Guillain-Barré syndrome: History, pathogenesis, treatment, and future directions.

BACKGROUND AND PURPOSE: Since its description by Guillain, Barré, and Strohl in 1916, Guillain-Barré syndrome (GBS) has attracted a large literature. The author reviews the history of research into its pathogenesis and treatment to highlight promising avenues for future research. METHODS: This is a nonsystematic personal review. RESULTS: Since the early 1900s, the clinical picture of GBS has been illustrated in multiple series culminating in the ongoing International Guillain-Barré Syndrome study of 2000 patients. In the 1950s and 1960s, the inflammatory nature of the commonest form, acute inflammatory demyelinating polyradiculoneuropathy (AIDP), was described. In the 1990s, two axonal forms, acute motor-sensory axonal neuropathy and acute motor axonal neuropathy, were recognized. In the 1990s and early 2000s, these forms were shown to be due to antibodies against Campylobacter jejuni glycans cross-reacting with glycolipids on axonal membranes. The pathogenesis of AIDP remains unknown, but T-cell responses to the compact myelin proteins, P2 and P0, which cause experimental autoimmune neuritis, suggest that T cells are important. Randomized controlled trials in the 1970s and 1980s showed no benefit from corticosteroids. Trials in the 1980s showed benefit from plasma exchange and in the 1990s from intravenous immunoglobulin. CONCLUSIONS: Future research should seek biomarkers to identify subgroups with different treatment responses, define the true natural history of the disease with population-based epidemiological studies, study the pathology in autopsies early in the disease, seek causative antibodies and confirm autoimmune T-cell responses in AIDP, and expand treatment trials to include anti-T-cell agents.

Precision medicine analysis of heterogeneity in individual-level treatment response to amyloid beta removal in early Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a neurological disorder with variability in pathology and clinical progression. AD patients may differ in individual-level benefit from amyloid beta removal therapy. METHODS: Random forest models were applied to the EMERGE trial to create an individual-level treatment response (ITR) score which represents individual-level benefit of high-dose aducanumab relative to the placebo. This ITR score was used to test the existence of heterogeneity in treatment effect (HTE). RESULTS: We found statistical evidence of HTE in the Clinical Dementia Rating-Sum of Boxes (CDR-SB;P =  0.034). The observed CDR-SB benefit was 0.79 points greater in the group with the top 25% of ITR score compared to the remaining 75% (P = 0.020). Of note, the highest treatment responders had lower hippocampal volume, higher plasma phosphorylated tau 181 and a shorter duration of clinical AD at baseline. DISCUSSION: This ITR analysis provides a proof of concept for precision medicine in future AD research and drug development. HIGHLIGHTS: Emerging trials have shown a population-level benefit from amyloid beta (Aß) removal in slowing cognitive decline in early Alzheimer's disease (AD). This work demonstrates significant heterogeneity of individual-level treatment effect of aducanumab in early AD. The greatest clinical responders to Aß removal therapy have a pattern of more severe neurodegenerative process.

An innovative phase 2 proof-of-concept trial design to evaluate SAR445088, a monoclonal antibody targeting complement C1s in chronic inflammatory demyelinating polyneuropathy.

BACKGROUND AND AIMS: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated disease of the peripheral nerves, with significant unmet treatment needs. Clinical trials in CIDP are challenging; thus, new trial designs are needed. We present design of an open-label phase 2 study (NCT04658472) evaluating efficacy and safety of SAR445088, a monoclonal antibody targeting complement C1s, in CIDP. METHODS: This phase 2, proof-of-concept, multicenter, open-label trial will evaluate the efficacy, and safety of SAR445088 in 90 patients with CIDP across three groups: (1) currently treated with standard-of-care (SOC) therapies, including immunoglobulin or corticosteroids (SOC-Treated); (2) refractory to SOC (SOC-Refractory); and (3) naïve to SOC (SOC-Naïve). Enrolled participants undergo a 24-week treatment period (part A), followed by an optional treatment extension for up to an additional 52 weeks (part B). In part A, the primary endpoint for the SOC-Treated group is the percentage of participants with a relapse after switching from SOC to SAR445088. The primary endpoint for the SOC-Refractory and SOC-Naïve groups is the percentage of participants with a response, compared to baseline. Secondary endpoints include safety, tolerability, immunogenicity, and efficacy of SAR445088 during 12-week overlapping period (SOC-Treated). Part B evaluates long-term safety and durability of efficacy. Data analysis will be performed using Bayesian statistics (predefined efficacy thresholds) and historical data-based placebo assumptions to support program decision-making. INTERPRETATION: This innovative trial design based on patient groups and Bayesian statistics provides an efficient paradigm to evaluate new treatment candidates across the CIDP spectrum and can help accelerate development of new therapies.

How Much Perioperative Pain and Dysfunction Underlie the HOOS JR and KOOS JR?

BACKGROUND: The Hip Disability and Osteoarthritis Outcome Score Joint Replacement (HOOS JR) and Knee Injury and Osteoarthritis Outcome Score Joint Replacement (KOOS JR) scores represent pain and dysfunction as a single number ranging from 0 (extreme pain and dysfunction) to 100 (no pain or functional limitations). However, scores between 0 and 100 lack a simple interpretation because they reflect varying combinations of pain levels and dysfunction. Given that most adverse events and improvement occur within the first 90 days after surgery, a deeper understanding of the level of pain and dysfunction may reveal missed opportunities for patient care. QUESTIONS/PURPOSES: (1) What does a given preoperative or postoperative HOOS JR and KOOS JR score indicate about pain and ability to perform daily activities? (2) How much of a change in score (that is, delta) is needed to indicate significant improvement in pain control and daily functioning? METHODS: The Michigan Arthroplasty Registry Collaborative Quality Initiative contains more than 95% of THAs and TKAs performed in Michigan. Between January 2017 and March 2019, 84,175 people in the registry underwent primary THA or TKA and were potentially eligible for this retrospective, comparative study of the first 90 postoperative days. Eighty-four percent (70,608 of 84,175) were excluded because their surgeons did not attain a target survey collection proportion of 70% and another 6% (5042) were missing covariate information or surveys, leaving 10% (8525) for analysis. The mean age and percentage of women were 65 ± 11 years and 55% (2060 of 3716), respectively, for patients undergoing THA and 67 ± 9 years and 61% (2936 of 4809), respectively, for those undergoing TKA. There were no clinically meaningful differences between patients who were analyzed and those who were excluded except for lower representation of non-White patients in the analyzed group. For interpretation, patient responses to Question 7 (pain) and Question 6 (function) from the Patient-Reported Outcomes Measurement Information System global items (PROMIS-10) were dichotomized into "much pain" (rating of pain 4 to 10 of 10) versus "less pain" (rating of ≤ 3) and "good function" (able to perform most activities) versus "poor function" (not able to perform most activities) and combined into four pain-function categories. We examined the mean preoperative and postoperative HOOS JR and KOOS JR scores for each pain-function category, adjusted for patient characteristics. We calculated the size of the delta associated with an increase to a more favorable category postoperatively (versus staying in the same or worse category) via multivariable logistic regression that controlled for patient characteristics. RESULTS: Patients in the least favorable "much pain, poor function" category preoperatively had adjusted mean scores of 40 (95% confidence interval 39 to 41) for both the HOOS JR and KOOS JR. Those with mixed levels of pain and function had mean scores between 46 and 55. Those in the most favorable "less pain, good function" category had means of 60 (95% CI 58 to 62) and 59 (95% CI 58 to 61) for the HOOS JR and KOOS JR, respectively. The adjusted delta to achieve a pain level of ≤ 3 or the ability to perform most activities was 30 (95% CI 26 to 36) on the HOOS JR and 27 (95% CI 22 to 29) on the KOOS JR scales. CONCLUSION: These adjusted means of the HOOS JR and KOOS JR provide context for understanding the levels of pain and dysfunction for individuals as well for patients reported in other studies. Potential quality improvement efforts could include tracking the proportion of patients with THA or TKA who achieved a sufficient delta to attain pain levels of ≤ 3 or the ability to perform most activities. Future studies are needed to understand pain and function represented by the HOOS JR and KOOS JR at 1 to 2 years, how these may differ by patient subgroups, and whether scores can be improved through quality improvement efforts. LEVEL OF EVIDENCE: Level III, therapeutic study.

Are Short Stems Associated With Higher Fracture Rates and Early Revision Rates in Primary Total Hip Arthroplasty? A Noninferiority Analysis.

BACKGROUND: This study aimed to determine if "short" femoral stems were noninferior to (at least as good as) standard-length stems in regards to 90-day periprosthetic fracture and 1-year revision rates. METHODS: Using the MARCQI implant registry, a retrospective study of statewide data was carried out on 64,084 total hip arthroplasties (THAs) between 2012 and 2017. We noticed an increase in the use of "short" uncemented femoral hip stems during THA. Chi-square tests were used to test homogeneity of categorical variables. The covariates included in the analyses were identified using modern epidemiological methods. A Type I probability of 0.05 was used as the level of statistical significance. Inverse probability of treatment weighting (IPTW) was used to mitigate confounding variables. RESULTS: One hundred and seven stems were implanted by surgeons in the state of Michigan. They were classified according to the Khanuja Classification System as Type 2A (trapezoidal, double-tapered calcar loading, n = 3,281), Type 3 (calcar loading with lateral flare, n = 1,898), and Type 4 (shortened, tapered, conventional, n = 19,580), and were compared to standard-length, type 5, stems (n = 33,322) in regards to the 2 outcomes (periprosthetic fractures and 1-year revision rates). Overall, 1-year revision and the 90-day fracture rates were 1.3% (791/57,853) and 1.1% (631/57,968), respectively. Noninferiority was established for all short stems at the clinical threshold of an odds ratio (OR) of 1.5 with P-values <0.05 for 90-day fractures. In regards to 1-year revision rates, noninferiority was also established for Type 3 and 4 stems (P < .05). CONCLUSION: The increased use of "short stems" in Michigan did not lead to increased 1-year revision or 90-day fracture rates.

A Reduction in Opioid Prescription Size After Total Joint Arthroplasty Can be Safely Performed Without an Increase in Complications.

BACKGROUND: Excessive opioid prescriptions after total joint arthroplasty (TJA) increase risks for adverse opioid-related events, chronic opioid use, and unlawful opioid diversion. Decreasing postoperative prescriptions may improve quality after TJA. Concerns exist that a decrease in opioids prescribed may increase complications, such as readmissions, emergency department (ED) visits, or worsened patient-reported outcomes (PROs). The purpose of this study was to explore whether a reduction in opioids prescribed after TJA resulted in increased complications. METHODS: Data originated from a statewide database prospectively abstracted, including oral morphine equivalents prescribed at discharge, readmissions, ED visits, and PROs. Data were collected from 84,998 TJA occurring 1 year before and after the creation of an opioid-prescribing protocol that had decreased prescriptions by approximately 50%. Trends were monitored using Shewhart control charts. Regression models were used to determine statistically significant changes over time. RESULTS: All groups showed a reduction in opioids prescribed by almost 50% without an increase in emergency room visits or readmissions and without a detrimental effect on PROs. Compared to baseline data before opioid reduction, opioid-naive total knee arthroplasty had significant improvements in all outcomes (P = .03, P = .02, P < .001, P < .001). Opioid-tolerant total knee arthroplasty and total hip arthroplasty had no worsened outcomes and significant improvement in (Knee Injury and Osteoarthritis Outcome score for Joint Replacement P = .03) and (Hip Disability and Osteoarthritis Outcome Score for Joint Replacement P = .03). Opioid-naive total hip arthroplasty had significant improvements in Hip Disability and Osteoarthritis Outcome Score Joint Replacement (P = .003) and Patient Reported Outcomes Measurement Information System (P = .001). CONCLUSIONS: Postoperative opioid prescription recommendations from a statewide registry decreased prescribing by approximately 50% without decreasing PROs or increasing ED visits or readmissions. A reduction in opioids prescribed after TJA can be accomplished safely and without increased complications.

Early Survivorship of Uncemented Total Knee Arthroplasty Varies by Age and Sex Based on Data From the Michigan Arthroplasty Registry Collaborative Quality Initiative.

BACKGROUND: Outcome data for newer uncemented total knee arthroplasty (TKA) designs has been mixed. Registry studies showed worse survivorship, but clinical trials have not demonstrated differences compared to cemented designs. There has been renewed interest in uncemented TKA with modern designs and improved technology. The utilizations of uncemented knees in Michigan, 2-year outcomes, and the effects of age and sex were evaluated. METHODS: A statewide database from 2017 through 2019 was analyzed for incidence, distribution, and early survivorship of cemented versus uncemented TKAs. There was 2-year minimum follow-up. Kaplan-Meier survival analysis was used to generate time to first revision cumulative percent revision curves. The impacts of age and sex were examined. RESULTS: Use of uncemented TKAs increased from 7.0 to 11.3%. Uncemented TKAs were more commonly men, younger, heavier, American Society of Anesthesiologists score > 2, and opioid users (P < .05). At 2 years, overall cumulative percent revision was higher in uncemented (2.44% [2.00, 2.99]) versus cemented (1.76% [1.64, 1.89]), particularly in women uncemented (2.41 [1.87, 3.12]) versus cemented (1.64 [1.50, 1.80]). Revision rates were greater with uncemented women >70 years (1.2% 1 year, 1.02% 2 years) versus < 70 years (0.56%, 0.53%), notably uncemented were inferior in both groups (P < .05). Men, regardless of age, had similar survivorships with both cemented and uncemented designs. CONCLUSION: The use of an uncemented TKA had an increased risk of early revision compared to cemented. This finding, however, was only apparent in women, especially those >70 years old. Surgeons should consider cement fixation in women >70 years.

The characteristics of men who have sex with men (MSM) using post-exposure prophylaxis for sexual exposure (PEPSE) in the pre-exposure prophylaxis (PrEP) era.

OBJECTIVES: HIV pre-exposure prophylaxis (PrEP) is now available in the UK. However, some men who have sex with men (MSM) continue to use HIV post-exposure prophylaxis following sexual exposure (PEPSE) and are not using PrEP. It is important to characterize MSM having condomless anal sex who are not using PrEP. METHODS: In a cross-sectional analysis, we compared the characteristics of MSM who used PEPSE in 2021 with MSM using PEPSE in 2017. RESULTS: Overall, 126 MSM used PEPSE in January to June 2017 and 28 MSM used PEPSE in January to June 2021, a 78% decline in PEPSE use. Those MSM using PEPSE in 2021 were significantly younger (27 vs. 35 years, p < 0.01), more likely to identify as black or from another minority ethnic group [29% (8/28) vs. 8% (10/126); p < 0.01], more likely to attend as a result of a group sex encounter [35% (10/28) vs. 16% (10/126); p = 0.03], more likely to attend following sex involving recreational drug use [32% (9/28) vs. 13% (16/126); p = 0.02], and more likely to initiate PEPSE in the emergency department [35% (10/28) vs. 19% (24/126); p = 0.04] compared with MSM attending in 2017. Those MSM using PEPSE in 2021 were significantly less likely to attend follow-up appointments compared with the 2017 cohort [71% (20/28) vs. 87% (110/126); p < 0.05]. Ninety-five per cent of MSM using PEPSE in 2021 were initiated on PrEP at follow-up. CONCLUSIONS: Despite PrEP being readily available, some MSM continue using PEPSE and these MSM are significantly more likely to be younger, from black or minority ethnic groups, to engage in group sex involving recreational drugs and to attend the emergency department for PEPSE compared with MSM attending in 2017. Increasing the accessibility of PrEP for this group of MSM is important in order to optimize HIV prevention strategies.

N-terminal ß-strand underpins biochemical specialization of an ATG8 isoform.

Autophagy-related protein 8 (ATG8) is a highly conserved ubiquitin-like protein that modulates autophagy pathways by binding autophagic membranes and a number of proteins, including cargo receptors and core autophagy components. Throughout plant evolution, ATG8 has expanded from a single protein in algae to multiple isoforms in higher plants. However, the degree to which ATG8 isoforms have functionally specialized to bind distinct proteins remains unclear. Here, we describe a comprehensive protein-protein interaction resource, obtained using in planta immunoprecipitation (IP) followed by mass spectrometry (MS), to define the potato ATG8 interactome. We discovered that ATG8 isoforms bind distinct sets of plant proteins with varying degrees of overlap. This prompted us to define the biochemical basis of ATG8 specialization by comparing two potato ATG8 isoforms using both in vivo protein interaction assays and in vitro quantitative binding affinity analyses. These experiments revealed that the N-terminal ß-strand-and, in particular, a single amino acid polymorphism-underpins binding specificity to the substrate PexRD54 by shaping the hydrophobic pocket that accommodates this protein's ATG8-interacting motif (AIM). Additional proteomics experiments indicated that the N-terminal ß-strand shapes the broader ATG8 interactor profiles, defining interaction specificity with about 80 plant proteins. Our findings are consistent with the view that ATG8 isoforms comprise a layer of specificity in the regulation of selective autophagy pathways in plants.

Aboveground carbon accumulation by second-growth forests after deforestation in Hawai'i.

Successional processes ultimately determine and define carbon accumulations in forested ecosystems. Although primary succession on wholly new substrate occurs across the globe, secondary succession, often following storm events or anthropogenic disturbance, is more common and is capable of globally significant accumulations of carbon (C) at a time when offsets to anthropogenic carbon dioxide (CO2 ) emissions are critically needed. In Hawai'i, prior studies have investigated ecosystem development during primary succession on lava flows, including estimates of C mass accumulation. Yet relatively little is known regarding secondary succession of Hawaii's native forests, particularly regarding C mass accumulation. Here we documented aboveground C mass accumulation by native- and nonnative-dominated second-growth forests following deforestation of mature native lowland rainforests in the Puna District of Hawai'i Island. We characterized species composition and stand structure of three distinct successional forest stand types: those dominated by the native tree, Metrosideros polymorpha ('Ohi'a), and those dominated by invasive nonnative trees, Falcataria moluccana (albizia) and Psidium cattleianum (strawberry guava). We compared M. polymorpha-dominated and F. moluccana-dominated second-growth forests to adjacent mature M. polymorpha-dominated forests as well as young M. polymorpha-dominated forests undergoing initial stages of primary succession on 36-years-old lava fields. Aboveground carbon density (ACD) values of mature primary forest stands (171 Mg/ha) were comparable to those of mature continental tropical forests. M. polymorpha-dominated second-growth stands attained nearly 50% of ACD values of mature primary forests after less than 30 years of post-disturbance succession and exhibited aboveground carbon accumulation rates of ~3 Mg C·ha-1 ·year-1 . Such rates were comparable to those of second-growth forests in continental tropics. Rates of ACD accumulation by second-growth forests dominated by nonnative F. moluccana stands were similar, or slightly greater than, those of M. polymorpha-dominated stands. However, M. polymorpha individuals were virtually absent from stands dominated by either P. cattleianum or F. moluccana. Taken together, results demonstrated that re-establishment and rapid accumulation of C mass by M. polymorpha stands during secondary succession is certainly possible, but only where populations of nonnative species have not already colonized areas during early stages of secondary succession.

Early detection of a tree pathogen using airborne remote sensing.

Native forests of Hawai'i Island are experiencing an ecological crisis in the form of Rapid 'Ohi'a Death (ROD), a recently characterized disease caused by two fungal pathogens in the genus Ceratocystis. Since approximately 2010, this disease has caused extensive mortality of Hawai'i's keystone endemic tree, known as 'ohi'a (Metrosideros polymorpha). Visible symptoms of ROD include rapid browning of canopy leaves, followed by death of the tree within weeks. This quick progression leading to tree mortality makes early detection critical to understanding where the disease will move at a timescale feasible for controlling the disease. We used repeat laser-guided imaging spectroscopy (LGIS) of forests on Hawai'i Island collected by the Global Airborne Observatory (GAO) in 2018 and 2019 to derive maps of foliar trait indices previously found to be important in distinguishing between ROD-infected and healthy 'ohi'a canopies. Data from these maps were used to develop a prognostic indicator of tree stress prior to the visible onset of browning. We identified canopies that were green in 2018, but became brown in 2019 (defined as "to become brown"; TBB), and a corresponding set of canopies that remained green. The data mapped in 2018 showed separability of foliar trait indices between TBB and green 'ohi'a, indicating early detection of canopy stress prior to the onset of ROD. Overall, a combination of linear and non-linear analyses revealed canopy water content (CWC), foliar tannins, leaf mass per area (LMA), phenols, cellulose, and non-structural carbohydrates (NSC) are primary drivers of the prognostic spectral capability which collectively result in strong consistent changes in leaf spectral reflectance in the near-infrared (700-1300 nm) and shortwave-infrared regions (1300-2500 nm). Results provide insight into the underlying foliar traits that are indicative of physiological responses of M. polymorpha trees infected with Ceratocycstis and suggest that imaging spectroscopy is an effective tool for identifying trees likely to succumb to ROD prior to the onset of visible symptoms.

A pilot study exploring sexual health clinician confidence and barriers to anal examination and proctoscopy in men who have sex with men.

Anal examination and proctoscopy are important skills needed to facilitate the diagnoses of STIs and cancer. Clinician (25 doctors/15 nurses) confidence was higher for anal examination versus proctoscopy (median Likert scores 4/5 vs 5/5, P≤0.05) and higher in doctors compared with nurses (median Likert scores 5/5 vs 4/5, P<0.008, 4/5 vs 2/5, P<0.005), and related to years of experience (5/5 vs 4/5, P<0.001, 3/5 vs 5/5, P=0.007). Barriers included lack of opportunities for training, concerns about patient reluctance, and lack of available equipment. We need to be innovative when up-skilling the specialist sexual health workforce using online training and optimising opportunities for clinical assessment of MSM.

John N. Insall Award: MARCQI's Pain-Control Optimization Pathway (POP): Impact of Registry Data and Education on Opioid Utilization.

BACKGROUND: In 2019, the Michigan Arthroplasty Registry Collaborative Quality Initiative (MARCQI) recommended an evidence-based opioid pain pathway to participating physicians and hospitals for patients undergoing total joint arthroplasty (TJA). The purpose of this study was to determine if the education could influence and have lasting effects on the prescribing patterns for TJA patients. METHODS: Using the MARCQI database, the number of oral morphine equivalents (OMEs) prescribed at discharge were collected from January 2018 through December 2019 for all primary arthroplasty procedures. Periods compared included before and after July 2018 Michigan opioid laws as well as before and after the March 2019 MARCQI recommendations. The data compared total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients, opioid-naive vs opioid-tolerant patients, individual surgeons, and MARCQI sites. RESULTS: The data included 84,998 TJAs: 22,774 opioid-naive THAs, 9124 opioid-tolerant THAs, 40,882 opioid-naive TKAs, and 12,218 opioid-tolerant TKAs. In all the groups and at all time periods there were a significant decrease in prescriptions (P < .001). Individual surgeons and participating sites also demonstrated decreased OMEs on discharge after the recommendations. Between the first and last months of collection, this represented an overall decrease of opioid OMEs for THA by 47.1% for opioid-naive patients and 53.4% for opioid-tolerant patients. For TKA patients, the OME decrease was 48.3% for opioid-naive patients, and 48.4% for opioid-tolerant patients. CONCLUSION: The MARCQI pain control optimization pathway (POP) program has been successful in drastically reducing opioid prescribing with lasting effects, which has substantially limited the overall opioid prescription burden for patients undergoing arthroplasty.

Causes of Early Hip Revision Vary by Age and Gender: Analysis of Data From a Statewide Quality Registry.

BACKGROUND: While total hip arthroplasty (THA) is extremely successful, early failures do occur. The purpose of this study was to determine the cause of revision in specific patient demographic groups at 3 time points to potentially help decrease the revision risk. METHODS: Data for cases performed between 2012 and 2018 from a statewide, quality improvement arthroplasty registry were used. The database included 79,205 THA cases and 1,433 revisions with identified etiology (1,584 in total). All revisions performed at <5 years from the primary THA were reviewed. Six groups, men/women, <65, 65-75, and >75 years, were compared at revision time points <6 months, <1 year, and <5 years. RESULTS: There were obvious and significant differences between subgroups based on demographics and time points (P < .0001). Seven hundred and fifty-six (53%) of all revisions occurred within 6 months. The most common etiologies within 6 months (756 revisions) were fracture (316, 41.8%), dislocation/instability (194, 25.7%), and infection (98, 12.9%). At this early time point, the most common revision cause was fracture for all age/gender-stratified groups, ranging from 27.6% in young men to 60% in older women. Joint instability became the leading cause for revision after 1 year in all groups. CONCLUSION: This quality improvement project demonstrated clinically meaningful differences in the reason for THA revision between gender, age, and time from surgery. Strategies based on these data should be employed by surgeons to minimize the factors that lead to revision.

Predators and habitat association of post-settlement snapper (Chrysophrys auratus).

Structured habitats play an important nursery role during the crucial early juvenile or post-settlement stages of many fish species. Predominantly, the utility of structured habitats to juvenile fish is thought to be associated with the provisioning of food or as a refuge from predation. Although snapper (Chrysophrys auratus) in New Zealand also have a strong affinity for structured habitats during their post-settlement phase, their predators are unknown as is the role of predation in determining habitat association. Here the authors investigated potential predators of post-settlement snapper by remotely observing interactions of restrained post-settlement snapper with potential predators and investigating the diet of potential predators. They also conducted tank experiments with a potential predator, both with and without the presence of structure. Restrained snapper were infrequently approached by predators, but two new nocturnal predators were identified. No snapper were observed in the diet of potential predators, although two piscivores were identified as potential candidates. No predation occurred during tank experiments, but there was a non-significant indication that under threat of predation post-settlement snapper may use habitat when it is present and aggregate together when it is not. The findings suggest that the pulsed nature of predation may have made it difficult to observe given the methods employed and that the threat of predation may be sufficient to drive the habitat selection of post-settlement snapper. Investigating the significance of predation via methods that do not require direct observations may therefore be more appropriate given this context.

A molecular roadmap to the plant immune system.

Plant diseases caused by pathogens and pests are a constant threat to global food security. Direct crop losses and the measures used to control disease (e.g. application of pesticides) have significant agricultural, economic, and societal impacts. Therefore, it is essential that we understand the molecular mechanisms of the plant immune system, a system that allows plants to resist attack from a wide variety of organisms ranging from viruses to insects. Here, we provide a roadmap to plant immunity, with a focus on cell-surface and intracellular immune receptors. We describe how these receptors perceive signatures of pathogens and pests and initiate immune pathways. We merge existing concepts with new insights gained from recent breakthroughs on the structure and function of plant immune receptors, which have generated a shift in our understanding of cell-surface and intracellular immunity and the interplay between the two. Finally, we use our current understanding of plant immunity as context to discuss the potential of engineering the plant immune system with the aim of bolstering plant defenses against disease.

Intravenous immunoglobulin treatment for mild Guillain-Barré syndrome: an international observational study.

OBJECTIVE: To compare the disease course in patients with mild Guillain-Barré syndrome (GBS) who were treated with intravenous immunoglobulin (IVIg) or supportive care only. METHODS: We selected patients from the prospective observational International GBS Outcome Study (IGOS) who were able to walk independently at study entry (mild GBS), treated with one IVIg course or supportive care. The primary endpoint was the GBS disability score four weeks after study entry, assessed by multivariable ordinal regression analysis. RESULTS: Of 188 eligible patients, 148 (79%) were treated with IVIg and 40 (21%) with supportive care. The IVIg group was more disabled at baseline. IVIg treatment was not associated with lower GBS disability scores at 4 weeks (adjusted OR (aOR) 1.62, 95% CI 0.63 to 4.13). Nearly all secondary endpoints showed no benefit from IVIg, although the time to regain full muscle strength was shorter (28 vs 56 days, p=0.03) and reported pain at 26 weeks was lower (n=26/121, 22% vs n=12/30, 40%, p=0.04) in the IVIg treated patients. In the subanalysis with persistent mild GBS in the first 2 weeks, the aOR for a lower GBS disability score at 4 weeks was 2.32 (95% CI 0.76 to 7.13). At 1 year, 40% of all patients had residual symptoms. CONCLUSION: In patients with mild GBS, one course of IVIg did not improve the overall disease course. The certainty of this conclusion is limited by confounding factors, selection bias and wide confidence limits. Residual symptoms were often present after one year, indicating the need for better treatments in mild GBS.

Pelvic MRI in spinal cord injury patients: incidence of muscle signal change and early heterotopic ossification.

STUDY DESIGN: Prospective observational study. OBJECTIVE: To evaluate pelvic MRI muscle signal changes and their association with early heterotopic ossification (HO) in patients with spinal cord injuries. SETTING: National Spinal Injuries Unit, Stoke Mandeville, UK. METHODS: Forty patients were imaged with at least two interval magnetic resonance (MR) studies of the pelvis in the first 6 months following a spinal cord injury. Scans were reviewed and scored for heterotopic ossification, muscle signal change and extent of muscle involvement. RESULTS: Muscle signal change was present in 28 (70%) on the initial MRI and 31 (77%) by the second study. Six patients developed MR changes of prodromal or immature heterotopic ossification (15%). No restricted diffusion was demonstrated and no patient developed mature HO. Patients developing MR changes of early HO were more likely to have grade 3 muscle changes. CONCLUSION: Increased T2 muscle signal is common following cord injury, is frequently progressive in the subacute period and is associated with complete injury and early MR signs of heterotopic ossification.

Non-Inferiority of Aspirin for Venous Thromboembolism Prophylaxis After Hip Arthroplasty in a Statewide Registry.

BACKGROUND: Uncertainty remains surrounding the use of aspirin as a sole chemoprophylactic agent to reduce the risk of venous thromboembolism (deep vein thrombosis or pulmonary embolism) and bleeding after primary total hip arthroplasty. METHODS: We performed a non-inferiority analysis of a retrospective cohort of patients undergoing total hip arthroplasty from April 1, 2013 to December 31, 2018. Cases were retrieved from the Michigan Arthroplasty Registry Collaborative Quality Initiative database and performed by 355 surgeons at 61 hospitals throughout Michigan. Surgical setting ranged from small community hospitals to large academic and non-academic centers. The primary outcomes were post-operative venous thromboembolism event or death and bleeding event. RESULTS: Of the 59,747 patients included, 32,878 (55.03%) were female, and the mean age was 64.5. A total of 462 (0.77%) composite venous thromboembolism events occurred. There were 221 (0.71%) and 129 (0.80%) venous thromboembolism events in patients receiving aspirin only and anticoagulants only, respectively. Aspirin was non-inferior to anticoagulants for composite venous thromboembolism events (odds ratio 0.99, 95% confidence interval 0.79-1.26, P < .001). Bleeding events occurred in 767 (1.28%) patients, with 304 (0.97%) and 281 (1.74%) bleeding events in patients receiving aspirin only and anticoagulants only, respectively. Aspirin was non-inferior to anticoagulants for bleeding events (odds ratio 0.62, 95% confidence interval 0.52-0.74, P < .001). CONCLUSION: Aspirin is not inferior to other anticoagulants as pharmacologic venous thromboembolism prophylaxis with regards to post-operative risk of venous thromboembolism or bleeding. Sole use of aspirin for venous thromboembolism prophylaxis after total hip arthroplasty should be considered in the appropriate patient.

Original research: Second IVIg course in Guillain-Barré syndrome with poor prognosis: the non-randomised ISID study.

OBJECTIVE: To compare disease course in patients with Guillain-Barré syndrome (GBS) with a poor prognosis who were treated with one or with two intravenous immunoglobulin (IVIg) courses. METHODS: From the International GBS Outcome Study, we selected patients whose modified Erasmus GBS Outcome Score at week 1 predicted a poor prognosis. We compared those treated with one IVIg course to those treated with two IVIg courses. The primary endpoint, the GBS disability scale at 4 weeks, was assessed with multivariable ordinal regression. RESULTS: Of 237 eligible patients, 199 patients received a single IVIg course. Twenty patients received an 'early' second IVIg course (1-2 weeks after start of the first IVIg course) and 18 patients a 'late' second IVIg course (2-4 weeks after start of IVIg). At baseline and 1 week, those receiving two IVIg courses were more disabled than those receiving one course. Compared with the one course group, the adjusted OR for a better GBS disability score at 4 weeks was 0.70 (95%CI 0.16 to 3.04) for the early group and 0.66 (95%CI 0.18 to 2.50) for the late group. The secondary endpoints were not in favour of a second IVIg course. CONCLUSIONS: This observational study did not show better outcomes after a second IVIg course in GBS with poor prognosis. The study was limited by small numbers and baseline imbalances. Lack of improvement was likely an incentive to start a second IVIg course. A prospective randomised trial is needed to evaluate whether a second IVIg course improves outcome in GBS.