Does adding exercise or physical activity to pharmacological osteoporosis therapy in patients with increased fracture risk improve bone mineral density and lower fracture risk? A systematic review and meta-analysis.

This prospectively registered systematic review and meta-analysis examines whether exercise (EX) training has an additive effect to osteoanabolic and/or antiresorptive pharmacological therapy (PT) in people with osteoporosis on bone mineral density (BMD), bone turnover markers (BTMs), fracture healing, and fractures. Four databases (inception to 6 May 2022), 5 trial registries, and reference lists were searched. Included were randomized controlled trials comparing the effect of EX + PT vs. PT with regard to BMD, BTM, fracture healing, and fractures. Risk of bias was assessed using the Cochrane RoB2 and certainty of evidence by the GRADE approach. Random-effects meta-analysis with Hartung-Knapp-Sidik-Jonkman adjustment was used to estimate standardized mean differences and 95% confidence intervals. Out of 2593 records, five RCTs with 530 participants were included. Meta-analysis showed with very low certainty evidence and wide confidence intervals that EX + PT compared to PT had larger effect sizes for BMD at 12 months at the hip (SMD [95%CI]: 0.18 [- 1.71; 2.06], n = 3 studies), tibia (0.25 [- 4.85; 5.34], n = 2), lumbar spine (0.20 [- 1.15; 1.55], n = 4), and forearm (0.05 [- 0.35; 0.46], n = 3), but not femoral neck (- 0.03 [- 1.80; 1.75], n = 3). Furthermore, no improvement was revealed for BTM such as bone ALP (- 0.68 [- 5.88; 4.53], n = 3), PINP (- 0.74 [- 10.42; 8.93], n = 2), and CTX-I (- 0.69 [- 9.61; 8.23], n = 2), but with very wide confidence intervals. Three potentially relevant ongoing trials were identified via registries. No data were found for fracture healing or fracture outcomes. It remains unclear whether EX has an additive impact to PT in people with osteoporosis. High-quality, adequately powered, targetted RCTs are required. PROTOCOL REGISTRATION: PROSPERO CRD42022336132.

Trends in fetal and neonatal outcomes during the COVID-19 pandemic in Alabama.

BACKGROUND: The current study evaluated the hypothesis that the COVID-19 pandemic is associated with higher stillbirth but lower neonatal mortality rates. METHODS: We compared three epochs: baseline (2016-2019, January-December, weeks 1-52, and 2020, January-February, weeks 1-8), initial pandemic (2020, March-December, weeks 9-52, and 2021, January-June, weeks 1-26), and delta pandemic (2021, July-September, weeks 27-39) periods, using Alabama Department of Public Health database including deliveries with stillbirths ≥20 weeks or live births ≥22 weeks gestation. The primary outcomes were stillbirth and neonatal mortality rates. RESULTS: A total of 325,036 deliveries were included (236,481 from baseline, 74,076 from initial pandemic, and 14,479 from delta pandemic period). The neonatal mortality rate was lower in the pandemic periods (4.4 to 3.5 and 3.6/1000 live births, in the baseline, initial, and delta pandemic periods, respectively, p < 0.01), but the stillbirth rate did not differ (9 to 8.5 and 8.6/1000 births, p = 0.41). On interrupted time-series analyses, there were no significant changes in either stillbirth (p = 0.11 for baseline vs. initial pandemic period, and p = 0.67 for baseline vs. delta pandemic period) or neonatal mortality rates (p = 0.28 and 0.89, respectively). CONCLUSIONS: The COVID-19 pandemic periods were not associated with a significant change in stillbirth and neonatal mortality rates compared to the baseline period. IMPACT: The COVID-19 pandemic could have resulted in changes in fetal and neonatal outcomes. However, only a few population-based studies have compared the risk of fetal and neonatal mortality in the pandemic period to the baseline period. This population-based study identifies the changes in fetal and neonatal outcomes during the initial and delta COVID-19 pandemic period as compared to the baseline period. The current study shows that stillbirth and neonatal mortality rates were not significantly different in the initial and delta COVID-19 pandemic periods as compared to the baseline period.

Comparison of the temperature changes in pulp using monophasic light-emitting diode curing unit at different exposure times: An in vivo study.

INTRODUCTION: This in vivo study evaluated the temperature changes in the pulp chamber at different exposure times using a monophasic light-emitting diode curing unit. METHODS: Forty-five patients (aged 13-25 years) requiring extraction of maxillary first premolars for orthodontic reasons were included in the study. After access opening, the temperature rise was recorded when exposed to monophasic light-emitting diode curing light (Elipar 3M ESPE; Pymble, New South Wales, Australia) at 5, 10, 15, and 20 seconds with K-type thermocouple probe. Teeth were atraumatically extracted on the same day. The results were analyzed with an analysis of variance and the Bonferroni test. RESULTS: There was a significant increase of 2.1°C ± 0.5°C of pulpal temperature in the maxillary first premolar tooth during exposure to a light curing unit from baseline to 20 seconds. The mean baseline temperature was 35.7°C ± 0.52°C. The highest mean temperature was recorded at 20 seconds (37.8°C ± 0.57°C), and the lowest mean temperature was recorded at 5 seconds (36.1°C ± 0.61°C). There were significant differences among each group (P <0.001) with a mean increase in pulpal temperature from baseline to exposure mode of 5, 10, 15, and 20 seconds. CONCLUSIONS: The study results reveal a statistically significant increase in pulpal temperature with a monophasic curing light, which can be used for up to 20 seconds without causing any detrimental effects on the pulp.

A narrative review of the training structure, role, and safety profile of advanced critical care practitioners in adult intensive services in the United Kingdom.

OBJECTIVE: Advanced clinical practitioners are a growing part of the National Health Service workforce in the United Kingdom (UK). The concept stems from the progression of skills, knowledge, and experience of healthcare professionals (including nursing, physiotherapists, paramedics, and pharmacists) to a higher level of practice. The addition of advanced critical care practitioners (ACCPs) to the multidisciplinary team of the UK adult critical care is recent; they form part of the fabric of the advanced clinical practitioner workforce. This is a narrative review of the role of ACCPs, considering the evolution of the role, training, accreditation, and evidence supporting the safety profile in adult intensive care in the UK. METHOD: This is a narrative review. CONCLUSION: ACCPs have evolved from an ad hoc and local training structure, to a UK-wide competency standard and training developed within the Faculty of Intensive Care Medicine. This formed in concert with the advanced clinical practitioner concept. As advanced practice is very much multiprofessional in the UK, a single regulator for multiple base professions is likely neither feasible nor realistic. Over the last 5 years, the UK picture of advanced practice has slowly standardised; an ACCP securely fits under the advanced clinical practitioner umbrella. The ACCP workforce has moved from a handful of early adopters, regional hubs, to a position across most critical care units now have or are developing a team of practitioners. The evidence base for the safety profile of ACCPs is evolving and shows parity in outcomes in the areas currently investigated. The ACCP role provides a vision of a multiprofessional workforce for the future of staffing of critical care services that is diverse and inclusive, not with the intention of competing with our medical colleagues.

Cervical spine and muscle adaptation after spaceflight and relationship to herniation risk: protocol from 'Cervical in Space' trial.

BACKGROUND: Astronauts have a higher risk of cervical intervertebral disc herniation. Several mechanisms have been attributed as causative factors for this increased risk. However, most of the previous studies have examined potential causal factors for lumbar intervertebral disc herniation only. Hence, we aim to conduct a study to identify the various changes in the cervical spine that lead to an increased risk of cervical disc herniation after spaceflight. METHODS: A cohort study with astronauts will be conducted. The data collection will involve four main components: a) Magnetic resonance imaging (MRI); b) cervical 3D kinematics; c) an Integrated Protocol consisting of maximal and submaximal voluntary contractions of the neck muscles, endurance testing of the neck muscles, neck muscle fatigue testing and questionnaires; and d) dual energy X-ray absorptiometry (DXA) examination. Measurements will be conducted at several time points before and after astronauts visit the International Space Station. The main outcomes of interest are adaptations in the cervical discs, muscles and bones. DISCUSSION: Astronauts are at higher risk of cervical disc herniation, but contributing factors remain unclear. The results of this study will inform future preventive measures for astronauts and will also contribute to the understanding of intervertebral disc herniation risk in the cervical spine for people on Earth. In addition, we anticipate deeper insight into the aetiology of neck pain with this research project. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00026777. Registered on 08 October 2021.

Advanced airway management and drug-assisted intubation skills in an advanced critical care practitioner team.

INTRODUCTION: Airway management, including endotracheal intubation, is one of the cornerstones of care of critically ill patients. Internationally, health professionals from varying backgrounds deliver endotracheal intubation as part of their critical care role. This article considers the development of airway management skills within a single advanced critical care practitioner (ACCP) team and uses case series data to analyse the safety profile in performing this aspect of critical care. Skills were acquired during and after the ACCP training pathway. A combination of theoretical teaching, theatre experience, simulation and work-based practice was used. Case series data of all critical care intubations by ACCPs were collected. Audit results: Data collection identified 675 intubations carried out by ACCPs, 589 of those being supervised, non-cardiac arrest intubations requiring drugs. First pass success was achieved in 89.6% of cases. A second intubator was required in 4.3% of cases. Some form of complication was experienced by 42.3% of patients; however, the threshold for complications was set at a low level. CONCLUSIONS: This ACCP service developed a process to acquire advanced airway management skills including endotracheal intubation. Under medical supervision, ACCPs delivered advanced airway management achieving a first pass success rate of 89.6%, which compares favourably with both international and national success rates. Although complications were experienced in 48.3% of patients, when similar complication cut-offs are compared with published data, ACCPs also matched favourably.

Visiting and Communication Policy in Intensive Care Units during COVID-19 Pandemic: A Cross-sectional Survey from South Asia and the Middle East.

Purpose: The coronavirus disease-2019 (COVID-19) pandemic had affected the visiting or communicating policies for family members. We surveyed the intensive care units (ICUs) in South Asia and the Middle East to assess the impact of the COVID-19 pandemic on visiting and communication policies. Materials and method: A web-based cross-sectional survey was used to collect data between March 22, 2021, and April 7, 2021, from healthcare professionals (HCP) working in COVID and non-COVID ICUs (one response per ICU). The topics of the questionnaire included current and pre-pandemic policies on visiting, communication, informed consent, and end-of-life care in ICUs. Results: A total of 292 ICUs (73% of COVID ICUs) from 18 countries were included in the final analysis. Most (92%) of ICUs restricted their visiting hours, and nearly one-third (32.3%) followed a "no-visitor" policy. There was a significant change in the daily visiting duration in COVID ICUs compared to the pre-pandemic times (p = 0.011). There was also a significant change (p <0.001) in the process of informed consent and end-of-life discussions during the ongoing pandemic compared to pre-pandemic times. Conclusion: Visiting and communication policies of the ICUs had significantly changed during the COVID-19 pandemic. Future studies are needed to understand the sociopsychological and medicolegal implications of revised policies. How to cite this article: Chanchalani G, Arora N, Nasa P, Sodhi K, Al Bahrani MJ, Al Tayar A, et al. Visiting and Communication Policy in Intensive Care Units during COVID-19 Pandemic: A Cross-sectional Survey from South Asia and the Middle East. Indian J Crit Care Med 2022;26(3):268-275.

ISCCM Guidelines on Acute Kidney Injury and Renal Replacement Therapy.

Acute kidney injury (AKI) is a complex syndrome with a high incidence and considerable morbidity in critically ill patients. Renal replacement therapy (RRT) remains the mainstay of treatment for AKI. There are at present multiple disparities in uniform definition, diagnosis, and prevention of AKI and timing of initiation, mode, optimal dose, and discontinuation of RRT that need to be addressed. The Indian Society of Critical Care Medicine (ISCCM) AKI and RRT guidelines aim to address the clinical issues pertaining to AKI and practices to be followed for RRT, which will aid the clinicians in their day-to-day management of ICU patients with AKI. How to cite this article: Mishra RC, Sodhi K, Prakash KC, Tyagi N, Chanchalani G, Annigeri RA, et al. ISCCM Guidelines on Acute Kidney Injury and Renal Replacement Therapy. Indian J Crit Care Med 2022;26(S2):S13-S42.

Comparing Nasopharyngeal and Midturbinate Nasal Swab Testing for the Identification of Severe Acute Respiratory Syndrome Coronavirus 2.

Testing of paired midturbinate (MT) nasal and nasopharyngeal (NP) swabs, collected by trained personnel from 40 patients with coronavirus disease 2019 (COVID-19), showed that more NP (76/95 [80%]) than MT swabs tested positive (61/95 [64%]) (P = .02). Among samples collected a week after study enrollment, fewer MT than NP samples were positive (45% vs 76%; P = .001).

Clinical characteristic and epidemiological features of SARS CoV -2 disease patients from a COVID 19 designated Hospital in New Delhi.

SARS CoV -2 infection is rapidly evolving as a serious global pandemic. The present study describes the clinical characteristics of SARS CoV-2 infection patients. The Samples were subjected to RT - PCR or Rapid Antigen test for diagnosis of SARS CoV- 2. A cohort of 3745 patients with confirmed diagnosis of SARS CoV -2 infection in a tertiary care center in New Delhi, India were included in this study. Data was collected from offline and online medical records over a period of six months. Amongst 3745 SARS CoV -2 infected patients, 2245 (60%) were symptomatic and 1500 (40%) were asymptomatic. Most common presenting symptom was cough (49.3%) followed febrile episodes (47.1%), breathlessness (42.7%) and sore throat (35.1%). Cough along with breathlessness (24.1) was the most common combination of symptoms followed by fever with cough (22.7). The most common comorbidity found among symptomatic group was diabetes (42.5%) followed by hypertension (21.4%) and chronic kidney disease (18%). Comorbidities like diabetes mellitus, chronic diseases of lungs, heart and kidneys were found to be common in symptomatic group and this was found to be statistically significant (p<0.05). COVID-19 is an evolving disease and data from our study help in understanding the clinic-epidemiological profile of patients. This article is protected by copyright. All rights reserved.

Evaluation of the safety of inter-hospital transfers of critically ill patients led by advanced critical care practitioners.

INTRODUCTION: Ten thousand inter-hospital transfers of critically ill adults take place annually in the UK. Studies highlight deficiencies in experience and training of staff, equipment, stabilisation before departure, and logistical difficulties. This article is a quality improvement review of an advanced critical care practitioner (ACCP)-led inter-hospital transfer service. METHODS: The tool Standards for Quality Improvement Reporting Excellence was used as the format for the review, combined with clinical audit of advanced critical care practitioner-led transfers over a period of more than 3 years. RESULTS: The transfer service has operated for 8 years; ACCPs conducted 934 critical care transfers of mechanically ventilated patients, including 286 inter-hospital transfers, between January 2017 and September 2020. The acuity of transfer patients was high, 82.2% required support of more than one organ, 49% required more than 50% oxygen. Uneventful transfer occurred in 81.4% of cases; the most common patient-related complication being hypotension, logistical issues were responsible for half of the complications. CONCLUSION: This quality improvement project provides an example of safe and effective advanced practice in an area that is traditionally a medically led domain. ACCPs can provide an alternative process of care for critically ill adults who require external transfer, and a benchmark for audit and quality improvement.

Organotypic models of type III interferon-mediated protection from Zika virus infections at the maternal-fetal interface.

Protecting the fetus from the hematogenous spread of viruses requires multifaceted layers of protection and relies heavily on trophoblasts, the fetal-derived cells that comprise the placental barrier. We showed previously that trophoblasts isolated from full-term placentas resist infection by diverse viruses, including Zika virus (ZIKV), and transfer this resistance to nonplacental cells through the activity of paracrine effectors, including the constitutive release of type III interferons (IFNs). Here, we developed 3D cell-line-based models of human syncytiotrophoblasts, cells that lie in direct contact with maternal blood, and show that these cells recapitulate the antiviral properties of primary trophoblasts through the constitutive release of type III IFNs (IFNλ1 and IFNλ2) and become resistant to ZIKV infection. In addition, using organotypic human midgestation chorionic villous explants, we show that syncytiotrophoblasts isolated from the second trimester of pregnancy also constitutively release type III IFNs and use these IFNs in autocrine and paracrine manners to restrict ZIKV infection. Collectively, these data provide important insights into the defense mechanisms used by syncytiotrophoblasts at various stages of human gestation to resist ZIKV infection and new human models to study the role of type III IFNs in the vertical transmission of ZIKV and other viruses associated with congenital disease.

A Retrospective Analysis of Pulp Stones in Patients following Orthodontic Treatment.

AIM: The present study aimed to find prevalence of pulp stones in known South Indian orthodontic patients and to find correlation between pulp stones and patients who underwent orthodontic treatment as well as to reveal any differences due to gender, tooth type, and dental arches. MATERIALS AND METHODS: The present retrospective study was carried out among 200 patients who underwent nonextraction orthodontic treatment. Maxillary and mandibular first and second premolar and molar teeth were selected for the purpose of the study using panoramic radiographs. A total of 3200 teeth of 200 patients were studied for the presence of pulp stones. Statistical analysis of the obtained data was carried out using Statistical Package for Social the Sciences (SPSS) version 22.0. Chi-square test was applied to find the significant value and p < 0.05 was considered as a significant value. RESULTS: In all, 11.5% of cases reported pulp stones before the commencement of the orthodontic treatment and 15.5% cases after completion of orthodontic treatment. Overall, 4% increase in cases were found which was statistically significant (p < 0.05); 5.1% of total number of teeth were evaluated in both arches before orthodontic treatment and 6.3% of teeth after orthodontic treatment revealed the presence of pulp stones. Maxillary first molar was found to be teeth with maximum number of pulp stones before and after orthodontic treatment. CONCLUSION: The present study reported the prevalence of pulp stones to be increased by 4% in the pre- and posttreat-ment radiographs, which was statistically significant. The study found the presence of pulp stones more in maxillary first molar and it was found to be teeth with maximum number of pulp stones before and after orthodontic treatment. However, further researches with larger samples are advisable. CLINICAL SIGNIFICANCE: Dentists performing endodontic treatment among patients who have undergone orthodontic treatment should be aware about the increased chances of presence of pulp stones and thus to avoid hindrances encountered during extirpating the pulp, they should thoroughly study the radiographs beforehand.

A case of mistaken identity: are reactive oxygen species actually reactive sulfide species?

Stepwise one-electron reduction of oxygen to water produces reactive oxygen species (ROS) that are chemically and biochemically similar to reactive sulfide species (RSS) derived from one-electron oxidations of hydrogen sulfide to elemental sulfur. Both ROS and RSS are endogenously generated and signal via protein thiols. Given the similarities between ROS and RSS, we wondered whether extant methods for measuring the former would also detect the latter. Here, we compared ROS to RSS sensitivity of five common ROS methods: redox-sensitive green fluorescent protein (roGFP), 2', 7'-dihydrodichlorofluorescein, MitoSox Red, Amplex Red, and amperometric electrodes. All methods detected RSS and were as, or more, sensitive to RSS than to ROS. roGFP, arguably the "gold standard" for ROS measurement, was more than 200-fold more sensitive to the mixed polysulfide H2Sn(n = 1-8) than to H2O2 These findings suggest that RSS may be far more prevalent in intracellular signaling than previously appreciated and that the contribution of ROS may be overestimated. This conclusion is further supported by the observation that estimated daily sulfur metabolism and ROS production are approximately equal and the fact that both RSS and antioxidant mechanisms have been present since the origin of life, nearly 4 billion years ago, long before the rise in environmental oxygen 600 million years ago. Although ROS are assumed to be the most biologically relevant oxidants, our results question this paradigm. We also anticipate our findings will direct attention toward development of novel and clinically relevant anti-(RSS)-oxidants.

Spectrum of disease and outcome in children with symptomatic congenital cytomegalovirus infection.

OBJECTIVE: To evaluate differences in presentation and outcomes in children with symptomatic congenital cytomegalovirus (cCMV) identified on newborn screening (screened group) and those identified based on clinical findings at birth (referred group). STUDY DESIGN: Data on 178 infants with symptomatic cCMV were analyzed. Demographic characteristics, clinical and laboratory findings documented in the nursery, and sequelae data were compared between the screened and the referred groups using χ(2) or Fisher exact test. RESULTS: Two or more clinical findings were detected at birth in 91% of referred infants, and only 58% of screened infants (P < .001). Significantly more children in the referred group had hearing loss compared with screened infants (P = .009). Fifty-one percent of screened children were free of sequelae compared with only 28% of the referred group (P < .003). CONCLUSIONS: Infants with symptomatic cCMV identified based on clinical suspicion have more severe disease at birth and more commonly have sequelae than those identified on newborn screening. Inclusion of referral infants in many previous reports may have overestimated the severity of disease because of selection bias. Defining the complete spectrum of symptomatic disease due to cCMV and providing precise estimates of disease burden can only be gathered from large newborn screening studies.

Health needs of regional Australian children in out-of-home care.

AIM: This study aims to identify the health needs of children placed in out-of-home care in regional Queensland and to compare them with the needs of similar children in metropolitan Queensland. METHODS: Retrospective chart review and subsequent analysis of data from the first assessments of the children placed in care from January 2005 to April 2011. Health needs based on assessment recommendations were then compared with needs and recommendations from a similar clinic in metropolitan Brisbane. RESULTS: Two hundred thirty-nine first assessments were reviewed. The average number of health referrals arising out of each assessment was 2. 72% children were between 2 and 12 years of age and accounted for 76% of the health referrals made. The 10-13% of the children needed referrals for medical and surgical specialties, audiology, speech pathology, dental, and ophthalmology/optometry, each. A percentage of 30 needed ongoing paediatric care. The 15% needed immunisation catch up, 35% counselling and behaviour management, and 15% formal mental health referrals. These were comparable to the health needs identified in out-of-home care children residing in metropolitan Queensland. CONCLUSION: Children in care who live in a regional setting have similar health-care needs compared with urban children. Given restricted health services in regional settings, there is difficulty in accessing services to meet these needs.

Effect of Aligning Forces by Two Preadjusted Edgewise Techniques on a Buccally Positioned Maxillary Canine at Varying Vertical Displacements: A Finite Element Study.

Objective: To evaluate the effect of continuous arch and piggyback mechanics in a straight wire appliance (SWA) for the alignment of buccal and variably vertically positioned maxillary canines. Methods: A three-dimensional finite element model with near-normal occlusion and buccal and vertically displaced maxillary canines was used. Two groups were created to simulate two commonly used SWAs techniques, continuous archwire (Group 1) and piggyback models (Group 2). Each group had three subgroups with varying vertical displacement of the canine from 2 to 6 mm from the occlusal plane. The displacement and stress distribution were noted in each group. Results: As the vertical displacement increased in Group 1, the concentration of von Mises stress increased progressively at the incisal third (0.36, 0.41 and 0.44 MPa) at 2, 4, and 6 mm, respectively, with decreased maximum occlusal movement in the vertical plane with respect to the canine. Group 2 exhibited a similar pattern but greater occlusal movement of the canine compared with Group 1. Conclusion: A vertical displacement of 4 mm is the optimal level at which continuous arch mechanics should be considered. For displacements beyond 4 mm, the piggyback wire technique is a suitable alternative.

The Impact of Exercise Prescription Variables on Intervention Outcomes in Musculoskeletal Pain: An Umbrella Review of Systematic Reviews.

BACKGROUND: Musculoskeletal pain conditions are the largest contributors to disability and healthcare burden globally. Exercise interventions improve physical function and quality of life in individuals with musculoskeletal pain, yet optimal exercise prescription variables (e.g. duration, frequency, intensity) are unclear. OBJECTIVE: We aimed to examine evidence gaps, methodological quality and exercise prescription recommendations in systematic reviews of exercise for musculoskeletal pain. METHODS: In our prospectively registered umbrella review, PubMed, SPORTDiscus, Cochrane Database of Systematic Reviews, EMBASE, and CINAHL were searched from inception to 14 February 2023. Backward citation tracking was performed. We included peer-reviewed, English language, systematic reviews and meta-analyses of randomized controlled trials (RCTs) and controlled clinical trials (CCTs) that compared exercise with conservative treatment, placebo or other exercise interventions in adults with musculoskeletal pain. Data were extracted from the following groups of reviews based on their reporting of exercise prescription data and analysis of the relationship between prescription variables and outcomes: (1) those that did not report any exercise prescription data, (2) those that reported exercise prescription data but did not perform a quantitative analysis and (3) those that performed a quantitative analysis of the relationship between exercise prescription variables and outcomes. Outcome measures were physical function, pain, mental health, adverse effects and adherence to treatment. AMSTAR-2 (A MeaSurement Tool to Assess systematic Reviews) was used to assess methodological quality. RESULTS: From 6757 records, 274 systematic reviews were included. 6.6% of reviews did not report any exercise prescription data, and only 10.9% quantitatively analyzed the relationship between prescription variables and the outcome(s). The overall methodological quality was critically low in 85% of reviews. CONCLUSION: High methodological quality evidence is lacking for optimal exercise training prescription variables in individuals with musculoskeletal pain. To better inform practice and evidence gaps, future systematic reviews should (1) identify optimum exercise prescription variables, for example, via dose-response (network) meta-analysis, (2) perform high-quality reviews per AMSTAR-2 criteria and (3) include outcomes of mental health, adverse events and exercise adherence. PROSPERO REGISTRATION NUMBER: CRD42021287440 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021287440 ).

Boosting treatment outcomes via the patient-practitioner relationship, treatment-beliefs or therapeutic setting. A systematic review with meta-analysis of contextual effects in chronic musculoskeletal pain.

OBJECTIVE: To ascertain whether manipulating contextual effects (e.g. interaction with patients, or beliefs about treatments) boosted the outcomes of non-pharmacological and non-surgicaltreatments for chronic primary musculoskeletal pain. DESIGN: Systematic review of randomized controlled trials. DATA SOURCES: We searched for trials in six databases, citation tracking, and clinical trials registers. We included trials that compared treatments with enhanced contextual effects with the same treatments without enhancement in adults with chronic primary musculoskeletal pain. DATA SYNTHESIS: The outcomes of interest were pain intensity, physical functioning, global ratings of improvement, quality of life, depression, anxiety, and sleep. We evaluated risk of bias and certainty of the evidence using Cochrane Risk of Bias tool 2.0 and the GRADE approach, respectively. RESULTS: Of 17637 records, we included 10 trials with 990 participants and identified 5 ongoing trials. The treatments were acupuncture, education, exercise training, and physical therapy. The contextual effects that were improved in the enhanced treatments were patient-practitioner relationship, patient beliefs and characteristics, therapeutic setting/environment, and treatment characteristics. Our analysis showed that improving contextual effects in non-pharmacological and non-surgical treatments may not make much difference on pain intensity (mean difference [MD] : -1.77, 95%-CI: [-8.71; 5.16], k = 7 trials, N = 719 participants, Scale: 0-100, GRADE: Low)) or physical functioning (MD: -0.27, 95%-CI: [-1.02; 0.49], 95%-PI: [-2.04; 1.51], k = 6 , N = 567, Scale: 0-10, GRADE: Low) in the short-term and at later follow-ups. Sensitivity analyses revealed similar findings. CONCLUSION: Whilst evidence gaps exist, per current evidence it may not be possible to achieve meaningful benefit for patients with chronic musculoskeletal pain by manipulating the context of non-pharmacological and non-surgical treatments. TRIAL REGISTRATION: This systematic review was prospectively registered in PROSPERO (registration number: CRD42023391601).

Inhibition of NFAT promotes loss of tissue resident uterine natural killer cells and attendant pregnancy complications in humans.

Uterine natural killer cells (uNKs) are a tissue resident lymphocyte population that are critical for pregnancy success. Although mouse models have demonstrated that NK deficiency results in abnormal placentation and poor pregnancy outcomes, the generalizability of this knowledge to humans remains unclear. Here we identify uterus transplant (UTx) recipients as a human population with reduced endometrial NK cells and altered pregnancy phenotypes. We further show that the NK reduction in UTx is due to impaired transcriptional programming of NK tissue residency due to blockade of the transcription factor nuclear factor of activated T cells (NFAT). NFAT-dependent genes played a role in multiple molecular circuits governing tissue residency in uNKs, including early residency programs involving AP-1 transcription factors as well as TGFß-mediated upregulation of surface integrins. Collectively, our data identify a previously undescribed role for NFAT in uterine NK tissue residency and provide novel mechanistic insights into the biologic basis of pregnancy complications due to alteration of tissue resident NK subsets in humans. One Sentence Summary: Role of NFAT in uterine NK cell tissue residency.