Association of Chartered Physiotherapists in Respiratory Care scoping review: Post-operative physiotherapy in people undergoing thoracic surgery

Introduction This scoping review was produced by the ACPRC editorial board. Following a preliminary scoping day, surgery was considered 1 of 5 key priorities for review. Surgery was subsequently separated into specialities. Objective The objective of this scoping review was to report the extent and methodological type of evidence associated with post-operative physiotherapy in people who underwent thoracic surgery. Inclusion criteria Studies with adult patients undergoing thoracic surgery and published between 2014 and 2020 were included. The thoracic procedure undertaken required post-operative physiotherapy intervention as part of the recovery process. Method Searches were undertaken in PEDro, CINAHL, EMBASE, MEDLINE, PubMed, Google Scholar and the Clinical Trials Registry. Article titles and abstracts were screened by one reviewer, and full text articles appraised by two reviewers. Quality was assessed and data was extracted using the relevant tools dependent on study methodology. Results Initially, 1809 articles were retrieved from which 28 articles were included in this scoping review, including a total of 6265 participants. Studies were randomised control trials (n = 10), observational studies (n = 7) and systematic review or meta-analysis (n = 5). The quality of the articles was good with the studies having structured protocols and blinding of subjects where appropriate, however there were some methodical flaws, including being underpowered. The variability in clinical physiotherapy practice between countries was highlighted. Included studies explored respiratory physiotherapy (n = 13), mobilisation (n = 10), combined respiratory and mobilisation (n = 3), kinesiology taping (n = 1) and outcomes (n = 1). Early and intensive mobilisation as part of an ERAS programme demonstrated statistically significant reduction in length of stay, post-operative pulmonary complications, and morbidity. The level of patients’ pre-operative mobility impacted on their post-operative outcomes and risk of developing post-operative pulmonary complications (PPC). Conclusion The scoping review included 28 studies with a range of methodologies providing evidence that supports post-operative physiotherapy intervention in people who undergo thoracic surgery. Future research should aim to clarify which respiratory physiotherapy techniques impact recovery and expand the diversity of methodologies to include more qualitative research

Association of Chartered Physiotherapists in Respiratory Care scoping review: Post-operative physiotherapy in people undergoing thoracic surgery

Introduction This scoping review was produced by the ACPRC ed- itorial board. Following a preliminary scoping day, surgery was considered 1 of 5 key priorities for review. Surgery was subsequently separated into specialities. Objective The objective of this scoping review was to report the extent and methodological type of evidence associ- ated with post-operative physiotherapy in people who underwent thoracic surgery. Inclusion criteria Studies with adult patients undergoing thoracic sur- gery and published between 2014 and 2020 were in- cluded. The thoracic procedure undertaken required post-operative physiotherapy intervention as part of the recovery process. Method Searches were undertaken in PEDro, CINAHL, EM- BASE, MEDLINE, PubMed, Google Scholar and the Clinical Trials Registry. Article titles and abstracts were screened by one reviewer, and full text articles appraised by two reviewers. Quality was assessed and data was extracted using the relevant tools dependent on study methodology. Results Initially, 1809 articles were retrieved from which 28 articles were included in this scoping review, including a total of 6265 participants. Studies were randomised control trials (n = 10), observational studies (n = 7) and systematic review or meta-analysis (n = 5). The quality of the articles was good with the studies having structured protocols and blinding of sub- jects where appropriate, however there were some methodical flaws, including being underpowered. The variability in clinical physiotherapy practice be- tween countries was highlighted. Included studies explored respiratory physiotherapy (n = 13), mobilisation (n = 10), combined respiratory and mobilisation (n = 3), kinesiology taping (n = 1) and outcomes (n = 1). Early and intensive mobilisation as part of an ERAS programme demonstrated statistically significant reduction in length of stay, post-operative pulmonary complications, and morbidity. The level of patients’ pre-operative mobility impacted on their post-operative outcomes and risk of developing post-operative pulmonary complications (PPC). Conclusion The scoping review included 28 studies with a range of methodologies providing evidence that supports post-operative physiotherapy intervention in people who undergo thoracic surgery. Future research should aim to clarify which respiratory physiotherapy tech- niques impact recovery and expand the diversity of methodologies to include more qualitative research

Coordination by Cdc42 of actin, contractility, and adhesion for melanoblast movement in mouse skin

YesThe individual molecular pathways downstream of Cdc42, Rac, and Rho GTPases are well documented, but we know surprisingly little about how these pathways are coordinated when cells move in a complex environment in vivo. In the developing embryo, melanoblasts originating from the neural crest must traverse the dermis to reach the epidermis of the skin and hair follicles. We previously established that Rac1 signals via Scar/WAVE and Arp2/3 to effect pseudopod extension and migration of melanoblasts in skin. Here we show that RhoA is redundant in the melanocyte lineage but that Cdc42 coordinates multiple motility systems independent of Rac1. Similar to Rac1 knockouts, Cdc42 null mice displayed a severe loss of pigmentation, and melanoblasts showed cell-cycle progression, migration, and cytokinesis defects. However, unlike Rac1 knockouts, Cdc42 null melanoblasts were elongated and displayed large, bulky pseudopods with dynamic actin bursts. Despite assuming an elongated shape usually associated with fast mesenchymal motility, Cdc42 knockout melanoblasts migrated slowly and inefficiently in the epidermis, with nearly static pseudopods. Although much of the basic actin machinery was intact, Cdc42 null cells lacked the ability to polarize their Golgi and coordinate motility systems for efficient movement. Loss of Cdc42 de-coupled three main systems: actin assembly via the formin FMNL2 and Arp2/3, active myosin-II localization, and integrin-based adhesion dynamics.Cancer Research UK (to L.M.M. [A17196], R.H.I. [A19257], and S.W.G.T.) and NIH grants P01-GM103723 and P41-EB002025 (to K.M.H.). N.R.P. is supported by a Pancreatic Cancer Research Fund grant (to L.M.M.). Funding to Prof. Rottner by the Deutsche Forschungsgemeinschaft (grant RO2414/3-2)

Delayed mucosal anti-viral responses despite robust peripheral inflammation in fatal COVID-19

Background While inflammatory and immune responses to SARS-CoV-2 infection in peripheral blood are extensively described, responses at the upper respiratory mucosal site of initial infection are relatively poorly defined. We sought to identify mucosal cytokine/chemokine signatures that distinguished COVID-19 severity categories, and relate these to disease progression and peripheral inflammation. Methods We measured 35 cytokines and chemokines in nasal samples from 274 patients hospitalised with COVID-19. Analysis considered the timing of sampling during disease, as either the early (0-5 days post-symptom onset) or late (6-20 days post-symptom onset). Results Patients that survived severe COVID-19 showed IFN-dominated mucosal immune responses (IFN-γ, CXCL10 and CXCL13) early in infection. These early mucosal responses were absent in patients that would progress to fatal disease despite equivalent SARS-CoV-2 viral load. Mucosal inflammation in later disease was dominated by IL-2, IL-10, IFN-γ, and IL-12p70, which scaled with severity but did not differentiate patients who would survive or succumb to disease. Cytokines and chemokines in the mucosa showed distinctions from responses evident in the peripheral blood, particularly during fatal disease. Conclusions Defective early mucosal anti-viral responses anticipate fatal COVID-19 but are not associated with viral load. Early mucosal immune responses may define the trajectory of severe COVID-19

Viral coinfections in hospitalized coronavirus disease 2019 patients recruited to the international severe acute respiratory and emerging infections consortium WHO clinical characterisation protocol UK study

Background We conducted this study to assess the prevalence of viral coinfection in a well characterized cohort of hospitalized coronavirus disease 2019 (COVID-19) patients and to investigate the impact of coinfection on disease severity. Methods Multiplex real-time polymerase chain reaction testing for endemic respiratory viruses was performed on upper respiratory tract samples from 1002 patients with COVID-19, aged <1 year to 102 years old, recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK study. Comprehensive demographic, clinical, and outcome data were collected prospectively up to 28 days post discharge. Results A coinfecting virus was detected in 20 (2.0%) participants. Multivariable analysis revealed no significant risk factors for coinfection, although this may be due to rarity of coinfection. Likewise, ordinal logistic regression analysis did not demonstrate a significant association between coinfection and increased disease severity. Conclusions Viral coinfection was rare among hospitalized COVID-19 patients in the United Kingdom during the first 18 months of the pandemic. With unbiased prospective sampling, we found no evidence of an association between viral coinfection and disease severity. Public health interventions disrupted normal seasonal transmission of respiratory viruses; relaxation of these measures mean it will be important to monitor the prevalence and impact of respiratory viral coinfections going forward

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570