A systematic review of Clinical Practice Guidelines for the development of the WHO's Package of Interventions for Rehabilitation: focus on schizophrenia.

Background: The identification of interventions for rehabilitation and related evidence is a crucial step in the development of World Health Organization's (WHO) Package of Interventions for Rehabilitation (PIR). Interventions for rehabilitation may be particularly relevant in schizophrenia, as this condition is associated with a high risk of disability, poor functioning, and lack of autonomy. Aiming to collect evidence for the WHO PIR, we conducted a systematic review of Clinical Practice Guidelines (CPG) on interventions for rehabilitation of schizophrenia. Methods: Methods for the systematic identification and critical appraisal of CPG were developed by WHO Rehabilitation Programme and Cochrane Rehabilitation under the guidance of WHO's guideline review committee secretariat. The Appraisal of Guidelines for Research & Evaluation Instrument (AGREE II) was used to evaluate the methodological quality of identified CPG. Results: After full text screening, nine CPG were identified, for a total of 130 recommendations. Three were excluded because their total AGREE-II scores were below cut-off. Six CPG were approved by the Technical Working Group and included for data extraction. Only one CPG with specific focus on rehabilitation of schizophrenia was retrieved. Other CPG were general, including some recommendations on rehabilitation. Some CPG gave no indications on the assessment of rehabilitation needs. Discrepancies were detectable, with different CPG emphasizing different domains. Most recommendations addressed "symptoms of schizophrenia," while "community and social life" was targeted by few recommendations. International CPG were often conceptualized for high-income countries, and CPG accounting for their implementation in lower income contexts were scarce. Quality of evidence was high/moderate for 41.54% (n = 54) of the recommendations, and very low only in two cases (1.52%). N = 45 (34.62%) were based on experts' opinion. Conclusions: The concepts of recovery and rehabilitation in schizophrenia are relatively new in medical sciences and somewhat ill-defined. An unbalanced distribution in the domains addressed by available CPG is therefore understandable. However, the need for more focus in some areas of rehabilitation is obvious. More clarity is also required regarding which interventions should be prioritized and which are more feasible for global implementation in the rehabilitation of schizophrenia.

Nrf2 as a therapeutic target in acetaminophen hepatotoxicity: A case study with sulforaphane.

Acetaminophen (APAP) overdose can cause severe liver injury and acute liver failure. The only clinically approved antidote, N-acetylcysteine (NAC), is highly effective but has a narrow therapeutic window. In the last 2 decades, activation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), which regulates acute phase proteins and antioxidant defense genes, has emerged as a putative new therapeutic target against APAP hepatotoxicity. However, virtually all studies that propose Nrf2 activation as mechanism of protection used prolonged pretreatment, which is not a clinically feasible approach to treat a drug overdose. Therefore, the objective of this study was to assess if therapeutic activation of Nrf2 is a viable approach to treat liver injury after APAP overdose. We used the water-soluble Nrf2 activator sulforaphane (SFN; 5 mg/kg) in a murine model of APAP hepatotoxicity (300 mg/kg). Our results indicate that short-term treatment (≤3 h) with SFN alone did not activate Nrf2 or its target genes. However, posttreatment with SFN after APAP partially protected at 6 h likely due to more rapid activation of the Nrf2-target gene heme oxygenase-1. A direct comparison of SFN with NAC given at 1 h after APAP showed a superior protection with NAC, which was maintained at 24 h unlike with SFN. Thus, Nrf2 activators have inherent problems like the need to create a cellular stress to activate Nrf2 and delayed adaptive responses which may hamper sustained protection against APAP hepatotoxicity. Thus, compared to the more direct acting antidote NAC, Nrf2 activators are less suitable for this indication.

Desorption Electrospray Ionization Mass Spectrometry Imaging Allows Spatial Localization of Changes in Acetaminophen Metabolism in the Liver after Intervention with 4-Methylpyrazole.

Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the US, and hepatotoxicity is initiated by a reactive metabolite which induces characteristic centrilobular necrosis. The only clinically available antidote is N-acetylcysteine, which has limited efficacy, and we have identified 4-methylpyrazole (4MP, Fomepizole) as a strong alternate therapeutic option, protecting against generation and downstream effects of the cytotoxic reactive metabolite in the clinically relevant C57BL/6J mouse model and in humans. However, despite the regionally restricted necrosis after APAP, our earlier studies on APAP metabolites in biofluids or whole tissue homogenate lack the spatial information needed to understand region-specific consequences of reactive metabolite formation after APAP overdose. Thus, to gain insight into the regional variation in APAP metabolism and study the influence of 4MP, we established a desorption electrospray ionization mass spectrometry imaging (DESI-MSI) platform for generation of ion images for APAP and its metabolites under ambient air, without chemical labeling or a prior coating of tissue which reduces chemical interference and perturbation of small molecule tissue localization. The spatial intensity and distribution of both oxidative and nonoxidative APAP metabolites were determined from mouse liver sections after a range of APAP overdoses. Importantly, exclusive differential signal intensities in metabolite abundance were noted in the tissue microenvironment, and 4MP treatment substantially influenced this topographical distribution.

A systematic review of clinical practice guidelines for persons with osteoarthritis. A "Best Evidence for Rehabilitation" (be4rehab) paper to develop the WHO's Package of Interventions for Rehabilitation: A systematic review of Clinical Practice Guidelines for persons with osteoarthritis for the identification of best evidence for rehabilitation.

AIM: Identifying existing interventions for rehabilitation and related evidence presents a crucial step in developing the World Health Organization's (WHO) Package of Interventions for Rehabilitation. This paper reports the results of a systematic search that aimed to identify clinical practice guidelines (CPGs) relevant to the rehabilitation of people with osteoarthritis and presents the CPG recommendations and the current state of evidence available for the interventions in the CPGs. METHODS: This paper is part of the "Best Evidence for Rehabilitation" (be4rehab) series, developed according to the methodology presented in the WHO's Package of Interventions for Rehabilitation introductory paper by Rauch et al, published in 2019. It is a systematic review of the existing CPGs on osteoarthritis published between 2009 and 2019. Identified CPGs were screened taking into consideration conflict of interest, the provision of information regarding the strength of recommendation(s), and quality to be selected. Quality of CPGs was assessed using the AGREE II tool. RESULTS: After title and abstract screening, 51 CPGs were identified. Considering the inclusion/exclusion criteria, 26 CPGs were selected. After checking for quality, comprehensiveness, multi-professionality, and publication date, five CPGs were finally included in the review. The strong recommendations for people with knee and hip osteoarthritis consistently included in all the selected CPGs, sometimes called "core treatments", were patient education, exercise training, and weight reduction if overweight or obese. Generally, recommendations overlap in the CPGs. CONCLUSION: The systematic search revealed high-quality CPGs on osteoarthritis for the identification of "Best Evidence for Rehabilitation (be4rehab)" regarding interventions for rehabilitation of people with osteoarthritis.

An Agent-based Model for Investigating the Effect of Myeloid-Derived Suppressor Cells and its Depletion on Tumor Immune Surveillance.

BACKGROUND: To predict the behavior of biological systems, mathematical models of biological systems have been shown to be useful. In particular, mathematical models of tumor-immune system interactions have demonstrated promising results in prediction of different behaviors of tumor against the immune system. METHODS: This study aimed at the introduction of a new model of tumor-immune system interaction, which includes tumor and immune cells as well as myeloid-derived suppressor cells (MDSCs). MDSCs are immune suppressor cells that help the tumor cells to escape the immune system. The structure of this model is agent-based which makes possible to investigate each component as a separate agent. Moreover, in this model, the effect of low dose 5-fluorouracil (5-FU) on MDSCs depletion was considered. RESULTS: Based on the findings of this study, MDSCs had suppressive effect on increment of immune cell number which consequently result in tumor cells escape the immune cells. It has also been demonstrated that low-dose 5-FU could help immune system eliminate the tumor cells through MDSCs depletion. CONCLUSION: Using this new agent-based model, multiple injection of low-dose 5-FU could eliminate MDSCs and therefore might have the potential to be considered in treatment of cancers.

Dual task cost of cognition is related to fall risk in patients with multiple sclerosis: a prospective study.

OBJECTIVE: To examine whether change in cognitive performance during dual task condition compared with a task in isolation, known as dual task cost, is related to fall risk of patients with multiple sclerosis. DESIGN: Prospective cohort. During baseline assessment, data about balance, walking and cognitive performance of patients with multiple sclerosis were collected under a single and dual task condition. The dual task cost was calculated as a percentage of change in parameters from single to dual task conditions. Falls were recorded prospectively for six months and participants were classified as none/one time fallers and recurrent fallers (⩾2 falls). The association between dual task costs and fall status was evaluated by logistic regression. SETTING: Balance research lab of university hospital. PARTICIPANTS: A total of 60 patients with relapsing-remitting multiple sclerosis. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The dual task cost of the center of pressure sway area, walking velocity and correct response rate were outcome measures for balance, walking and cognitive performance, respectively. RESULTS: A total of 79 falls were reported by 38 of the participants who experienced one or more falls; 26 (43.3%) of them had recurrent falls. Dual tasking resulted in increased sway area and decreased walking velocity and correct response rate during walking (all p values <0.05). Logistic regressions showed that the dual task cost of the correct response rate during walking and walking velocity were associated with increased risk of recurrent falls ( P = 0.02, odds ratio = 1.34; confidence interval (CI) 1.04-3.74; P = 0.05, odds ratio = 1.23, CI = 1.02-4.45, respectively). CONCLUSIONS: The dual task cost of cognition was related to fall, which should be considered as a target for falls evaluation and prevention strategies.

Balance recovery reactions in individuals with recurrent nonspecific low back pain: Effect of attention.

People who suffer from Low Back Pain (LBP) demonstrate impaired postural control. Deficits in sensory-motor systems have been proposed to be related to these changes. Considering higher cognitive process contribution to postural control, the aim of this study was to investigate the effects of cognitive load on balance control of patients with LBP. Twenty subjects with recurrent non-specific LBP and 20 healthy controls participated. They stood on a moveable platform with each foot placed on a separate force plate. They were asked to maintain their balance (a) while expecting translations of the support surface at two sizes of perturbation (b) with and without performing a cognitive (auditory Stroop) task. The outcomes included reaction time (RT), latency, initial velocity and amplitude of center of pressure response for balance, and RT for cognitive performance. Compared to the healthy group, LBP group demonstrated delayed RT and latency, and reduced initial velocity (P<0.05). Moreover, they had slower Stroop RT (F=70.88, P<0.001). Concurrent performance of tasks resulted in increased Stroop RT (F=3.42, P=0.03) and adaptation in initial velocity (F=6.70, P=0.01). At the smaller size of perturbation, cognitive load increased velocity in LBP group but decreased this variable in the healthy group. When the cognitive load was added at the larger size of perturbation, velocity of response decreased in LBP group (P<0.05). These findings imply altered cognitive regulation of dynamic balance in patients with LBP and suggest that the adopted strategy might alter depending upon the characteristics of the postural challenge.

Military exercises, knee and ankle joint position sense, and injury in male conscripts: a pilot study.

CONTEXT: The high incidence of lower limb injuries associated with physical exercises in military conscripts suggests that fatigue may be a risk factor for injuries. Researchers have hypothesized that lower limb injuries may be related to altered ankle and knee joint position sense (JPS) due to fatigue. OBJECTIVE: To evaluate if military exercises could alter JPS and to examine the possible relation of JPS to future lower extremity injuries in military service. DESIGN: Cohort study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 50 male conscripts (age = 21.4 ± 2.3 years, height = 174.5 ± 6.4 cm, mass = 73.1 ± 6.3 kg) from a unique military base were recruited randomly. main outcome measure(s): Participants performed 8 weeks of physical activities at the beginning of a military course. In the first part of the study, we instructed participants to recognize predetermined positions before and after military exercises so we could examine the effects of military exercise on JPS. The averages of the absolute error and the variable error of 3 trials were recorded. We collected data on the frequency of lower extremity injuries over 8 weeks. Next, the participants were divided into 2 groups: injured and uninjured. Separate 2 × 2 × 2 (group-by-time-by-joint) mixed-model analyses of variance were used to determine main effects and interactions of these factors for each JPS measure. In the second part of the study, we examined whether the effects of fatigue on JPS were related to the development of injury during an 8-week training program. We calculated Hedges effect sizes for JPS changes postexercise in each group and compared change scores between groups. RESULTS: We found group-by-time interactions for all JPS variables (F range = 2.86-4.05, P < .01). All participants showed increases in JPS errors postexercise (P < .01), but the injured group had greater changes for all the variables (P < .01). CONCLUSIONS: Military conscripts who sustained lower extremity injuries during an 8-week military exercise program had greater loss of JPS acuity than conscripts who did not sustain injuries. The changes in JPS found after 1 bout of exercise may have predictive ability for future musculoskeletal injuries.

Comparison of functional outcome measures after ACL reconstruction in competitive soccer players: a randomized trial.

BACKGROUND: The choice of graft for anterior cruciate ligament (ACL) reconstruction remains controversial. Although many outcome studies comparing bone-patellar tendon-bone and semitendinosus and gracilis tendon grafts have been performed, most have not included tests of functional outcomes that challenge the graft. The objective of the current study was to compare the functional performances of soccer players after ACL reconstruction that was performed with either a bone-patellar tendon-bone or a semitendinosus and gracilis tendon graft. METHODS: Forty-two soccer players with unilateral ACL injury were prospectively randomized to a bone-patellar tendon-bone group (BPTB group; twenty-one subjects) or a semitendinosus and gracilis tendon group (STG group; twenty-one subjects) and followed a rehabilitation protocol. At the time of return to sports, the patients were asked to execute strength, hop, and jump tests and the results were compared between the groups. Twenty-one healthy athletes were recruited as the control group to evaluate their performance of the same tests. RESULTS: The limbs with the ACL reconstruction in the STG group had greater values for quadriceps torque as well as on the triple-hop, crossover-hop, and jump-landing test (p < 0.01), but the STG and BPTB groups showed similar results in terms of hamstrings peak torque and the results of two other hop tests (p > 0.05). Moreover, the subjects with ACL reconstruction had significantly lower values with regard to quadriceps and hamstrings peak torques and the results of the hop and jump tests compared with the healthy athletes (p < 0.01). CONCLUSIONS: At the time of return to sports, the STG group had better performance in terms of quadriceps strength and the results of the triple-hop, crossover-hop, and jump-landing tests compared with the BPTB group. Compared with controls, soccer players who had undergone ACL reconstruction had less quadriceps and hamstrings strength and inferior hop performance and jump-landing strategy.