Chronic restraint stress promotes oral squamous cell carcinoma development by inhibiting ALDH3A1 via stress response hormone.

BACKGROUND: Chronic restraint stress (CRS) has iteratively been reported to be possibly implicated in the development of numerous cancer types. However, its role in oral squamous cell carcinoma (OSCC) has not been well elucidated. Here we intended to evaluate the role and mechanism. METHODS: The effects of CRS were investigated in xenograft models of OSCC by using transcriptome sequencing, LC-MS, ELISA and RT-PCR. Moreover, the role of CRS and ALDH3A1 on OSCC cells was researched by using Trans-well, flow cytometry, western blotting, immunofluorescence, ATP activity and OCR assay. Furthermore, immunohistochemical staining was employed to observe the cell proliferation and invasion of OSCC in xenotransplantation models. RESULTS: CRS promoted the progression of OSCC in xenograft models, stimulated the secretion of norepinephrine and the expression of ADRB2, but decreased the expression of ALDH3A1. Moreover, CRS changed energy metabolism and increased mitochondrial metabolism markers. However, ALDH3A1 overexpression suppressed proliferation, EMT and mitochondrial metabolism of OSCC cells. CONCLUSION: Inhibition of ALDH3A1 expression plays a pivotal role in CRS promoting tumorigenic potential of OSCC cells, and the regulatory of ALDH3A1 on mitochondrial metabolism may be involved in this process.

A multicomponent intervention program to Prevent and Reduce AgItation and phySical rEstraint use in the ICU (PRAISE): study protocol for a multicenter, stepped-wedge, cluster randomized controlled trial.

BACKGROUND: Physical restraints remain to be commonly used in agitated intensive care unit (ICU) patients worldwide, despite a lack of evidence on efficacy and safety and reports of detrimental short and long-term consequences, such as prolonged delirium and a longer ICU length of stay. Physical restraint minimization approaches have focused mainly on educational strategies and other non-pharmacological interventions. Combining these interventions with goal-directed light sedation therapy if needed may play an important contributory role in further reducing the use of physical restraints. The aim of the study is to determine the effectiveness of a multicomponent intervention (MCI) program, combining person-centered non-pharmacological interventions with goal-directed light sedation, compared to physical restraints. METHODS: A multicenter stepped-wedge cluster randomized controlled trial will be conducted in six Dutch ICUs. A power calculation based total of 480 (expected to become) agitated adult patients will be included in 26 months with a subsequent 2-year follow-up. Patients included in the control period will receive standard care with the current agitation management protocol including physical restraints. Patients included in the intervention period will be treated with the MCI program, consisting of four components, without physical restraints: education of ICU professionals, identification of patients at risk for agitation, formulation of a multidisciplinary person-centered care plan including non-pharmacological and medical interventions, and protocolized goal-directed light sedation using dexmedetomidine. Primary outcome is the number of days alive and outside of the ICU within 28 days after ICU admission. Secondary outcomes include length of hospital stay; 3-, 12-, and 24-month post-ICU quality of life; physical (fatigue, frailty, new physical problems), mental (anxiety, depression, and post-traumatic stress disorder), and cognitive health; and 1-year cost-effectiveness. A process evaluation will be conducted. DISCUSSION: This will be the first multicenter randomized controlled trial determining the effect of a combination of non-pharmacological interventions and light sedation using dexmedetomidine compared to physical restraints in agitated ICU patients. The results of this study, including long-term patient-centered outcomes, will provide relevant insights to aid ICU professionals in the management of agitated patients. TRIAL REGISTRATION: NCT05783505, registration date 23 March 2023.

Protective effect of alpha-ketoglutarate against water-immersion restraint stress-induced gastric mucosal damage in mice.

Gastric lesions have several aetiologies, among which stress is the most prominent. Therefore, identification of new therapies to prevent stress is of considerable importance. Alpha-ketoglutarate (α-kg) several beneficial effects and has shown promise in combating oxidative stress, inflammation, and premature aging. Thus, this study aimed to evaluate the protective effect of α-kg in a gastric damage model by water-immersion restraint stress (WIRS). Pretreatment with α-kg decreased stress-related histopathological scores of tissue oedema, cell loss, and inflammatory infiltration. The α-kg restored the percentage of type III collagen fibres. Mucin levels were preserved as well as the structure and area of the myenteric plexus ganglia were preserved after pretreatment with α-kg. Myeloperoxidase (MPO) levels and the expression of pro-inflammatory cytokines (TNF-α and IL-1ß) were also reduced following α-kg pretreatment. Decreased levels of glutathione (GSH) in the stress group were restored by α-kg. The omeprazole group was used as standard drug e also demonstrated improve on some parameters after the exposition to WIRS as inflammatory indexes, GSH and mucin. Through this, was possible to observe that α-kg can protect the gastric mucosa exposed to WIRS, preserve tissue architecture, reduce direct damage to the mucosa and inflammatory factors, stimulate the production of type III collagen and mucin, preserve the myenteric plexus ganglia, and maintain antioxidant potential. Due to, we indicate that α-kg has protective activity of the gastric mucosa, demonstrating its ability to prevent damage associated with gastric lesions caused by stress.

Experience of patients with restraints in acute care hospitals and the view of their relatives: A qualitative study.

AIM: To describe the experiences of patients and relatives with any form of restraints in somatic acute care hospitals. DESIGN: Qualitative explorative design. METHODS: Qualitative research methods were used. Participants were recruited through clinical nursing specialists in participating departments of a university hospital between June and August 2020. Individual interviews were conducted and analysed using content analysis. RESULTS: Four interviews with patients and five interviews with relatives were conducted with a mean duration of 25 min. The following three topics emerged in the analysis as important: What was perceived as restraints, Assessing the experiences of restraint use on a continuum, and Lack of information about restrictive measures. Patients and relatives defined restraint very broadly and assessed the experiences of restraint on a continuum from positive to negative, with a more critical view from patients. Relatives clearly seemed to approve of the use of restraints in acute care hospitals because it provided them with a sense of security. In general, there seemed to be a lack of information about the use of restraint and its effects on patients and relatives alike. CONCLUSION: The involvement of patients and relatives in the decision-making process about restraint use seems to be low. Healthcare professionals need to be better educated to be able to pass on adequate information and to involve patients and their relatives adequately in all processes of restraint use. However, when relatives are involved in decision-making as proxies for patients, it is important to consider that patients' and relatives' opinions on restraints may differ. PATIENT OR PUBLIC CONTRIBUTION: Patients and relatives agreed to participate in the study and shared their experiences with us.

Factors influencing agitation, de-escalation, and physical restraint at a children's hospital.

BACKGROUND: Children hospitalized in medical hospitals are at risk of agitation. Physical restraint may be used to maintain patient and staff safety during de-escalation, but physical restraint use is associated with physical and psychological adverse events. OBJECTIVE: We sought to better understand which work system factors help clinicians prevent patient agitation, improve de-escalation, and avoid physical restraint. DESIGN, SETTING, AND PARTICIPANTS: We used directed content analysis to extend the Systems Engineering Initiative for Patient Safety model to clinicians working with children at risk for agitation at a freestanding children's hospital. INTERVENTION, MAIN OUTCOME, AND MEASURES: We conducted semistructured interviews to examine how five clinician work system factors affected patient agitation, de-escalation, and restraint: person, environment, tasks, technology and tools, and organization. Interviews were recorded, transcribed, and analyzed until saturation. RESULTS: Forty clinicians participated in this study, including 21 nurses, 15 psychiatric technicians, 2 pediatric physicians, 1 psychologist, and 1 behavior analyst. Work system factors that contributed to patient agitation were medical tasks like vital signs and the hospital environment including bright lights and neighboring patients' noises. Supports that helped clinicians de-escalate patients included adequate staffing and accessible toys and activities. Participants indicated that organizational factors were integral to team de-escalation, drawing connections between units' teamwork and communication cultures and their likelihood of successful de-escalation without the use of physical restraint. CONCLUSION: Clinicians perceived that medical tasks, hospital environmental factors, clinician attributes, and team communication influenced patients' agitation, de-escalation, and physical restraint. These work system factors provide opportunities for future multi-disciplinary interventions to reduce physical restraint use.

Response to "Scrutinizing the causal link between excited delirium syndrome and restraint - a commentary on: 'The role of restraint in fatal excited delirium: a research synthesis and pooled analysis' by E.M.F. Strömmer, W. Leith, M.P. Zeegers and M.D. Freeman".

de Boer et al. criticize the conclusions in our 2020 paper on the validity of Excited Delirium Syndrome (ExDS) as "egregiously misleading." Our conclusion was that there "is no existing evidence that indicates that ExDS is inherently lethal in the absence of aggressive restraint." The basis for de Boer and colleague's criticism of our paper is that the ExDS literature does not provide an unbiased view of the lethality of the condition, and therefore the true epidemiologic features of ExDS cannot be determined from what has been published. The criticism is unrelated to the goals or methods of the study, however. Our stated purpose was to investigate "how the term ExDS has evolved in the literature and been endowed with a uniquely lethal quality," and whether there is "evidence for ExDS as a unique cause of a death that would have occurred regardless of restraint, or a label used when a restrained and agitated person dies, and which erroneously directs attention away from the role of restraint in explaining the death." We cannot fathom how de Boer et al. missed this clearly stated description of the study rationale, or why they would endorse a series of fallacious and meaningless claims that gave the appearance that they failed to grasp the basic design of the study. We do acknowledge and thank these authors for pointing out 3 minor citation errors and an equally minor table formatting error (neither of which altered the reported results and conclusions in the slightest), however.

Prone restraint death: Possible role of the Valsalva maneuver.

There is an on-going debate about the safety of prone restraint and the exact role of the prone position in physical restraint death. Cardiac arrest in prone restraint death is essentially the end-result of a violent physical altercation wherein a combative individual suddenly loses consciousness while trying to counteract an opposing force. The direct correlations of increased static weight force with decreased inferior vena cava diameter, decreased cardiac output, and decreased stroke volume in prone restraint studies suggest that decreased venous return and decreased cardiac output could have a significant role to play in prone restraint death. Although the degree of changes observed in those studies might not be sufficient to cause cardiac arrest, they could predispose people who instinctively try to free themselves of the restraints to severe complications. The Valsalva maneuver, or forceful expiration against a closed airway, is frequently performed spontaneously in daily activities involving straining and resistance exercise, but has never been considered in restraint death. Pre-existing diminished venous return could increase the risk of major complications in individuals performing the Valsalva maneuver. A substantial decrease in venous return and cardiac output could increase the risk of cerebral hypoperfusion, loss of consciousness, hypoventilation, and sudden death. By increasing the risk of increased intra-abdominal pressure and its negative effect on venous return, high body mass index may be a significant risk factor in prone restraint death. The Valsalva maneuver may have different roles in prone restraint cardiac arrest and might be overlooked in prone restraint death.

[The arrest-related excited delirium syndrome; prevention, treatment and controversies]. / Het opwindingsdelier bij gewelddadige arrestatie: preventie, behandeling en controverses.

BACKGROUND: Patients with an acute confusional state can develop a potentially life-threatening medical emergency when arres­ted by police. This phenomenon has been named the excited delirium syndrome. Controversy regarding this topic has arisen both in the medical literature and in the civil media. AIM: To provide an overview regarding the pathophysiological, epidemiological and clinical aspects of the excited delirium syndrome, the controversy and the opportunities for prevention of a fatal outcome. METHOD: A systematic review of the literature from 1985 to 2021. RESULTS: We included 103 studies in our review. The excited delirium syndrome occurs predominantly in young, physically healthy men who are under the influence of drugs or a psychiatric illness. Several pathophysiological theories exist: the dopaminergic and catecholaminergic hypotheses and restraint asphyxia. There is controversy both in the medical scientific discourse and in the civil media regarding the existence of this syndrome and the cause of death. There are suggestions that mortality can be decreased by timely recognition, de-escalation and medical treatment. CONCLUSION: The excited delirium syndrome is a medical emergency that can arise during physical arrest of patients with a drugs intoxication or psychiatric illness. Improved collaboration between mental health care professionals and police could prevent fatal outcomes.

Association of physical restraint duration and undesirable outcomes amongst inpatients comorbid with dementia and pneumonia in acute care settings.

AIMS AND OBJECTIVES: This study aimed to examine the association between physical restraint duration and undesirable outcomes amongst inpatients comorbid with dementia and pneumonia in acute care hospitals. BACKGROUND: Physical restraints are frequently used in the management of patients, especially amongst patients with dementia. No previous study investigated the potential undesirable effects of physical restraints in patients with dementia. METHODS: This was a cohort study using a nationwide discharge abstract database in Japan. Patients aged ≥65 years with dementia hospitalised for pneumonia or aspiration pneumonia between April 1, 2016 and March 31, 2019 were identified. The exposure was physical restraint. The primary outcome was hospital discharge to the community. Secondary outcomes included hospitalisation costs, functional decline, in-hospital mortality, and institutionalisation for long-term care. RESULTS: A total of 18,255 inpatients with pneumonia and dementia in 307 hospitals were included in this study. Of them, 21.5% and 23.7% had physical restraint during full and partial days of hospital stays, respectively. Discharge to the community incidence rates was lower in the full-restraint vs. the no-restraint group (27 vs. 29 per 1000 person-days; HR, 1.05 [95% CI, 1.01-1.10]) and the partial-restraint vs. the no-restraint group (17 vs. 29 per 1000 person-days; HR, 1.79 [95% CI, 1.71-1.87]). The risks of functional decline were higher in the full-restraint vs. the no-restraint group (27.8% vs. 20.8%; RR, 1.33 [95% CI, 1.22, 1.46]) and the partial-restraint vs. the no-restraint group (29.2% vs. 20.8%; RR, 1.40 [95% CI, 1.29, 1.53]). CONCLUSIONS: The use of physical restraints was associated with a lower incidence rate of discharge to the community and an increased risk of functional decline at discharge. Further research is needed to judge the benefit-risk balance of physical restraints in acute care settings. RELEVANCE TO CLINICAL PRACTICE: Understanding the risk of physical restraints allows medical staff to improve the process of decision making in everyday practice. No Patient or Public Contribution. REPORTING METHODS: The reporting of this article conforms to the STROBE statement.

Use of physical restraints and its associated risk factors in the aged care facilities: A multicentre cross-sectional study.

AIMS AND OBJECTIVES: To investigate the use of physical restraints in aged care facilities(ACFs)and analyse its associated risk factors. BACKGROUND: Physical restraints have been widely used in ACFs worldwide, but they can cause physical and mental harm to older people. It is important to regulate the use of physical restraint. DESIGN: A cross-sectional observational and correlational multicentre study. METHODS: By convenience sampling method, we selected eight ACFs in four representative regions of Hunan province, China, for this study. The ACF-related information was obtained by interviewing the managers and reviewing records. We conducted investigation and observation on the elderly in the ACFs to understand the use of physical restraints at three different times: 9:30-11:30, 16:00-18:00 and 19:30-21:30 on a working day. The STROBE checklist was followed for this cross-sectional study. RESULTS: This study found that the utilisation rate of physical restraints was 23.2%. The critical risk factors affecting the use of physical restrains include the following: (1) the ratio of nursing staff to the elderly residents; (2)whether there is a dementia care unit at the facility; (3) the number of elderly residents in each room; (4) the elderly residents' age, degree of education, marital status, care dependence and cognitive impairment; (5) whether the elderly has suffered from a stroke or senile dementia; (6) whether the elderly carries medical catheters. CONCLUSION: There is a lack of standardisation in the use of physical restraints in ACFs of central China. Chinese ACFs should develop guidelines and reduction measures to standardise the use of physical restraints, basing on the key factors affecting the use of physical restraints. RELEVANCE TO CLINICAL PRACTICE: The use of physical restraints in ACFs is threatening the safety of the elderly residents. Understanding the implementation of physical restraint in ACFs can provide reference for reducing the use of physical restraint.

CRS induces depression-like behavior after MCAO in rats possibly by activating p38 MAPK.

Post-stroke depression (PSD) is a common neuropsychiatric complication of stroke, which seriously affects the quality of life and prognosis of patients. Nevertheless, the pathogenesis of PSD remains unclear. In our study, a PSD rat model was established by chronic restraint stress (CRS) combined with middle cerebral artery occlusion (MCAO). Depressive and anxiety-like behaviors were tested, as well as Neuronal loss and Apoptosis. The expression of synapse and p38 MAPK signaling pathway -relevant proteins was detected. Our data indicated that CRS combined with MCAO could induce depression-like and anxiety-like behaviors, which led to neuronal damage, apoptosis, and cellular loss in the left parietal cortex and left hippocampus. Furthermore, CRS combined with MCAO decreased synaptic plasticity in the parietal cortex and left hippocampus. We found that CRS combined with MCAO had activated the p38 MAPK signaling pathway, and decreased the expression of pathway-related proteins MKK6 and MKK3. These results suggested that CRS combined with MCAO could lead to depression-like behavior via neuronal damage, apoptosis and reduced synaptic plasticity, which might be related to the activation of the p38 MAPK pathway. Therefore, it provides novel ideas for the research on the intervention and prevention mechanisms of PSD.

Hand and Wrist Injuries Associated With Application of Physical Restraints: A Systematic Review.

While handcuffs and zip ties are common methods of physical restraint used by law enforcement, they have been noted to damage soft tissue and bony structures of the hand and wrist. This paper seeks to characterize the safety of physical restraints by summarizing its effects on hand and wrist function and disability. Relevant studies were gathered through an independent double selection and extraction process using 3 electronic databases (EMBASE, MEDLINE, and CINAHL) from database inception to June 19, 2020. A total of 16 studies involving 807 participants were included. Lesion to the superficial branch of the radial nerve was the most commonly reported injury noted in 82% (42/55) of hands examined. A total of 6% (5/77) of examined hands had bony injury, including 3 radial styloid fractures and 2 scaphoid fractures. Both studies on zip ties noted presence of handcuff neuropathy, with 1 case report documenting severe rapidly progressing ischemic monomelic neuropathy. Overall, the use of handcuffs and zip ties is associated with entrapment neuropathies and bony injury to the hand and wrist. Further studies of higher quality evidence are necessary to understand the effects of physical restraint on hand function and disability.

What factors contribute to the need for physical restraint in institutionalized residents in Taiwan?

BACKGROUND: In Taiwan, physical restraint is commonly used in institutions to protect residents from falling or injury. However, physical restraint should be used cautiously to avoid side effects, such as worse cognition, mobility, depression, and even death. OBJECTIVES: To identify the rate of physical restraint and the associated risk factors in institutionalized residents in Taiwan. METHODS: A community-based epidemiological survey was conducted from July 2019 to February 2020 across 266 residential institutions. Among the estimated 6,549 residents being surveyed, a total of 5,752 finished the study. The questionnaires were completed by residents, his/her family or social workers. The cognition tests were conducted by specialists and a multilevel analysis approach was used to identify cognition/disability/medical history/special nursing care/BPSD risk factors for physical restraints. RESULTS: Of the 5,752 included institutionalized residents, 30.2% (1,737) had been previously restrained. Older age, lower education level, lower cognitive function, higher dependence, residents with cerebrovascular disease, pulmonary disease, dementia, and intractable epilepsy, all contributed to a higher physical restraint rate, while orthopedic disease and spinal cord injury were associated with a lower physical restraint rate. Furthermore, residents with special nursing care had a higher restraint rate. Residents with most of the behavior and psychological symptoms were also associated with an increased restraint rate. CONCLUSIONS: We studied the rate of physical restraint and associated risk factors in institutionalized residents in Taiwan. The benefits and risks of physical restraint should be evaluated before application, and adjusted according to different clinical situations.

Impact of maternal physical exercise on inflammatory and hypothalamic-pituitary-adrenal axis markers in the brain and lungs of prenatally stressed neonatal mice.

This study aimed to evaluate the effects of maternal exercise on alterations induced by prenatal stress in markers of the inflammatory process and the hypothalamic-pituitary-adrenal axis in the brain and lungs of neonatal mice. Female Balb/c mice were divided into three groups: control, prenatal restraint stress, prenatal restraint stress and physical exercise before and during the gestational period. On day 0 (PND0) and 10 (PND10), mice were euthanized for brain and lung analyses. The gene expression of GR, MR, IL-6, IL-10, and TNF in the brain and lungs and the protein expression of MMP-2 in the lungs were analyzed. Maternal exercise reduced IL-6 and IL-10 gene expression in the brain of PND0 mice. Prenatal stress and maternal exercise decreased GR, MR, IL-6, and TNF gene expression in the lungs of PND0 mice. In the hippocampus of PND10 females, exercise inhibited the effects of prenatal stress on the expression of MR, IL-6, and IL-10. In the lungs of PND10 females, exercise prevented the decrease in GR expression caused by prenatal stress. In the hippocampus and lungs of PND10 males, prenatal stress decreased GR gene expression. Our findings confirm the effects induced by prenatal stress and demonstrate that physical exercise before and during the gestational period may have a protective role on inflammatory changes.

Prone restraint cardiac arrest in in-custody and arrest-related deaths.

We postulate that most atraumatic deaths during police restraint of subjects in the prone position are due to prone restraint cardiac arrest (PRCA), rather than from restraint asphyxia or a stress-induced cardiac condition, such as excited delirium. The prone position restricts ventilation and diminishes pulmonary perfusion. In the setting of a police encounter, metabolic demand will be high from anxiety, stress, excitement, physical struggle, and/or stimulant drugs, leading to metabolic acidosis and requiring significant hyperventilation. Although oxygen levels may be maintained, prolonged restraint in the prone position may result in an inability to adequately blow off CO2 , causing blood pCO2 levels to rise rapidly. The uncompensated metabolic acidosis (low pH) will eventually result in loss of myocyte contractility. The initial electrocardiogram rhythm will generally be either pulseless electrical activity (PEA) or asystole, indicating a noncardiac etiology, more consistent with PRCA and inconsistent with a primary role of any underlying cardiac pathology or stress-induced cardiac etiology. We point to two animal models: in one model rats unable to breathe deeply due to an external restraint die when their metabolic demand is increased, and in the other model, pressure on the chest of rats results in decreased venous return and cardiac arrest rather than death from asphyxia. We present two cases of subjects restrained in the prone position who went into cardiac arrest and had low pHs and initial PEA cardiac rhythms. Our cases demonstrate the danger of prone restraint and serve as examples of PRCA.