Complex regulation in a Comamonas platform for diverse aromatic carbon metabolism.

Critical to a sustainable energy future are microbial platforms that can process aromatic carbons from the largely untapped reservoir of lignin and plastic feedstocks. Comamonas species present promising bacterial candidates for such platforms because they can use a range of natural and xenobiotic aromatic compounds and often possess innate genetic constraints that avoid competition with sugars. However, the metabolic reactions of these species are underexplored, and the regulatory mechanisms are unknown. Here we identify multilevel regulation in the conversion of lignin-related natural aromatic compounds, 4-hydroxybenzoate and vanillate, and the plastics-related xenobiotic aromatic compound, terephthalate, in Comamonas testosteroni KF-1. Transcription-level regulation controls initial catabolism and cleavage, but metabolite-level thermodynamic regulation governs fluxes in central carbon metabolism. Quantitative 13C mapping of tricarboxylic acid cycle and cataplerotic reactions elucidates key carbon routing not evident from enzyme abundance changes. This scheme of transcriptional activation coupled with metabolic fine-tuning challenges outcome predictions during metabolic manipulations.

Evolution and engineering of pathways for aromatic O-demethylation in Pseudomonas putida KT2440.

Biological conversion of lignin from biomass offers a promising strategy for sustainable production of fuels and chemicals. However, aromatic compounds derived from lignin commonly contain methoxy groups, and O-demethylation of these substrates is often a rate-limiting reaction that influences catabolic efficiency. Several enzyme families catalyze aromatic O-demethylation, but they are rarely compared in vivo to determine an optimal biocatalytic strategy. Here, two pathways for aromatic O-demethylation were compared in Pseudomonas putida KT2440. The native Rieske non-heme iron monooxygenase (VanAB) and, separately, a heterologous tetrahydrofolate-dependent demethylase (LigM) were constitutively expressed in P. putida, and the strains were optimized via adaptive laboratory evolution (ALE) with vanillate as a model substrate. All evolved strains displayed improved growth phenotypes, with the evolved strains harboring the native VanAB pathway exhibiting growth rates ∼1.8x faster than those harboring the heterologous LigM pathway. Enzyme kinetics and transcriptomics studies investigated the contribution of selected mutations toward enhanced utilization of vanillate. The VanAB-overexpressing strains contained the most impactful mutations, including those in VanB, the reductase for vanillate O-demethylase, PP_3494, a global regulator of vanillate catabolism, and fghA, involved in formaldehyde detoxification. These three mutations were combined into a single strain, which exhibited approximately 5x faster vanillate consumption than the wild-type strain in the first 8 h of cultivation. Overall, this study illuminates the details of vanillate catabolism in the context of two distinct enzymatic mechanisms, yielding a platform strain for efficient O-demethylation of lignin-related aromatic compounds to value-added products.

Biosensors for the detection of chorismate and cis,cis-muconic acid in Corynebacterium glutamicum.

Corynebacterium glutamicum ATCC 13032 is a promising microbial chassis for industrial production of valuable compounds, including aromatic amino acids derived from the shikimate pathway. In this work, we developed two whole-cell, transcription factor based fluorescent biosensors to track cis,cis-muconic acid (ccMA) and chorismate in C. glutamicum. Chorismate is a key intermediate in the shikimate pathway from which value-added chemicals can be produced, and a shunt from the shikimate pathway can divert carbon to ccMA, a high value chemical. We transferred a ccMA-inducible transcription factor, CatM, from Acinetobacter baylyi ADP1 into C. glutamicum and screened a promoter library to isolate variants with high sensitivity and dynamic range to ccMA by providing benzoate, which is converted to ccMA intracellularly. The biosensor also detected exogenously supplied ccMA, suggesting the presence of a putative ccMA transporter in C. glutamicum, though the external ccMA concentration threshold to elicit a response was 100-fold higher than the concentration of benzoate required to do so through intracellular ccMA production. We then developed a chorismate biosensor, in which a chorismate inducible promoter regulated by natively expressed QsuR was optimized to exhibit a dose-dependent response to exogenously supplemented quinate (a chorismate precursor). A chorismate-pyruvate lyase encoding gene, ubiC, was introduced into C. glutamicum to lower the intracellular chorismate pool, which resulted in loss of dose dependence to quinate. Further, a knockout strain that blocked the conversion of quinate to chorismate also resulted in absence of dose dependence to quinate, validating that the chorismate biosensor is specific to intracellular chorismate pool. The ccMA and chorismate biosensors were dually inserted into C. glutamicum to simultaneously detect intracellularly produced chorismate and ccMA. Biosensors, such as those developed in this study, can be applied in C. glutamicum for multiplex sensing to expedite pathway design and optimization through metabolic engineering in this promising chassis organism. ONE-SENTENCE SUMMARY: High-throughput screening of promoter libraries in Corynebacterium glutamicum to establish transcription factor based biosensors for key metabolic intermediates in shikimate and ß-ketoadipate pathways.

Impact of radiocapitellar interposition arthroplasty on ulnohumeral joint biomechanics.

BACKGROUND: Radial head excision (RHE) has been shown to increase contact pressures within the ulnohumeral joint. Radiocapitellar interposition arthroplasty (RCIA) with the use of a soft tissue graft is an alternative for the treatment of isolated radiocapitellar arthritis or with failure of radial head replacement. We investigated contact pressures and contact area within the ulnohumeral joint after RHE compared to RCIA with dermal autograft. METHODS: Six fresh-frozen cadaver elbows were tested on a custom dynamic elbow frame. A pressure sensor was inserted into the intact elbow joint, and mean contact pressure, peak contact pressure, contact area, and force within the ulnohumeral joint were recorded at 0°, 30°, 60°, 90°, and 120° of flexion as a valgus load was applied to the elbow. The radial head was then excised and specimens were retested. Finally, a dermal graft matched to the size of the resected radial head was inserted in the radiocapitellar space and the specimens were tested a third time. RESULTS: At 90° of flexion, contact pressure within the ulnohumeral joint was significantly lower with RCIA compared with RHE (110.8 kPa vs 216.8 kPa; P = .013). The mean peak contact pressure was also significantly lower with RCIA compared with RHE at 90° (279.4 vs 626.7 kPa; P = .025). No statistically significant differences were seen in mean contact area or force between the 3 testing conditions at any flexion position. CONCLUSION: RCIA with a dermal graft reduced contact pressures within the ulnohumeral joint compared to RHE at 90° of flexion without a significant change in contact area or contact force.

Adaptive laboratory evolution for improved tolerance of isobutyl acetate in Escherichia coli.

Previously, Escherichia coli was engineered to produce isobutyl acetate (IBA). Titers greater than the toxicity threshold (3 g/L) were achieved by using layer-assisted production. To avoid this costly and complex method, adaptive laboratory evolution (ALE) was applied to E. coli for improved IBA tolerance. Over 37 rounds of selective pressure, 22 IBA-tolerant mutants were isolated. Remarkably, these mutants not only tolerate high IBA concentrations, they also produce higher IBA titers. Using whole-genome sequencing followed by CRISPR/Cas9 mediated genome editing, the mutations (SNPs in metH, rho and deletion of arcA) that confer improved tolerance and higher titers were elucidated. The improved IBA titers in the evolved mutants were a result of an increased supply of acetyl-CoA and altered transcriptional machinery. Without the use of phase separation, a strain capable of 3.2-fold greater IBA production than the parent strain was constructed by combing select beneficial mutations. These results highlight the impact improved tolerance has on the production capability of a biosynthetic system.

Fragility of randomized controlled trials on treatment of proximal humeral fracture.

BACKGROUND: Proximal humeral fracture represents an increasingly common pathology with evaluation and treatment often guided by evidence from randomized controlled trials (RCTs), but the strength of an RCT must be considered in this process. The purpose of this study was to evaluate the strength of outcomes in RCTs on the management of proximal humeral fractures using the fragility index (FI), a method used with statistically significant dichotomous outcomes to assess the number of patients that would change an outcome measure from significant (P ≤ .05) to nonsignificant if the patient outcome changed. We also aimed to correlate the FI with other measures of study strength. METHODS: A systematic review was performed using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to evaluate RCTs on the management of proximal humeral fractures. The PubMed, Ovid MEDLINE, Web of Science, and Embase databases were searched from database inception to May 2021. RCTs with at least 1 statistically significant (P ≤ .05) dichotomous outcome were included. The FI was calculated for each included trial using the Fisher exact test. The FI was correlated with the study sample size and journal impact factor. RESULTS: Ten RCTs reporting on 656 patients and published between 2011 and 2020 were included. The median patient sample size was 67 (mean, 65.6; range, 40-86). Complications were the most commonly reported dichotomous statistically significant outcome. The median FI was 1 (mean, 2.6; range, 0-18), with 4 studies having an FI of 0. A median FI of 1 indicates that 1 patient experiencing an alternative outcome or having not been lost to follow-up could have changed the pertinent conclusions of the trial for a given outcome. The median number of patients lost to follow-up was 3 (mean, 4.9; range, 0-16) and exceeded the FI in 50% of studies. There was no correlation between the FI and sample size (Spearman coefficient = 0.0592, P = .865) or between the FI and journal impact factor (Spearman coefficient = -0.0229, P = .522). CONCLUSION: In most studies of proximal humeral fractures, only 1 or 2 patients experiencing an alternative outcome or lost to follow-up would change the conclusions for the dichotomous outcome studied. Although the FI cannot be used to assess continuous variables, which are often the primary outcome variables of RCTs, it does offer an additional unique measure of study strength that surgeons should consider when evaluating RCTs.

Abnormal neurological pupil index is associated with malignant cerebral edema after mechanical thrombectomy in large vessel occlusion patients.

BACKGROUND AND OBJECTIVES: Malignant cerebral edema (MCE) is a feared complication in patients suffering from large vessel occlusion. Variables associated with the development of MCE have not been clearly elucidated. Use of pupillometry and the neurological pupil index (NPi) as an objective measure in patients undergoing mechanical thrombectomy (MT) has not been explored. We aim to evaluate variables significantly associated with MCE in patients that undergo MT and hypothesize that abnormal NPi is associated with MCE in this population. METHODS: A retrospective analysis of patients with acute ischemic stroke who had undergone MT at our institution between 2017 and 2020 was performed. Baseline and outcome variables were collected, including NPi values from pupillometry readings of patients within 72 h after the MT. Patients were divided into two groups: MCE versus non-MCE group. A univariate and multivariate analysis was performed. RESULTS: Of 284 acute ischemic stroke patients, 64 (22.5%) developed MCE. Mean admission glucose (137 vs. 173; p < 0.0001), NIHSS on admission (17 vs. 24; p < 0.01), infarct core volume (27.9 vs. 17.9 mL; p = 0.0036), TICI score (p = 0.001), and number of passes (2.9 vs. 1.8; p < 0.0001) were significantly different between the groups. Pupillometry data was present for 64 patients (22.5%). Upon multivariate analysis, abnormal ipsilateral NPi (OR 21.80 95% CI 3.32-286.4; p = 0.007) and hemorrhagic conversion were independently associated with MCE. CONCLUSION: Abnormal NPi and hemorrhagic conversion are significantly associated with MCE in patients following MT. Further investigation is warranted to better define an association between NPi and patient outcomes in this patient population.

Management of Intracranial Hemorrhage in Patients with a Left Ventricular Assist Device: A Systematic Review and Meta-Analysis.

BACKGROUND: Intracranial hemorrhage (ICH) has been reported to occur in up to 23% of patients with left ventricular assist devices (LVADs). Currently, limited data exists to guide neurosurgical management strategies to optimize outcomes in patients with an LVAD who develop ICH. METHODS: A systematic review and meta-analysis of the literature was performed to evaluate the mortality rate in these patients following medical and/or surgical management and to evaluate antithrombotic reversal and resumption strategies after hemorrhage. RESULTS: 17 studies reporting on 3869 LVAD patients and 545 intracranial hemorrhages spanning investigative periods from 1996 to 2019 were included. The rate of ICH in LVAD patients was 10.6% (411/3869) with 58.6% (231/394) being intraparenchymal hemorrhage (IPH), 23.6% (93/394) subarachnoid hemorrhage (SAH), and 15.5% (61/394) subdural hemorrhage (SDH). Total mortality rates for surgical management 65.6% (40/61) differed from medical management at 45.2% (109/241). There was an increased relative risk of mortality (RR=1.45, 95% CI: 1.10-1.91, p = 0.01) for ICH patients undergoing surgical intervention. The hemorrhage subtype most frequently managed with anticoagulation reversal was IPH 81.8% (63/77), followed by SDH 52.2% (12/23), and SAH 39.1% (18/46). Mean number of days until antithrombotic resumption ranged from 6 to 10.5 days. CONCLUSION: Outcomes remain poor, specifically for those undergoing surgery. As experience with this population increases, prospective studies are warranted to contribute to management and prognostication .

'HepCheck Dublin': an intensified hepatitis C screening programme in a homeless population demonstrates the need for alternative models of care.

BACKGROUND: Hepatitis C virus (HCV) is one of the main causes of chronic liver disease worldwide. Prevalence of HCV in homeless populations ranges from 3.9 to 36.2%. The HepCheck study sought to investigate and establish the characterisation of HCV burden among individuals who attended an intensified screening programme for HCV in homeless services in Dublin, Ireland. METHODS: The HepCheck study was conducted as part of a larger European wide initiative called HepCare Europe. The study consisted of three phases; 1) all subjects completed a short survey and were offered a rapid oral HCV test; 2) a convenience sample of HCV positive participants from phase 1 were selected to complete a survey on health and social risk factors and 3) subjects were tracked along the referral pathway to identify whether they were referred to a specialist clinic, attended the specialist clinic, were assessed for cirrhosis by transient elastography (Fibroscan) and were treated for HCV. RESULTS: Five hundred ninety-seven individuals were offered HCV screening, 73% were male and 63% reported having had a previous HCV screening. We screened 538 (90%) of those offered screening, with 37% testing positive. Among those who tested positive, 112 (56%) were 'new positives' and 44% were 'known positives'. Undiagnosed HCV was prevalent in 19% of the study sample. Active past 30-day drug use was common, along with attendance for drug treatment. Unstable accommodation was the most common barrier to attending specialist appointments and accessing treatment. Depression and anxiety, dental problems and respiratory conditions were common reported health problems. Forty-six subjects were referred to specialised services and two subjects completed HCV treatment. CONCLUSIONS: This study demonstrates that the current hospital-based model of care is inadequate in addressing the specific needs of a homeless population and emphasises the need for a community-based treatment approach. Findings are intended to inform HepCare Europe in their development of a community-based model of care in order to engage with homeless individuals with multiple co-morbidities including substance abuse, who are affected by or infected with HCV.

Making sense of street chaos: an ethnographic exploration of homeless people's health service utilization.

BACKGROUND: Homeless people have poor health and mortality indices. Despite this they make poor usage of health services. This study sought to understand why they use health services differently from the domiciled population. METHODS: Ethnographic observations were conducted at several homeless services, in Dublin. This was supplemented with 47 semi-structured interviews with homeless people and two focus groups of homeless people and hospital doctors. A critical-realist approach was adopted for interpretation of the data. RESULTS: Homeless people tended to present late in their illness; default early from treatment; have low usage of primary-care, preventative and outpatient services; have high usage of Emergency and Inpatient services; and poor compliance with medication. They tended to avoid psychiatric services. A number of external barriers were identified. These were classified as physical (distance) administrative (application process for medical care; appointments; queues; the management of addiction in hospital; rules of service; and information providing processes); and attitudinal (stigma; differing attitudes as to appropriate use of services. A new form of barrier, Conversations of Exclusion was identified and described. Internalised barriers were identified which were in nature, either cognitive (fatalistic, denial, deferral to future, presumption of poor treatment or discrimination, self blame and survival cognitions) or emotional (fear; embarrassment, hopelessness and poor self-esteem). Generative mechanisms for these factors were identified which either affected participants prior to homelessness (marginalization causing hopelessness, familial dysfunction, substance misuse, fear of authority, illiteracy; mental health; and poor English) or after becoming homeless (homelessness; ubiquity of premature death; substance misuse; prioritization of survival over health; threat of violence; chaotic nature of homelessness; negative experiences of authority; and stigma. CONCLUSIONS: An explanatory critical realist model integrating the identified generative mechanisms, external and internalised barriers was developed to explain why the Health service Utilization of homeless people differs from the domiciled populations. This new model has implications for health service policy makers and providers in how they design and deliver accessible health services to homeless people.

Metabolic engineering tools in model cyanobacteria.

Developing sustainable routes for producing chemicals and fuels is one of the most important challenges in metabolic engineering. Photoautotrophic hosts are particularly attractive because of their potential to utilize light as an energy source and CO2 as a carbon substrate through photosynthesis. Cyanobacteria are unicellular organisms capable of photosynthesis and CO2 fixation. While engineering in heterotrophs, such as Escherichia coli, has result in a plethora of tools for strain development and hosts capable of producing valuable chemicals efficiently, these techniques are not always directly transferable to cyanobacteria. However, recent efforts have led to an increase in the scope and scale of chemicals that cyanobacteria can produce. Adaptations of important metabolic engineering tools have also been optimized to function in photoautotrophic hosts, which include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9, 13C Metabolic Flux Analysis (MFA), and Genome-Scale Modeling (GSM). This review explores innovations in cyanobacterial metabolic engineering, and highlights how photoautotrophic metabolism has shaped their development.

Exploring levers and barriers to accessing primary care for marginalised groups and identifying their priorities for primary care provision: a participatory learning and action research study.

BACKGROUND: The involvement of patients and the public in healthcare has grown significantly in recent decades and is documented in health policy documents internationally. Many benefits of involving these groups in primary care planning have been reported. However, these benefits are rarely felt by those considered marginalised in society and they are often excluded from participating in the process of planning primary care. It has been recommended to employ suitable approaches, such as co-operative and participatory initiatives, to enable marginalised groups to highlight their priorities for care. METHODS: This Participatory Learning and Action (PLA) research study involved 21 members of various marginalised groups who contributed their views about access to primary care. Using a series of PLA techniques for data generation and co-analysis, we explored barriers and facilitators to primary healthcare access from the perspective of migrants, Irish Travellers, homeless people, drug users, sex workers and people living in deprivation, and identified their priorities for action with regard to primary care provision. RESULTS: Four overarching themes were identified: the home environment, the effects of the 'two-tier' healthcare system on engagement, healthcare encounters, and the complex health needs of many in those groups. The study demonstrates that there are many complicated personal and structural barriers to accessing primary healthcare for marginalised groups. There were shared and differential experiences across the groups. Participants also expressed shared priorities for action in the planning and running of primary care services. CONCLUSIONS: Members of marginalised groups have shared priorities for action to improve their access to primary care. If steps are taken to address these, there is scope to impact on more than one marginalised group and to address the existing health inequities.

Health and use of health services of people who are homeless and at risk of homelessness who receive free primary health care in Dublin.

BACKGROUND: Homeless populations experience poorer physical and mental health, and more barriers to accessing adequate healthcare. This study investigates the health of this population, following the provision of a free to access primary care service for homeless people in Dublin (Safetynet). The health of this group will be compared to previous studies on homelessness conducted in Dublin prior to the establishment of this service (in 1997 and 2005). METHODS: Participants were recruited through Safetynet clinics. A 133-item questionnaire was administered to determine participants' physical and mental well-being, use of health services and healthcare needs. Prescription data was extracted from participants' electronic health records. RESULTS: A total of 105 participants were recruited. The majority were < 45 years of age (69%), male (75%), single (52%), Irish (74%) and had children (52%). Multimorbidity was common; with 5.3 ± 2.7 (mean ± SD) physical conditions reported per person. A large proportion of participants had at some point received a formal diagnosis of a mental health condition (70%; 73/105), including depression (50%; 52/105), addiction disorder (39%), anxiety (36%; 38/105), schizophrenia (13%; 14/105) and bipolar disorder (6%; 6/105). With regards to illicit drug use, 60% (63/105) of participants reported ever using drugs, while 33% (35/105) reported being active drug users. Based on AUDIT C criteria, 53% had an alcohol problem. Compared to previous studies, participants reported more positive ratings of health (70% vs. 57% in 1997 and 46% in 2005). The proportion of participants on one or more prescription medication was higher than in previous studies (81% vs. 32% in 1997 and 49% in 2005) and there was a decrease in attendance at outpatients departments (17% vs. 27% in 2005) and a trend towards a decrease in attendance at Accident and Emergency departments (A & E) (29% vs. 37% in 2005). CONCLUSIONS: This vulnerable population has many physical and mental health problems. Use of drugs, alcohol and smoking is common. Following the establishment of Safetynet, self-reported health was rated more positively, there was also a decrease in the use of A & E and outpatient services and an increase in prescription medicines.

Evaluation and Treatment of Primary Spinal Epidural Lymphoma Presenting as Acute Myelopathy in a Young Adult: A Case Report.

CASE: Primary spinal epidural lymphoma (PSEL) presenting as myelopathy is extremely rare, particularly within young, healthy adults. This case report describes a 26-year-old man presenting with progressive thoracic myelopathy. Magnetic resonance imaging revealed spinal epidural masses spanning T5-T10 and T12-L2 with multilevel cord compression and edema. After evaluation, the patient underwent emergent posterior decompression to prevent progressive neurological decline. Histology was consistent with diffuse large B-cell lymphoma, germinal center type. At 3 months postoperatively, the patient regained full neurologic function. CONCLUSION: Although rare, PSELs should be considered in patients presenting with myelopathy to facilitate timely diagnosis and treatment.

Structural contributions of different manganese oxide minerals on the redox transformations and proliferation of iodine.

The redox capabilities of birnessite minerals are contingent upon the physical characteristics of the solid, indicating that different allotropes have various reactivities. Here, the role of these structural differences on the oxidation of iodine, a risk driving environmental contaminant in several federal complexes, was investigated. The mechanism of which can be seen here, with one of the minerals of study, acid birnessite. The pH range chosen for this study was pH 5-6. Throughout the experiments it was seen that the average oxidation state (AOS) had the greatest contribution to the differences in redox capabilities of the various birnessite minerals. Several trends were observed throughout this study: as AOS decreased, oxidation of iodide (I-) increased; as specific surface area (SSA) increased, the sorption of iodate (IO3-) increased. Additional experiments were conducted at trace levels of iodine, to better model environmental conditions. In that case, a one-step conversion of I- to IO3- occurred, to a greater extent than under artificially elevated concentrations.

Opioid Use Consequences, Governmental Strategies, and Alternative Pain Control Techniques Following Total Hip Arthroplasties.

Over the last several decades, rates of opioid use and associated problems have dramatically increased in the United States leading to laws limiting prescription duration for acute pain management. As a result, orthopedic surgeons who perform total hip arthroplasty (THA), a procedure that often leads to significant postoperative pain, have been faced with substantial challenges to adequately mitigate patient pain while also reducing opioid intake. Current strategies include identifying and correcting modifiable risk factors associated with postoperative opioid use such as preoperative opioid use, alcohol and tobacco abuse, and untreated psychiatric illness. Additionally, recent evidence has emerged in the form of Enhanced Recovery After Surgery (ERAS) protocols suggesting that a multidisciplinary focus on patient factors perioperatively can lead to reduced postoperative opioid administration and decreased hospital stays. A cornerstone of ERAS protocols includes multimodal pain regimens with opioid rescue only as needed, which often includes multiple systemic pain therapies such as acetaminophen, gabapentin, non-steroidal anti-inflammatory drugs, as well as targeted pain therapies that include epidural catheters and ultrasound-guided nerve blocks. Many hospital systems and states have also implemented opioid prescribing limitations with mixed success. As the opioid epidemic continues in the United States, while contributing to poor outcomes following elective surgeries, further research is warranted to identify multidisciplinary strategies that mitigate opioid use while also allowing for adequate pain control and rehabilitation.

Can Clinical Response Predict Pathologic Response Following Neoadjuvant Chemoradiation for Esophageal Cancer?

OBJECTIVES: Approximately 20-40% of patients with locally advanced esophageal cancer will achieve a pathologic complete response (ypCR) following neoadjuvant chemoradiotherapy (nCRT). Predicting ypCR based on a clinical complete response (ycCR) has been a challenge. This study assessed the correlation between ycCR and ypCR, as determined from esophagectomy specimens. METHODS: Patients undergoing esophagectomy following nCRT at three major institutions between 2005 and 2018 were reviewed. Restaging, including PET/CT, endoscopy with biopsy, and esophageal ultrasound (EUS), was performed to determine ycCR. RESULTS: Six hundred sixty patients were included, with 93.3% with esophageal adenocarcinoma histology. Six hundred fifty-eight of these patients underwent PET, 304 EUS, and 584 underwent a biopsy. Following nCRT, 148 (22.4%) were found to have a ypCR. Only 12/32 (37.5%) determined to have a ycCR were found to have a ypCR, while 136/628 (21.6%) with a non-ycCR were found to have a ypCR (p 0.075). Individual modality PPV was 28% for PET, 54% for EUS, and 26% for biopsy. When PET was combined with EUS, 168 reports were concordant and the PPV of ypCR was 50%, though the number of patients was low (1/2). With all 3 re-staging modalities combined, the PPV and NPV both rose to 100%. CONCLUSIONS: Current restaging tools cannot reliably predict ypCR after nCRT. While multimodal restaging appears to be a more accurate predictor of ypCR than any testing modality alone, patients cannot reliably be advised to avoid an esophagectomy on the assumption that ycCR predicts ypCR at this time.

The Ramifications of Opioid Utilization and Outcomes of Alternative Pain Control Strategies for Total Knee Arthroplasties.

Morbidity and mortality related to opioid use has generated a public health crisis in the United States. Total knee arthroplasty (TKA) is an increasingly common procedure and is often accompanied by post-operative opioid utilization. Unfortunately, post-operative opioid usage after TKA has been shown to lead to higher rates of complications, longer hospital stays, increased costs, and more frequent need for revision surgery. Pre-operative opioid utilization has been shown to be one of the most important predictors of post-operative opioid usage. Additional risk factors for continued post-operative opioid utilization after TKA include pre-operative substance and tobacco use as well as higher post-operative prescription dosages, younger age, female gender, and Medicaid insurance. One method for mitigating excessive post-operative opioid utilization are Enhanced Recovery After Surgery (ERAS) protocols, which include a multidisciplinary approach that focuses on perioperative factors to optimize patient recovery and function after surgery. Additional strategies include multimodal pain regimens with epidural anesthetics, extended duration local anesthetics and adjuvants, and ultrasound guided peripheral nerve blocks. In recent years, opioid prescribing duration limitations have also been put into place by state and federal government, hospital systems, and ambulatory surgery centers making effective acute pain management imperative for all stakeholders. In this regard, as rates of TKA continue to increase across the United States, multidisciplinary efforts by all stakeholders are needed to ensure adequate pain control while preventing the negative sequalae of opioid medications.

A Scoping Review of the Health Impact of the COVID-19 Pandemic on Persons Experiencing Homelessness in North America and Europe.

Persons experiencing homelessness (PEH) are at heightened risk for infection, morbidity, and mortality from COVID-19. However, health consequences of the pandemic extend far beyond those directly caused by the virus. This scoping review aimed to explore the impacts of the COVID-19 pandemic on the health and well-being of PEH in North America and Europe. A systematic search of academic and grey literature was conducted in September 2021. To be included, studies had to include primary data related to the impact of the pandemic on health or well-being of PEH and be written in English. All potentially relevant references were independently screened by two reviewers, and minor conflicts were settled with input of a third reviewer. A total of 96 articles met criteria for inclusion. Data extraction was completed for all included studies, and findings synthesised and presented thematically. Numerous health impacts of the pandemic on PEH were identified, including SARS-CoV-2 infection, morbidity, mortality, and hospitalisation, fear of infection, access to housing, hygiene, PPE, food, as well as mental health, substance use, other health-related outcomes and treatment services. Gaps in the literature relating to persons using alcohol, access to mental health support, and violence were also identified. Implications for future research are discussed.