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BACKGROUND: Intravenous immunoglobulin (IVIg) is a critical replacement therapy for immunodeficiencies and immunomodulatory treatment for autoimmune and inflammatory diseases. Adequate supply of IVIg is a global issue, necessitating supply restrictions. In Australia, despite strict criteria for use, demand for IVIg has increased over time and exceeds domestic supply. OBJECTIVE: Factors associated with the upward trend in overall IVIg use were examined, including in the number of unique patients, IVIg dosing and treatment frequency and variations by prescribing discipline and disease group. METHODS: De-identified data of IVIg dispensed in the largest Australian state (New South Wales) from 2007 to 2013 were provided by Australian Red Cross Lifeblood. Trends and projections were calculated using log-linear regression of unique patients, treatment episodes and grams of IVIg for overall use and use stratified by discipline and disease group. RESULTS: During the study period, 169 453 treatment episodes were recorded for 12 547 unique patients accounting for 5 827 787 g of IVIg use. Overall, IVIg use increased by 12.0% (11.5-12.6%) per year representing a 97.7% increase (91.6-104%) over the study period. The highest growth was among neurological conditions (16.0% (14.9-17.1%) per year). An increase in the number of unique patients was the primary driver of this growth, augmented by increases in the frequency and average dose per treatment. CONCLUSIONS: Clinically acceptable measures to improve management of IVIg supply are needed including optimising dose, frequency and duration of treatment. Formal evaluation of IVIg versus alternatives, including cost-effectiveness and comparative efficacy, is warranted.

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INTRODUCTION: Microsatellite instability (MSI) and mismatch repair (MMR) deficiency represent a distinct oncogenic process and predict response to immune checkpoint inhibitors (ICIs). The clinicopathologic features of MSI-high (MSI-H) and MMR deficiency (MMR-D) in lung cancers remain poorly characterized. METHODS: MSI status from 5171 patients with NSCLC and 315 patients with SCLC was analyzed from targeted next-generation sequencing data using two validated bioinformatic pipelines. RESULTS: MSI-H and MMR-D were identified in 21 patients with NSCLC (0.41%) and six patients with SCLC (1.9%). Notably, all patients with NSCLC had a positive smoking history, including 11 adenocarcinomas. Compared with microsatellite stable cases, MSI-H was associated with exceptionally high tumor mutational burden (37.4 versus 8.5 muts/Mb, p < 0.0001), MMR mutational signatures (43% versus 0%, p < 0.0001), and somatic biallelic alterations in MLH1 (52% versus 0%, p < 0.0001). Loss of MLH1 and PMS2 expression by immunohistochemistry was found in MLH1 altered and wild-type cases. Similarly, the majority of patients with MSI-H SCLC had evidence of MLH1 inactivation, including two with MLH1 promoter hypermethylation. A single patient with NSCLC with a somatic MSH2 mutation had Lynch syndrome as confirmed by the presence of a germline MSH2 mutation. Among patients with advanced MSI-H lung cancers treated with ICIs, durable clinical benefit was observed in three of eight patients with NSCLC and two of two patients with SCLC. In NSCLC, STK11, KEAP1, and JAK1 were mutated in nonresponders but wild type in responders. CONCLUSIONS: We present a comprehensive clinicogenomic landscape of MSI-H lung cancers and reveal that MSI-H defines a rare subset of lung cancers associated with smoking, high tumor mutational burden, and MLH1 inactivation. Although durable clinical benefit to ICI was observed in some patients, the broad range of responses suggests that clinical activity may be modulated by co-mutational landscapes.

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Background: Hypoglossal-facial nerve (12-7) anastomosis can restore symmetry and voluntary movement on the face in patients with facial nerve paralysis. Traditional 12-7 transfer includes direct end-to-end nerve anastomosis, sacrificing the entire hypoglossal nerve. Contemporary, end-to-side anastomosis, or split anastomosis techniques limit tongue morbidity by preserving some hypoglossal nerve. Direct outcome comparisons between these techniques are limited. Objective: To compare reported outcomes of facial movement, tongue, speech, and swallow outcomes among the different types of hypoglossal-facial nerve anastomosis schemes. Evidence Review: For this systematic review and meta-analysis, a comprehensive strategy was designed to search PubMed, Scopus, and the Cochrane Database from inception to January 2021, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis, reporting guideline yielding 383 results. Any participant who underwent 12-7 transfer using any of the three techniques, with or without an interposition graft, and had documented preoperative and postoperative evaluation of facial nerve function with a validated instrument such as House-Brackmann (HB), was considered for inclusion. Secondary outcomes of synkinesis, tongue atrophy, and speech or swallowing dysfunction were also compared. Forty-nine studies met inclusion criteria, representing data from 961 total patients who underwent 12-7 transfer. Results: The proportion of good HB outcomes (HB I-III) did not differ by anastomosis type: End-to-side and end-to-end anastomosis (73% vs. 59%, p = 0.07), split and end-to-end anastomosis (62% vs. 59%, p = 0.88), and end-to-side anastomosis and split anastomosis (73% vs. 62%, p = 0.46). There was no difference in reported synkinesis rates between the anastomosis types. However, end-to-side anastomosis (z = 6.55, p < 0.01) and split anastomosis (z = 3.58, p < 0.01) developed less tongue atrophy than end-to-end anastomosis. End-to-side anastomosis had less speech/swallowing dysfunction than end-to-end anastomosis (z = 3.21, p < 0.01). Conclusion: End-to-side and split anastomoses result in similar HB facial nerve outcomes as the traditional end-to-end 12-7 anastomosis. End-to-side anastomosis has decreased complications of tongue atrophy and speech/swallow dysfunction compared to end-to-end anastomosis. In addition, split anastomosis has decreased rates of tongue atrophy compared to end-to-end anastomosis.

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In the past 10 years, we have witnessed major advances in clinical immunology. Newborn screening for severe combined immunodeficiency has become universal in the United States and screening programs are being extended to severe combined immunodeficiency and other inborn errors of immunity globally. Early genetic testing is becoming the norm for many of our patients and allows for informed selection of targeted therapies including biologics repurposed from other specialties. During the COVID-19 pandemic, our understanding of essential immune responses expanded and the discovery of immune gene defects continued. Immunoglobulin products, the backbone of protection for antibody deficiency syndromes, came into use to minimize side effects. New polyclonal and monoclonal antibody products emerged with increasing options to manage respiratory viral agents such as SARS-CoV-2 and respiratory syncytial virus. Against these advances, we still face major challenges. Atypical is becoming typical as phenotypes of distinct genetic disease overlap whereas the clinical spectrum of the same genetic defect widens. Therefore, clinical judgment needs to be paired with repeated deep immune phenotyping and upfront genetic testing, as technologies rapidly evolve, and clinical disease often progresses with age. Managing patients with organ damage resulting from immune dysregulation poses a special major clinical challenge and management often lacks standardization, from autoimmune cytopenias, granulomatous interstitial lung disease, enteropathy, and liver disease to endocrine, rheumatologic, and neurologic complications. Clinical, translational, and basic science networks will continue to advance the field; however, cross-talk and education with practicing allergists/immunologists are essential to keep up with the ever-changing clinical and genetic landscape of inborn errors of immunity.

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Background: Open septorhinoplasty is a common facial plastic surgery procedure that requires extensive planning and knowledge to achieve predictable outcomes. Many patients want to keep their nasal tip characteristics, and the surgeon's task is to reliably meet this expectation and provide stable long-term results. Techniques used to reconstruct nasal tip support include the tongue-in-groove, caudal septal extension graft, and caudal septal replacement graft procedures. Methods: We assessed the 1-year reliability of tongue-in-groove, caudal septal extension graft, and caudal septal replacement graft procedures in maintaining nasal tip rotation and projection in open septorhinoplasty. We conducted a retrospective case series review of septorhinoplasty cases between 2015 and 2019 at the Medical University of South Carolina. Cases with intention to change nasal tip rotation or projection were excluded. Two blinded reviewers analyzed standardized preoperative and 1-year postoperative photographs. Results: Fifty-seven patients fit the inclusion criteria and were included in the analysis. Mean preoperative and postoperative nasal tip rotations and projection ratios were similar (P=0.62, P=0.22, respectively). Twenty-six patients underwent a tongue-in-groove procedure, 24 had a caudal septal extension graft, and 7 had a caudal septal replacement graft with preoperative nasal tip rotations of 98.93°, 99.35°, and 96.89°, respectively (P=0.73). At 1 year, patients who received a tongue-in-groove procedure had a significant increase in nasal tip rotation to 101.24° (P=0.013), while patients who received a caudal septal extension graft had a significant decrease in nasal tip rotation to 97.25° (P=0.009). Patients who received a caudal septal replacement graft had no significant change in nasal tip rotation (P=0.117). The preoperative and postoperative projection ratios were not significantly different among the 3 techniques. Conclusion: Tongue-in-groove, caudal septal extension graft, and caudal septal replacement graft are reliable techniques for maintaining nasal tip projection in open septorhinoplasty. In our experience, when attempting to maintain preoperative nasal tip rotation, the tongue-in-groove technique resulted in a significant increase in tip rotation of 2.31°, while the caudal septal extension graft resulted in a significant decrease of 2.1° at 1 year postoperatively.

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The ongoing COVID-19 pandemic constitutes a critical phase for the transnationalization of public spheres. Against this backdrop, we ask how transnational COVID-19 related online discourse has been throughout the EU over the first year of the pandemic. Which events triggered higher transnational coherence or national structuration of this specific issue public on Twitter? In order to study these questions, we rely on Twitter data obtained from the TBCOV database, i.e., a dataset for multilingual, geolocated COVID-19 related Twitter communication. We selected corpora for the 27 member states of the EU plus the United Kingdom. We defined three research periods representing different phases of the pandemic, namely April (1st wave), August (interim) and December 2020 (2nd wave) resulting in a set of 51,893,966 unique tweets for comparative analysis. In order to measure the level and temporal variation of transnational discursive linkages, we conducted a spatiotemporal network analysis of so-called Heterogeneous Information Networks (HINs). HINs allow for the integration of multiple, heterogeneous network entities (hashtags, retweets, @-mentions, URLs and named entities) to better represent the complex discursive structures reflected in social media communication. Therefrom, we obtained an aggregate measure of transnational linkages on a daily base by relating these linkages back to their geolocated authors. We find that the share of transnational discursive linkages increased over the course of the pandemic, indicating effects of adaptation and learning. However, stringent political measures of crisis management at the domestic level (such as lockdown decisions) caused stronger national structuration of COVID-19 related Twitter discourse.

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OBJECTIVES: The indications and outcomes of masseteric-to-facial nerve transfer in pediatric patients with short-term facial paralysis is incompletely understood as compared to its use in adult patients. This report aims to retrospectively quantify outcomes with both clinician-based measurements and objective facial analysis software. METHODS: Retrospective case series at a single institution. The Sunnybrook Facial Grading System was used for clinician-based measurements and Emotrics software for objective measurements. RESULTS: Four pediatric patients underwent masseteric-to-facial nerve transfers from 2016 to 2018. The mean patient age at the time of surgery was 4.5 years (range = 2-7) and the mean time from paralysis onset to surgical intervention was 12.9 months (range = 10.0-16.2). The mean follow-up was 18.3 months (range = 14.5-23.6). With regards to the Sunnybrook resting nasolabial fold symmetry, 3 of the 4 patients improved from 2 (absent nasolabial fold) to 1 (less pronounced nasolabial fold). Per the Emotrics analysis, the pre- and post-operative mean absolute differences for commissure excursion between the normal functioning and paralyzed sides were 11.8 mm and 6.7 mm, respectively (p = 0.04). CONCLUSION: The masseteric-to-facial nerve transfer technique leads to an objective improvement in dynamic smile function in select pediatric patients.

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Aspiring physicians face a large amount of information that must be learned and retrieved in real time. The skills that helped medical students reach residency may not be the enough to succeed as a physician. For example, like many students, cramming the night before an exam probably helped achieve a satisfactory score. Unfortunately, cramming does not require that the information be retained and applied overtime. The content acquired in medical school is cumulative, that is, the information learned remains relevant months and even years later. Not only does content need to remembered, the knowledge must be constantly updated as new research makes some information more relevant and other information less important. Finally, the stakes as a physician are high. Forgetting a critical piece of information will not result in a lower test score, it can seriously harm patients. This article is a practical approach to teaching medical doctors, based on a literature review, including practical, scientific, and applied research and strategies ways in which teaching can be done that result in depth of learning in the resident.

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Sterile α motif domain-containing protein 9-like (SAMD9L) is encoded by a hallmark interferon-induced gene with a role in controlling virus replication that is not well understood. Here, we analyze SAMD9L function from the perspective of human mutations causing neonatal-onset severe autoinflammatory disease. Whole-genome sequencing of two children with leukocytoclastic panniculitis, basal ganglia calcifications, raised blood inflammatory markers, neutrophilia, anemia, thrombocytopaenia, and almost no B cells revealed heterozygous de novo SAMD9L mutations, p.Asn885Thrfs*6 and p.Lys878Serfs*13. These frameshift mutations truncate the SAMD9L protein within a domain a region of homology to the nucleotide-binding and oligomerization domain (NOD) of APAF1, ∼80 amino acids C-terminal to the Walker B motif. Single-cell analysis of human cells expressing green fluorescent protein (GFP)-SAMD9L fusion proteins revealed that enforced expression of wild-type SAMD9L repressed translation of red fluorescent protein messenger RNA and globally repressed endogenous protein translation, cell autonomously and in proportion to the level of GFP-SAMD9L in each cell. The children's truncating mutations dramatically exaggerated translational repression even at low levels of GFP-SAMD9L per cell, as did a missense Arg986Cys mutation reported recurrently as causing ataxia pancytopenia syndrome. Autoinflammatory disease associated with SAMD9L truncating mutations appears to result from an interferon-induced translational repressor whose activity goes unchecked by the loss of C-terminal domains that may normally sense virus infection.

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OBJECTIVE: Broad adoption of digital pathology (DP) is still lacking, and examples for DP connecting diagnostic, research, and educational use cases are missing. We blueprint a holistic DP solution at a large academic medical center ubiquitously integrated into clinical workflows; researchapplications including molecular, genetic, and tissue databases; and educational processes. MATERIALS AND METHODS: We built a vendor-agnostic, integrated viewer for reviewing, annotating, sharing, and quality assurance of digital slides in a clinical or research context. It is the first homegrown viewer cleared by New York State provisional approval in 2020 for primary diagnosis and remote sign-out during the COVID-19 (coronavirus disease 2019) pandemic. We further introduce an interconnected Honest Broker for BioInformatics Technology (HoBBIT) to systematically compile and share large-scale DP research datasets including anonymized images, redacted pathology reports, and clinical data of patients with consent. RESULTS: The solution has been operationally used over 3 years by 926 pathologists and researchers evaluating 288 903 digital slides. A total of 51% of these were reviewed within 1 month after scanning. Seamless integration of the viewer into 4 hospital systems clearly increases the adoption of DP. HoBBIT directly impacts the translation of knowledge in pathology into effective new health measures, including artificial intelligence-driven detection models for prostate cancer, basal cell carcinoma, and breast cancer metastases, developed and validated on thousands of cases. CONCLUSIONS: We highlight major challenges and lessons learned when going digital to provide orientation for other pathologists. Building interconnected solutions will not only increase adoption of DP, but also facilitate next-generation computational pathology at scale for enhanced cancer research.

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Nasal reconstruction following a total or subtotal resection presents a challenging clinical scenario. Ample external skin coverage is readily available using the paramedian forehead flap (PMFF), but restoring adequate internal lining of sufficient size and pliability is a major limitation. Intranasal mucosal flaps or free tissue transfer is often employed for this purpose, each with their own sets of limitations. Prelamination of the PMFF with a skin graft prior to transfer is a method to create a composite flap with both internal and external lining. Another challenge in subtotal nasal reconstruction centres around restoring adequate dimensions to the nose without an existing template to work from. Three-dimensional (3D) printing has become an increasingly popular tool in reconstructive surgery as it captures precise patient-specific dimensions to guide reconstruction. Herein, we describe a case of subtotal nasal reconstruction using a prelaminated PMFF using a patient-specific 3D printed model as a template for reconstruction.

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BACKGROUND: Post-operative dysphagia is one of the most common complications of anterior cervical spine surgery (ACSS). OBJECTIVE: Examine post-operative structural and physiologic swallowing changes in patients with dysphagia following ACSS as compared with healthy age and gender matched controls. METHODS: Videofluoroscopic swallow studies of adults with dysphagia after ACSS were retrospectively reviewed. Seventy-five patients were divided into early (≤2 months) and late (> 2 months) post-surgical groups. Modified Barium Swallow Impairment Profile (MBSImP), Penetration-Aspiration Scale (PAS) scores, and pharyngeal wall thickness (PWT) metrics were compared. RESULTS: Significant differences were identified for all parameters between the control and early post-operative group. MBSImP Pharyngeal Total (PT) scores were greater in the early group (Interquartile Range (IQR) = 9-14, median = 12) versus controls (4-7, 5, P < 0.001) and late group (0.75-7.25, 2, P < 0.001). The early group had significantly higher maximum PAS scores (IQR = 3-8, median = 7) than both the control group (1-2, 1, P < 0.001) and late post-operative group (1-1.25, 1, P < 0.001). PWT was significantly greater in the early (IQR = 11.12-17.33 mm, median = 14.32 mm) and late groups (5.31-13.01, 9.15 mm) than controls (3.81-5.41, 4.68 mm, P < 0.001). CONCLUSION: Dysphagic complaints can persist more than two months following ACSS, but often do not correlate with validated physiologic swallowing dysfunction on VFSS. Future studies should focus on applications of newer technology to elucidate relevant deficits.

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Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.

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Giant cell myocarditis (GCM) is a rare and rapidly fatal cardiovascular condition most often seen in young adults. It is characterized microscopically by myocardial necrosis with multinucleated giant cells in the absence of well-defined granulomas. This disorder has typically been attributed to manifest as heart failure, but in some individuals, GCM may present as sudden cardiac death. Herein, we present a fatal case of GCM in a 36-year-old male with a history of autoimmune disorders. The decedent presented to the emergency room due to vomiting and was treated for nausea due to suspected dehydration. He was discharged that night and found dead on his bathroom floor the following day. Postmortem examination revealed psoriasis and granulomatous lesions in the lungs consistent with sarcoidosis, further supporting circumstantial evidence existing between GCM and autoimmune disorders. Additionally, this case provides an opportunity to distinguish GCM from the distinct clinical entity of cardiac sarcoidosis (CS), especially in the setting of systemic sarcoidosis. We hope to raise awareness of this rare disease process and its potential to cause sudden cardiac death so that it may be considered in a differential diagnosis as immunosuppression and early cardiac transplantation largely determine the prognosis.

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[This retracts the article DOI: 10.1186/2045-7022-5-S3-P30.].

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Giant cell myocarditis (GCM) is a rare and rapidly fatal cardiovascular condition most often seen in young adults. It is characterized microscopically by myocardial necrosis with multinucleated giant cells in the absence of well-defined granulomas. This disorder has typically been attributed to manifest as heart failure, but in some individuals, GCM may present as sudden cardiac death. Herein, we present a fatal case of GCM in a 36-year-old male with a history of autoimmune disorders. The decedent presented to the emergency room due to vomiting and was treated for nausea due to suspected dehydration. He was discharged that night and found dead on his bathroom floor the following day. Postmortem examination revealed psoriasis and granulomatous lesions in the lungs consistent with sarcoidosis, further supporting circumstantial evidence existing between GCM and autoimmune disorders. Additionally, this case provides an opportunity to distinguish GCM from the distinct clinical entity of cardiac sarcoidosis (CS), especially in the setting of systemic sarcoidosis. We hope to raise awareness of this rare disease process and its potential to cause sudden cardiac death so that it may be considered in a differential diagnosis as immunosuppression and early cardiac transplantation largely determine the prognosis.

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