Alberta reconstructive technique (ART): An innovative approach using digital surgical design and simulation in advanced jaw reconstruction with occlusion-based prefabricated vascularized fibular flaps and primary osseointegrated implant installation.

The Alberta reconstructive technique (ART) is an innovative surgical procedure performed on patients undergoing primary jaw resection and reconstruction. The ART procedure was developed in collaboration with the Institute for Reconstructive Sciences in Medicine and the Division of Otolaryngology-Head and Neck Surgery, University of Alberta.

Feasibility and safety of Heavy Lifting Strength Training in Head and Neck Cancer survivors post-surgical neck dissection (the LIFTING trial).

BACKGROUND: Light-to-moderate intensity strength training (LMST) improves muscular strength, physical functioning, and some side effects in head and neck cancer survivors (HNCS). Heavy lifting strength training (HLST) may further improve these outcomes; however, it has not been studied in HNCS. The primary aim of the LIFTING trial was to examine the feasibility and safety of a HLST program in HNCS ≥1-year post-surgical neck dissection. METHODS: In this single-arm feasibility study, HNCS were asked to complete a twice weekly, 12-week, supervised HLST program, gradually progressing to lifting heavy loads of 80-90% of 1 repetition maximum (1RM) for barbell squat, bench press, and deadlift. The feasibility outcomes included recruitment rate, 1RM completion rate, program adherence, barriers, and motivation. The preliminary efficacy outcomes included changes in upper and lower body strength. RESULTS: Nine HNCS were recruited over an 8-month period during the COVID-19 pandemic. All 9 (100%) completed the 1RM tests and successfully progressed to heavy loads at approximately 5 weeks. The median attendance was 95.8% (range 71-100%), and few barriers were reported. Weight lifted increased for squat/leg press (median change: +34kg; 95% CI +25 to +47), bench press (median change: +6kg; 95% CI +2 to +10), and deadlift (median change: +12kg; 95% CI +7 to +24). No adverse events were reported and participants were motivated to continue HLST after the study. CONCLUSIONS: HLST appears feasible and safe for HNCS and may result in meaningful improvements in muscular strength. Future research should consider additional recruitment strategies and compare HLST to LMST in this understudied survivor population. TRIAL REGISTRATION: NCT04554667.

Interlimb differences in T1ρ MRI relaxation times linked with symptomatic knee osteoarthritis following anterior cruciate ligament reconstruction.

BACKGROUND: Lower proteoglycan density, as estimated by greater T1ρ magnetic resonance imaging (MRI) relaxation times, may be an indicator of early osteoarthritis development. We examined associations between femoral cartilage inter-limb T1ρ MRI relaxation time ratios and clinically relevant knee symptoms at 12 months following anterior crucial ligament reconstruction (ACLR). METHODS: Twenty-nine individuals completed the Knee Osteoarthritis Outcome Score (KOOS) and underwent MRI 12 months following ACLR for this cross-sectional study. Participants were categorized as symptomatic or asymptomatic for clinically relevant knee symptoms consistent with osteoarthritis based on a standard KOOS classification. T1ρ MRI relaxation times were segmented in the weightbearing regions of lateral and medial femoral condyle (LFC and MFC). Inter-limb T1ρ MRI relaxation time ratios were calculated by normalizing the ACLR to the uninjured knee. T-tests were used to compare LFC and MFC interlimb T1ρ relaxation time ratios between individuals with and without knee symptoms. A Receiver Operating Characteristic (ROC) Curve analysis was used to determine a critical inter-limb T1ρ relaxation time ratio identifying symptomatic patients. Odds ratios (OR) and 95% confidence intervals (CI) estimated the association between the critical value and clinically relevant knee symptoms. RESULTS: Symptomatic individuals had significantly higher LFC inter-limb T1ρ MRI relaxation time ratios compared to asymptomatic individuals (p = 0.04). Individuals with an LFC inter-limb T1ρ MRI relaxation time ratio >1.11 were more likely to have symptoms (OR 8.5; 95%CI = 1.25-57.93). CONCLUSION: Individuals with greater inter-limb LFC T1ρ MRI relaxation time ratios 12 months post-ACLR may be more likely to exhibit symptoms consistent with knee OA.

Effects of the COVID-19 pandemic on secondary care for cardiovascular disease in the UK: an electronic health record analysis across three countries.

BACKGROUND: Although morbidity and mortality from COVID-19 have been widely reported, the indirect effects of the pandemic beyond 2020 on other major diseases and health service activity have not been well described. METHODS AND RESULTS: Analyses used national administrative electronic hospital records in England, Scotland, and Wales for 2016-21. Admissions and procedures during the pandemic (2020-21) related to six major cardiovascular conditions [acute coronary syndrome (ACS), heart failure (HF), stroke/transient ischaemic attack (TIA), peripheral arterial disease (PAD), aortic aneurysm (AA), and venous thromboembolism(VTE)] were compared with the annual average in the pre-pandemic period (2016-19). Differences were assessed by time period and urgency of care.In 2020, there were 31 064 (-6%) fewer hospital admissions [14 506 (-4%) fewer emergencies, 16 560 (-23%) fewer elective admissions] compared with 2016-19 for the six major cardiovascular diseases (CVDs) combined. The proportional reduction in admissions was similar in all three countries. Overall, hospital admissions returned to pre-pandemic levels in 2021. Elective admissions remained substantially below expected levels for almost all conditions in all three countries [-10 996 (-15%) fewer admissions]. However, these reductions were offset by higher than expected total emergency admissions [+25 878 (+6%) higher admissions], notably for HF and stroke in England, and for VTE in all three countries. Analyses for procedures showed similar temporal variations to admissions. CONCLUSION: The present study highlights increasing emergency cardiovascular admissions during the pandemic, in the context of a substantial and sustained reduction in elective admissions and procedures. This is likely to increase further the demands on cardiovascular services over the coming years.

Masticator space abscess following intramuscular stimulation.

A male in his 50s presented to the hospital with preauricular tenderness, trismus and dysphagia. He had intramuscular stimulation of his left temporomandibular joint region performed 4 days prior and described worsening pain and swelling since. A CT scan revealed an abscess involving the left masticator space. Incision and drainage of the abscess was performed, and the patient was discharged home on oral antibiotics 11 days later. This is the first report of masticatory space abscess following intramuscular stimulation of the temporomandibular joint area. Acupuncture and intramuscular stimulation are common complementary medicine therapies that are generally considered safe; however, adverse events such as deep neck space infection have been reported in the literature. Current regulation of training requirements and licensure for needling therapies is highly variable. Standardisation of training and practice guidelines may help mitigate the risk of adverse events related to needling therapies in the future.

Opioid-stimulant trends in overdose toxicology by race, ethnicity, & gender: An analysis in Delaware, 2013-2019.

Recent upticks of stimulant presence in overdose deaths suggest the opioid epidemic is morphing, which raises questions about what drugs are involved and who is impacted. We investigate annual and growth rate trends in combined opioid-stimulant overdose toxicology between 2013 and 2019 for White, Black, and Hispanic male and female decedents in Delaware. During these years, toxicology shifted to illegal drugs for all with fentanyl leading the increase and opioid-cocaine combinations rising substantially. While combined opioid-cocaine toxicology grew among Black and Hispanic Delawareans, White males continue to report the highest rates overall. These findings depart from historical patterns and may challenge existing opioid epidemic policies.

Clinical Outcomes of Neonatal Intensive Care Unit Graduates with Bridled Nasogastric Feeding Tubes.

OBJECTIVE: The aim of this study was to describe clinical outcomes of bridled nasogastric tube (NGT) program implementation for infants requiring assisted home feeding (AHF) to discharge from the neonatal intensive care unit (NICU). STUDY DESIGN: This was a descriptive prospective analysis of a pilot cohort of infants after implementation of a bridled NGT AHF program to facilitate discharge from level III and IV NICUs from March 2019 to October 2020. RESULTS: Of 29 attempts in infants, 22 infants were discharged with bridled NGTs over 18 months. Bridle placement was unsuccessful in three patients, and four bridles were removed before discharge. Bridle use ranged from 7 to 125 days, with a median duration of 37 days. Dislodgement rate was 0.69 per 100 days. Seventeen infants (77%) achieved full oral feeds, while five (23%) discharged with bridled NGTs later converted to gastrostomy tubes. CONCLUSION: Implementation of a bridled NGT program is feasible for level III and IV NICUs to facilitate discharging infants who require feeding support to transition home. KEY POINTS: · Bridled NGT use after NICU is typically 1 month.. · Infants have low bridle NGT dislodgement.. · Most bridled NGT NICU grads attain full oral feeds..

Transaminase Elevation in Nutritional Infantile Failure to Thrive.

INTRODUCTION: Laboratory investigations pursued for infants with failure to thrive (FTT) often show mild transaminase elevations, the incidence and significance of which are unknown. METHODS: This retrospective chart review included infants diagnosed with simple nutritional FTT at a single academic tertiary care system. Comparisons of diagnostic studies and outcomes between children with and without transaminase elevation were performed using chi-square and Wilcoxon rank sum tests. RESULTS: None of the infants with abnormal transaminases required additional follow-up or developed alternative diagnoses in the following year. DISCUSSION: Transaminase elevation may be common in infants with FTT and may not warrant further investigation if the history indicates an isolated etiology of insufficient nutrition.

The Modified Alberta Reconstructive Technique: A prospective cohort study.

INTRODUCTION: Jaw defect reconstructions have been transformed by the development of free tissue transfer using vascularized bone incorporating osseointegrated dental implants. We recently developed a modification our method this procedure and termed it the Modified Alberta Reconstruction Technique (MART). The objective of this study aimed to assess the soft tissue component and outcomes of the MART as compared to the Alberta Reconstructive Technique (ART) or conventional (BDD) reconstructions. PATIENTS AND METHODS: This was a prospective cohort study of adult patients who underwent jaw reconstruction with dental implant rehabilitation between 2000 and 2019 in Edmonton, Alberta. Patients were aged-matched and placed into a cohort based on the type of reconstruction they received. Outcomes were compared between the groups. Expert and aesthetic analyses were performed. Statistical analysis was conducted to determine significance. RESULTS: A total of 46 patients (15 BDD, 15 ART and 16 MART) were included. Demographics were similar between groups. There was no difference in complications. The soft tissue component of the MART cohort was more favourable to work with as judged by the occlusal reconstructive experts. The MART was rated as more aesthetically appealing in comparison to the BDD and ART (p = 0.049). CONCLUSIONS: The MART is a safe, effective, and aesthetically appealing procedure. It yields a good functional result and a clinically better soft tissue component for occlusal reconstructions. For a select group of patients requiring jaw reconstruction, the MART is an ideal reconstructive option as the modification provides good control of the soft tissue around the implants.

CRISPR-based gene disruption and integration of high-avidity, WT1-specific T cell receptors improve antitumor T cell function.

T cell receptor (TCR)-based therapy has the potential to induce durable clinical responses in patients with cancer by targeting intracellular tumor antigens with high sensitivity and by promoting T cell survival. However, the need for TCRs specific for shared oncogenic antigens and the need for manufacturing protocols able to redirect T cell specificity while preserving T cell fitness remain limiting factors. By longitudinal monitoring of T cell functionality and dynamics in 15 healthy donors, we isolated 19 TCRs specific for Wilms' tumor antigen 1 (WT1), which is overexpressed by several tumor types. TCRs recognized several peptides restricted by common human leukocyte antigen (HLA) alleles and displayed a wide range of functional avidities. We selected five high-avidity HLA-A*02:01-restricted TCRs, three that were specific to the less explored immunodominant WT137-45 and two that were specific to the noncanonical WT1-78-64 epitopes, both naturally processed by primary acute myeloid leukemia (AML) blasts. With CRISPR-Cas9 genome editing tools, we combined TCR-targeted integration into the TCR α constant (TRAC) locus with TCR ß constant (TRBC) knockout, thus avoiding TCRαß mispairing and maximizing TCR expression and function. The engineered lymphocytes were enriched in memory stem T cells. A unique WT137-45-specific TCR showed antigen-specific responses and efficiently killed AML blasts, acute lymphoblastic leukemia blasts, and glioblastoma cells in vitro and in vivo in the absence of off-tumor toxicity. T cells engineered to express this receptor are being advanced into clinical development for AML immunotherapy and represent a candidate therapy for other WT1-expressing tumors.

Development of a patient reported outcome instrument for chronic sialadenitis.

BACKGROUND: Sialendoscopy assisted treatments are a minimally invasive management modality for chronic sialadenitis. Clinicians report improved patient quality of life (QoL) following sialendoscopy assisted treatments, but there exist gaps in current literature about patient reported outcomes (PROs). PROs are outcome measures developed based on patient perceptions. OBJECTIVE: The objective of this study was to create a PRO instrument for chronic sialadenitis, to assess the efficacy of sialendoscopy assisted treatments in improve patients' QoL. DESIGN: This four-phase qualitative study employed grounded theory methodology and a modified Delphi technique. In Phase I, ten patients were interviewed to identify the QoL domains impacted by chronic sialadenitis. In Phase II, these QoL domains were presented to a focus group of different chronic sialadenitis patients, who were asked to rank them by order of importance. A conceptual framework of QoL domains impacted by chronic sialadenitis was created based on patient consensus. Itemization of the PRO questionnaire was done by a focus group of four Otolaryngologists in phase III. Lastly, the questionnaire was completed in Phase IV by cognitive interviewing of five new chronic sialadenitis patients; ensuring ease of understanding and clarity. RESULTS: Patients identified 15 domains of QoL impacted by chronic sialadenitis, divided into three sub-scales: physical symptoms, psychosocial symptoms, and activity restriction. These domains provided the basis for creation of a 22-item PRO questionnaire, with a Likert-type response scale. CONCLUSION: Clinical application of the novel questionnaire produced by this study will allow for a patient-centered assessment of the patient reported effectiveness of sialendoscopy assisted therapies for management of chronic sialadenitis. Level of evidence Level V.

Rapid Infliximab Biosimilar Infusion in Children With Inflammatory Bowel Disease.

OBJECTIVES: Compare prevalence of infusion reaction (IR) between infliximab (IFX) and infliximab biosimilar (IFX-abda) at standard and rapid rates and measure the impact on health care cost in children with inflammatory bowel disease (IBD). METHODS: Records of subjects receiving IFX and IFX-abda were reviewed over a 21-month period. Demographics and IRs were recorded. Cost analysis utilized average wholesale pricing, infusion duration, nursing time, and infusion center throughput. RESULTS: Fifty-six subjects received 498 infusions. Sixteen subjects received both IFX and IFX-abda. Thirteen IRs occurred for an overall prevalence of 2.6%. One outlier subject accounted for 8 of 13 (62%) of IRs. Data were analyzed with and without the outlier. Standard rate infusion of both IFX and IFX-abda was associated with increased risk of IR compared with rapid rate but only reached significance for IFX when calculated with the outlier removed. Risk of IR was not statistically significant between IFX and IFX-abda for both standard and rapid rates. IFX-abda saved an average of $2,611 per infusion. Rapid infusion saved 70 minutes of infusion time, 20 minutes of estimated nursing time per infusion, and decreased infusion center appointment length by as much as 2 hours per infusion. CONCLUSIONS: Rapid IFX-abda appears safe without increased IRs and decreases cost.

Utility of droplet digital polymerase chain reaction for TERT and BRAF mutational profiling of thyroid nodules.

BACKGROUND: Mutations involving BRAF and TERT are important predictors of disease severity in thyroid cancer, but molecular testing is limited by cost and lack of adequate tissue sample. This study aimed to assess the utility of BRAFV600E and TERT testing using droplet digital PCR (ddPCR) as a diagnostic and prognostic tool for thyroid fine needle aspirate biopsy (FNAB). METHODS: Patients with thyroid nodules were prospectively enrolled from March 2015 to September 2018. Pre-operative FNAB was collected for standard cytology and molecular testing. BRAFV600E and TERT levels were analyzed by ddPCR. Cytology (Bethesda system) and ddPCR results were correlated to surgical pathology. RESULTS: A total of 222 patients were enrolled, of which 124 received thyroid surgery. Pre-operative cytology alone with Bethesda ≥5 was 100% specific and 70% sensitive for malignancy on final surgical pathology. BRAFV600E positivity or TERT overexpression was 100% specific and 60.0% sensitive. Combining cytology (Bethesda ≥5) with BRAFV600E and TERT testing increased the sensitivity of a malignant diagnosis to 80.0%. High TERT levels and/or BRAFV600E was associated with aggressive or advanced stage pathology. CONCLUSIONS: Combining cytology with ddPCR analysis of BRAFV600E and TERT can improve the diagnostic accuracy of thyroid FNAB, and help predict aggressive pathology.

Implementing a Culture of Health Among Probationers.

Justice-involved individuals struggle with a multitude of health issues, and addressing the needs of these individuals requires the efforts of multiple agencies working across traditionally siloed systems. This study provides evidence on the implementation of a one-stop health services delivery model, Culture of Health, piloted in an urban probation office. This model uses a change team approach to focus the efforts of multiple agencies toward improving the alignment, collaboration, and synergy of health and other social service delivery to this underserved population. This article reports on the development and application issues involved in instituting such a novel design. The study demonstrates that the health culture within probation, buy-in from probation officers, and dwindling support from change team members all posed noteworthy issues for program implementation.

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS: After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS: Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS: In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.).

Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption.

Bone formation and resorption are typically coupled, such that the efficacy of anabolic osteoporosis treatments may be limited by bone destruction. The multi-kinase inhibitor YKL-05-099 potently inhibits salt inducible kinases (SIKs) and may represent a promising new class of bone anabolic agents. Here, we report that YKL-05-099 increases bone formation in hypogonadal female mice without increasing bone resorption. Postnatal mice with inducible, global deletion of SIK2 and SIK3 show increased bone mass, increased bone formation, and, distinct from the effects of YKL-05-099, increased bone resorption. No cell-intrinsic role of SIKs in osteoclasts was noted. In addition to blocking SIKs, YKL-05-099 also binds and inhibits CSF1R, the receptor for the osteoclastogenic cytokine M-CSF. Modeling reveals that YKL-05-099 binds to SIK2 and CSF1R in a similar manner. Dual targeting of SIK2/3 and CSF1R induces bone formation without concomitantly increasing bone resorption and thereby may overcome limitations of most current anabolic osteoporosis therapies.

Inhibition of the Complement Alternative Pathway by Chemically Modified DNA Aptamers That Bind with Picomolar Affinity to Factor B.

The complement system is a conserved component of innate immunity that fulfills diverse roles in defense and homeostasis. Inappropriate activation of complement contributes to many inflammatory diseases, however, which has led to a renewed emphasis on development of therapeutic complement inhibitors. Activation of complement component C3 is required for amplification of complement and is achieved through two multisubunit proteases called C3 convertases. Of these, the alternative pathway (AP) C3 convertase is responsible for a majority of the C3 activation products in vivo, which renders it an attractive target for inhibitor discovery. In this study, we report the identification and characterization of two related slow off-rate modified DNA aptamers (SOMAmer) reagents that inhibit formation of the AP C3 convertase by binding to the proprotease, factor B (FB). These aptamers, known as SL1102 (31 bases) and SL1103 (29 bases), contain uniform substitutions of 5-(N-2-naphthylethylcarboxyamide)-2'-deoxyuridine for deoxythymidine. SL1102 and SL1103 bind FB with K d values of 49 and 88 pM, respectively, and inhibit activation of C3 and lysis of rabbit erythrocytes under AP-specific conditions. Cocrystal structures of SL1102 (3.4 Å) and SL1103 (3.1 Å) bound to human FB revealed that SL1102 and SL1103 recognize a site at the juncture of the CCP1, CCP3, and vWF domains of FB. Consistent with these structures and previously published information, these aptamers inhibited FB binding to C3b and blocked formation of the AP C3 convertase. Together, these results demonstrate potent AP inhibition by modified DNA aptamers and expand the pipeline of FB-binding molecules with favorable pharmacologic properties.

Hemosuccus Pancreaticus Following Acute Pancreatitis in a 12-years-old Boy Secondary to Pancreatic Pseudoaneurysm Treated With Endovascular Coil Embolization.

Hemosuccus pancreaticus is a very rare cause of upper gastrointestinal bleeding in children. It is defined as bleeding from the pancreatic or peripancreatic vessels into the main pancreatic duct and may be life-threatening. We present the case of a 12-year-old boy with hematemesis and severe anemia that developed following an episode of acute pancreatitis. Upper endoscopy did not reveal a bleeding source. An endoscopic retrograde cholangiopancreatography performed for the evaluation of common bile duct obstruction identified bleeding from the pancreatic duct. Subsequently, the bleeding source, a pseudoaneurysm of the splenic artery, was identified by conventional angiography and occluded with coil embolization. The diagnosis of hemosuccus pancreaticus may be difficult in children due to rare occurrence and the unusual anatomical site; hence, a high index of suspicion is needed in a patient with a history of pancreatitis who presents with intermittent upper gastrointestinal bleeding and normal upper endoscopy.