Rejected

Ideally, humane endpoints allow for early termination of experiments by minimizing an animal's discomfort, distress and pain, while ensuring that scientific objectives are reached. Yet, lack of commonly agreed methodology and heterogeneity of cut-off values published in the literature remain a challenge to the accurate determination and application of humane endpoints. With the aim to synthesize and appraise existing humane endpoint definitions for commonly used physiological parameters, we conducted a systematic review of mouse studies of acute and chronic disease models, which used body weight, temperature and/or sickness scores for endpoint definition. In the second part of the study, we used previously published and unpublished data on weight, temperature and sickness scores from mouse models of sepsis and stroke and applied machine learning algorithms to assess the usefulness of this method for parameter selection and endpoint definition across models. Studies were searched for in two electronic databases (MEDLINE/Pubmed and Embase). Out of 110 retrieved full-text manuscripts, 34 studies were included. We found large intra- and inter-model variance in humane endpoint determination and application due to varying animal models, lack of standardized experimental protocols and heterogeneity of performance metrics (part 1). Machine learning models trained with physiological data and sickness severity score or modified DeSimoni neuroscore identified animals with a high risk of death at an early time point in both mouse models of stroke (male: 93.2% at 72h post-treatment; female: 93.0% at 48h post-treatment) and sepsis (96.2% at 24h post-treatment), thus demonstrating generalizability in endpoint determination across models (part 2).

Both universal goniometer and electro-goniometer are used for measuring joint range of motion in physiotherapy. Active knee extension test is a way to assess hamstring shortness in patients with chronic low back pain. The aim of this study was to assess universal goniometer and electro-goniometer reliability in measuring knee angle during active knee extension test.

Keratitis is a sight-threatening inflammatory condition of the cornea that can be caused by both infectious and non-infectious agents. Physical or chemical trauma are typically related to non-infectious keratitis, which may then become secondarily infected or remain non-infected. Etiology of infectious keratitis is most often associated with bacteria; but viruses, fungi, and parasites are common causative pathogens as well. As a global concern, common risk factors include: systemic immunosuppression (secondary to malnutrition, alcoholism, diabetes, steroid use), previous corneal surgery (refractive corneal surgery, penetrating keratoplasty), extended wear contact lens use, pre-existing ocular surface diseases (dry eye, epithelial defect) and ocular trauma (agriculture- or farm-related) [1-8]. Annual rates of incidence include nearly one million clinical visits due to keratitis in the United States, while it has been reported that roughly two million people develop corneal ulcers in India. Clinically, patients may show signs of eye pain (ranging from mild to severe), blurred vision, photophobia, chemosis and redness. Pathogenesis is generally characterized by rapid progression, focal white infiltrates with underlying stromal inflammation, corneal thinning, stromal edema, mucopurulent discharge and hypopyon, which can lead to corneal scarring, endophthalmitis, and perforation. In fact, corneal opacity is not only a complication of keratitis, but among the leading causes of legal blindness worldwide. Despite that empirical treatment effectively controls most of the pathogens implicated in infectious keratitis, improved clinical outcomes are not guaranteed. Further, if treatment is not initiated in a timely manner, good visual outcome is reduced to approximately 50% of keratitis patients [9]. Moreover, resultant structural alterations, loss of tissue and an unresolved host response remain unaddressed through current clinical management of this condition.

Blast overpressure exposure has been linked to transient, but measurably deteriorated performance and symptomatologies in law enforcement and military personnel. Overlapping sub-concussive symptomatology associated with the very low level blast overpressures (vLLB) but high sound pressure (<3 psi) associated with these exposures has largely been ignored. Notably, the current vLLB or acoustic literature has focused exclusively on auditory defects, and has not addressed the broader concerns of Soldier health and readiness. This work was prompted by reports of symptomatology such as headache, nausea, slowed reaction time, and balance/hearing complications among personnel undergoing frequent exposures to low overpressure accompanied by high acoustic pressures. To more fully address the consequences associated with low overpressure exposures (<3 psi), a pilot proof-of-concept study was implemented, and data was acquired at two sites on the Fort Benning grenade course range. Findings indicated overpressures ranged from 0.14 to 0.42 psi (0.97-2.89 kPa) at range 1 and 0.22-0.30 psi (1.52-2.07 kPa) on range 2 of the grenade course. Corresponding sound-meter data varied from 153.72 to 163.22 dBP. Headache and long think were the most frequently reported symptoms (3/6 instructors), with lightheadedness, ringing of the ears, restlessness, frustration, and irritability also increasing in 2/6 of the instructors post exposure. Long think (prolonged thinking), ringing of the ears, restlessness, and irritability were the most severe symptoms, with the highest reported post exposure value rating a 3 on the 0-4-point scale. We demonstrate that low-level repeated overpressure exposure can result in transient symptomatology that overlaps with sub-concussive like effects.

Interstitial electrostimulation (IES) is used to treat spinal pain syndromes. The phenomena occurring in tissue around the electrode that is connected to a vertebra remain unknown.

Response-shift has been cited as an important measurement consideration when assessing patient reported quality of life (QoL) outcomes over time among patients with severe chronic conditions. Here we report the results of a systematic review of response shift in studies assessing QoL among cancer patients. A systematic review using MEDLINE, EMBASE, and PsychINFO along with a manual search of the cited references of the articles selected, was conducted. A quality review was performed using STROBE criteria and reported according to PRISMA guidelines. A systematic review of 1,487 records published between 1,887 and December 2018 revealed 104 potentially eligible studies, and 35 studies met inclusion criteria for content and quality. The most common cancer patient populations investigated in these studies were breast (18 studies), lung (14 studies), prostate (eight studies), and colorectal (eight studies). Response shift was identified among 34 of the 35 studies reviewed. Effect sizes were reported in 17 studies assessing QoL outcomes among cancer patients; 12 of which had negligible to small effect sizes, four reported medium effect sizes which were related to physical, global QoL, pain, and social (role) functioning and one reported a large effect size (fatigue). The most prevalent method for assessing response shift was the , which is prone to recall bias, followed by the method. Given the heterogeneity among the characteristics of the samples and designs reviewed, as well as the overall small to negligible effect sizes for the effects reported, conclusions stating that changes due to internal cognitive shifts in perceived QoL should account for changes observed in cancer patients' QoL outcomes should be interpreted with caution. Further work is needed in this area of research. Future studies should control for patient characteristics, time elapsed between diagnosis and baseline assessment and evaluate their contribution to the presence of response shift. Time between assessments should include short and longer periods between assessments and evaluate whether the presence of response shift holds over time. Possible avenues for inquiry for future investigation are discussed.

Diabetic myonecrosis (DMN) is a rare microangiopathic disorder that can present as an acutely painful and swollen limb in patients with established diabetes mellitus. The condition can be diagnosed noninvasively with magnetic resonance imaging and resolves with analgesia, bed rest, and glycemic control. Due to a relative lack of awareness regarding the condition, avoidable interventions such as muscle biopsies and even surgery are sometimes pursued, which have been associated with prolonged recovery times. The majority of patients with DMN have diabetic nephropathy, yet this condition is not widely recognized in the nephrology community, resulting in delayed diagnosis and patients undergoing unnecessary and potentially harmful investigations. There is therefore a need for increased awareness of the condition among renal physicians. Here, we report the cases of two patients on hemodialysis who were ultimately diagnosed with DMN, along with a review of the literature.

Pain is a common phenomenon among emergency patients which may lead to chronic pain conditions and alteration of physiological function. However, it is widely reported that proper pain assessment and management, which is often accomplished by adequately trained nurses reduce the suffering of patients. Therefore, the aim of this study was to assess the emergency nurses´ knowledge, attitude and perceived barriers regarding pain management.

Atopic eczema is an itchy inflammatory disorder characterised by skin barrier dysfunction. Loss-of-function mutations in the gene encoding filaggrin ( ) are a major risk factor, but the mechanisms by which filaggrin haploinsufficiency leads to atopic inflammation remain incompletely understood. Skin as an organ that can be modelled using primary cells provides the opportunity for selected genetic effects to be investigated in detail. Primary human keratinocytes and donor-matched primary fibroblasts from healthy individuals were used to create skin organoid models with and without siRNA-mediated knockdown of . Biological replicate sets of organoids were assessed using histological, functional and biochemical measurements. knockdown leads to subtle changes in histology and ultrastructure including a reduction in thickness of the stratum corneum and smaller, less numerous keratohyalin granules. Immature organoids showed some limited evidence of barrier impairment with knockdown, but the mature organoids showed no difference in transepidermal water loss, water content or dye penetration. There was no difference in epidermal ceramide content. Mass spectrometry proteomic analysis detected >8000 proteins per sample. Gene ontology and pathway analyses identified an increase in transcriptional and translational activity but a reduction in proteins contributing to terminal differentiation, including caspase 14, dermokine, AKT1 and TGF-beta-1. Aspects of innate and adaptive immunity were represented in both the up-regulated and down-regulated protein groups, as was the term 'axon guidance'.      This work provides further evidence for keratinocyte-specific mechanisms contributing to immune and neurological, as well as structural, aspects of skin barrier dysfunction. Individuals with filaggrin deficiency may derive benefit from future therapies targeting keratinocyte-immune crosstalk and neurogenic pruritus.