet its exact role in acting upstream of the 26S proteasome remains elusive. Ubiquitinated proteins destined for degradation by the proteasome require an unstructured initiation region to engage with the proteasomal translocation machinery, and Cdc48 was proposed to generate these unfolded segments, yet direct evidence has been missing. Here, we used an in vitro reconstituted system to demonstrate the collaboration of Cdc48 and the 26S proteasome from S. cerevisiae in degrading ubiquitinated, well-folded proteins that lack unstructured segments. Our data indicate that a critical role for Cdc48 in the ubiquitin-proteasome system is to create flexible initiation regions in compact substrates that otherwise would be refractory to engagement and degradation by the proteasome.

Feminizing effects of exposure to Corexit-enhanced water-accommodated fraction of crude oil in vitro on sex determination in Alligator mississippiensis.

Deepwater Horizon spilled over 200 million gallons of oil into the waters of the Gulf of Mexico in 2010. In an effort to contain the spill, chemical dispersants were applied to minimize the amount of oil reaching coastal shorelines. However, the biological impacts of chemically-dispersed oil are not well characterized, and there is a particular lack of knowledge concerning sublethal long-term effects of exposure. This study examined potential estrogenic effects of CWAF, Corexit 9500-enhanced water-accommodated fraction of oil, by examining its effect on estrogen receptors and sex determination in the American alligator, Alligator mississippiensis. The alligator exhibits temperature-dependent sex determination which is modulated by estrogen signals, and exposure to 17ß-estradiol (E2) and estrogenic compounds in ovo during the thermosensitive period of embryonic development can induce ovarian development at a male-producing temperature (MPT). CWAF induced transactivation up to 50% of the maximum induction by E2 via alligator estrogen receptors in vitro. To determine potential endocrine-disrupting effects of exposure directly on the gonad, gonad-adrenal-mesonephric (GAM) organ complexes were isolated from embryos one day prior to the thermosensitive period and exposed to E2, CWAF, or medium alone in vitro for 8-16 days at MPT. Both CWAF and E2 exposure induced a significant increase in female ratios. CWAF exposure suppressed GAM mRNA abundances of anti-Müllerian hormone (AMH), sex determining region Y-box 9, and aromatase, whereas E2 exposure suppressed AMH and increased Forkhead box protein L2 mRNA abundances in GAM. These results indicate that the observed endocrine-disrupting effects of CWAF are not solely estrogenically mediated, and further investigations are required.

Design, synthesis and evaluation of XZH-5 analogues as STAT3 inhibitors.

Inhibition of the signaling pathways of signal transducer and activator of transcription 3 (STAT 3) has shown to be a promising strategy to combat cancer. In this paper we report the design, synthesis and evaluation of a novel class of small molecule inhibitors, that is, XZH-5 and its analogues, as promising leads for further development of STAT3 inhibitors. Preliminary SARs was established for XZH-5 and its derivatives; and the binding modes were predicted by molecular docking. Lead compounds with IC50 as low as 6.5µM in breast cancer cell lines and 7.6µM in pancreatic cancer cell lines were identified.

Guanylin peptides regulate electrolyte and fluid transport in the Gulf toadfish (Opsanus beta) posterior intestine.

The physiological effects of guanylin (GN) and uroguanylin (UGN) on fluid and electrolyte transport in the teleost fish intestine have yet to be thoroughly investigated. In the present study, the effects of GN, UGN, and renoguanylin (RGN; a GN and UGN homolog) on short-circuit current (Isc) and the transport of Cl-, Na+, bicarbonate (HCO3-), and fluid in the Gulf toadfish (Opsanus beta) intestine were determined using Ussing chambers, pH-stat titration, and intestinal sac experiments. GN, UGN, and RGN reversed the Isc of the posterior intestine (absorptive-to-secretory), but not of the anterior intestine. RGN decreased baseline HCO3- secretion, but increased Cl- and fluid secretion in the posterior intestine. The secretory response of the posterior intestine coincides with the presence of basolateral NKCC1 and apical cystic fibrosis transmembrane conductance regulator (CFTR), the latter of which is lacking in the anterior intestine and is not permeable to HCO3- in the posterior intestine. However, the response to RGN by the posterior intestine is counterintuitive given the known role of the marine teleost intestine as a salt- and water-absorbing organ. These data demonstrate that marine teleosts possess a tissue-specific secretory response, apparently associated with seawater adaptation, the exact role of which remains to be determined.

Melanoma: A new strategy to reduce morbidity and mortality.

BACKGROUND: Public awareness campaigns could address risk factors for melanoma to reinforce their sun protection message. The objective of this study is to prioritise risk factors associated with malignant melanoma (MM) to improve public awareness. DESIGN: A cross-sectional study with retrospective data analysis from 2004 to 2010. SETTING: Western Australian Melanoma Advisory Service (WAMAS), a tertiary referral multidisciplinary organisation providing MM management advice. WAMAS data files were analysed with histologically confirmed cutaneous MM. Forty- seven patients had two or more melanomas, but the patient file was counted only once. Six MM data files with missing or incomplete information were excluded. MAIN OUTCOME MEASURES: The number of naevi, blood relatives with MM, and previous sunburns were the primary variables collected. RESULTS: The results showed that 70.9 per cent (268/378) had previous sunburn; 40.2 per cent (152/378) had multiple naevi; and 22.5 per cent (85/378) had a positive family history. In the 110 MM data files not associated with sunburn, multiple naevi and a positive family history represented 34.5 per cent (38/110) and 20.0 per cent (22/110), respectively. CONCLUSION: The results confirm the findings of previous studies that multiple naevi and a positive family history are important risk factors associated with MM. We suggest that MM can be detected earlier and its mortality decreased by focusing on these high-risk groups who are not targeted by current public awareness campaigns.

An examination of resveratrol's mechanisms of action in human tissue: impact of a single dose in vivo and dose responses in skeletal muscle ex vivo.

The current study tested the hypothesis that a single, moderate dose of RSV would activate the AMPK/SIRT1 axis in human skeletal muscle and adipose tissue. Additionally, the effects of RSV on mitochondrial respiration in PmFBs were examined. Eight sedentary men (23.8±2.4 yrs; BMI: 32.7±7.1) reported to the lab on two occasions where they were provided a meal supplemented with 300 mg of RSV or a placebo. Blood samples, and a muscle biopsy were obtained in the fasted state and again, with the addition of an adipose tissue biopsy, two hours post-prandial. The effect of RSV on mitochondrial respiration was examined in PmFBs taken from muscle biopsies from an additional eight men (23.4±5.4 yrs; BMI: 24.4±2.8). No effect of RSV was observed on nuclear SIRT1 activity, acetylation of p53, or phosphorylation of AMPK, ACC or PKA in either skeletal muscle or adipose tissue. A decrease in post absorptive insulin levels was accompanied by elevated skeletal muscle phosphorylation of p38 MAPK, but no change in either skeletal muscle or adipose tissue insulin signalling. Mitochondrial respiration in PmFBs was rapidly inhibited by RSV at 100-300 uM depending on the substrate examined. These results question the efficacy of a single dose of RSV at altering skeletal muscle and adipose tissue AMPK/SIRT1 activity in humans and suggest that RSV mechanisms of action in humans may be associated with altered cellular energetics resulting from impaired mitochondrial ATP production.

Effects of protocol and obesity on dose conversion factors in adult body CT.

PURPOSE: In computed tomography (CT), organ dose, effective dose, and risk index can be estimated from volume-weighted CT dose index (CTDI(vol)) or dose-length product (DLP) using conversion coefficients. Studies have investigated how these coefficients vary across scanner models, scan parameters, and patient size. However, their variability across CT protocols has not been systematically studied. Furthermore, earlier studies of the effect of patient size have not included obese individuals, which currently represent more than one-third of U.S. adults. The purpose of this study was to assess the effects of protocol and obesity on dose and risk conversion coefficients in adult body CT. METHODS: Whole-body computational phantoms were created from clinical CT images of six adult patients (three males, three females), representing normal-weight patients and patients of three obesity classes. Body CT protocols at our institution were selected and categorized into ten examination categories based on anatomical region examined. A validated Monte Carlo program was used to estimate organ dose. Organ dose estimates were normalized by CTDI(vol) and size-specific dose estimate (SSDE) to obtain organ dose conversion coefficients (denoted as h and h(ss) factors, respectively). Assuming each phantom to be 20, 40, and 60 years old, effective dose and risk index were calculated and normalized by DLP to obtain effective dose and risk index conversion coefficients (denoted as k and q factors, respectively). Coefficient of variation was used to quantify the variability of each conversion coefficient across examination categories. The effect of obesity was assessed by comparing each obese phantom with the normal-weight phantom of the same gender. RESULTS: For a given organ, the variability of h factor across examination categories that encompassed the entire organ volume was generally within 15%. However, k factor varied more across examination categories (15%-27%). For all three ages, the variability of q factor was small for male (<10%), but large for female phantoms (21%-43%). Relative to the normal-weight phantoms, the reduction in h factor (an average across fully encompassed organs) was 17%-42%, 17%-40%, and 51%-63% for obese-class-I, obese-class-II, and obese-class-III phantoms, respectively. h(ss) factor was not independent of patient diameter and generally decreased with increasing obesity. Relative to the normal-weight phantoms, the reduction in k factor was 12%-40%, 14%-46%, and 44%-59% for obese-class-I, obese-class-II, and obese-class-III phantoms, respectively. The respective reduction in q factor was 11%-36%, 17%-42%, and 48%-59% at 20 years of age and similar at other ages. CONCLUSIONS: In adult body CT, dose to an organ fully encompassed by the primary radiation beam can be estimated from CTDI(vol) using a protocol-independent conversion coefficient. However, fully encompassed organs only account for 50% ± 19% of k factor and 46% ± 24% of q factor. Dose received by partially encompassed organs is also substantial. To estimate effective dose and risk index from DLP, it is necessary to use conversion coefficients specific to the anatomical region examined. Obesity has a significant effect on dose and risk conversion coefficients, which cannot be predicted using body diameter alone. SSDE-normalized organ dose is not independent of diameter. SSDE itself generally overestimates organ dose for obese patients.

Burn injuries inflicted on children or the elderly: a framework for clinical and forensic assessment.

LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Understand the difference between battery and assault in U.S. law and the concepts of the phrase "child abuse" and "elder abuse." 2. Understand that state statutes vary and can define abuse narrowly or with great specificity, and that either definition has inherent problems for physicians treating victims of abuse and neglect. 3. Know where to find the state-specific legal criteria for child or elder abuse and neglect, along with the corresponding standards for mandatory reporting and physician accountability. 4. Understand the relevant law regarding physician-patient privilege and the repercussions of incorrect but good faith reporting and of failing to report suspected abuse or neglect of children or the elderly. 5. Understand that there are no pathognomic signs for inflicted burn injury. 6. Clinically assess burned pediatric or elderly patients within a framework that will minimize the risk of missing or inappropriately suspecting injuries that stem from abuse or neglect. SUMMARY: This article deals with burns inflicted on children and the elderly, two particularly vulnerable societal groups. Though inflicted burning is a relatively rare method of inflicting physical abuse, failure to diagnose it has far-reaching ramifications. These injuries pose both medical and forensic problems for physicians, along with unique ethical dilemmas. This article is a collaboration between surgeons and lawyers providing a holistic, workable approach to the management of inflicted burn injury. The authors first describe the legal considerations that must be appreciated by U.S. physicians, then they suggest a rational and balanced clinical approach to the assessment of burn injuries that may have been inflicted intentionally or negligently on children and the elderly.