Are isolated ocular motor nerve palsies in the elderly truly 'low risk' for abnormal neuro-imaging outcomes?

BACKGROUND: Neurologically isolated ocular motor nerve palsies often present a management dilemma. Neuroimaging is more likely to be offered to patients <50 years without coexisting ischaemic risk factors as their risk of sinister underlying causes is thought to be higher. However, populations are rapidly ageing and advanced neuroimaging is now more widely available. We thus investigated the incidence of abnormal neuroimaging outcomes in the traditionally low-risk older patient group. METHODS: This is a retrospective cohort study of 353 patients presenting with isolated ocular motor nerve palsies to a tertiary neuro-ophthalmology service in Singapore over a four-year (2015 to 2019) period. Clinical data was obtained through manual review of case records. Common aetiologies, age-based differences in prevalence of causes and abnormal neuroimaging outcomes were statistically analysed. RESULTS: Abnormal neuroimaging outcomes were significantly greater in the younger cohort only when age segregation was performed at 60 years of age. In a multivariate analysis, acute onset rather than ischaemic risk factors were independently predictive of normal neuroimaging outcomes. After adjusting for prior cancer risk and clinical bias from presumed ischaemic palsies, abnormal neuroimaging outcomes were seen in 14.1% ≥ 50 yrs, 10.9% ≥ 60 yrs and 15.1% ≥ 70 yrs. CONCLUSIONS: In patients presenting with isolated ocular motor nerve palsies, acute onset may be a more reliable indicator of an ischaemic palsy rather than advanced age or presence of ischaemic risk factors. If onset is not acute, neuroimaging should be considered irrespective of age and coexisting ischaemic risk factors.

Dental student oral surgery training-Comparing the impact of COVID-19 and cohort sizes.

INTRODUCTION: The response to the COVID-19 pandemic potentially reduced the clinical experience and academic education of dental trainees through reduced supervised clinical sessions. Graduating dental students, future employers and regulators may be concerned over the level of clinical experience of graduates trained within the COVID-19 pandemic. The purpose of this study was to try and document the evidence for, and significance of, this impact. MATERIALS AND METHODS: From dental student data in the 2017, 2018, 2019 and 2020 cohorts attending the University of Sydney, Australia, the number of dental extractions and adjunct oral surgery procedures, as well as final end-of-year examination results, was recorded. Results were compared to determine whether differences in experience and final academic achievement existed between these cohorts. RESULTS: The smallest student cohort, 2017, demonstrated greater clinical experience than the 2018, 2019 and 2020 cohorts. The 2020 COVID-19-affected cohort demonstrated no statistically significant reduction in clinical experience in all measured clinical procedures when compared to the 2018 and 2019 cohorts. The decrease in city teaching hospital clinical experience was compensated by an increase in rural placements. The 2020 cohort achieved the lowest academic results, and this was statistically significant. CONCLUSION: The oral surgery clinical experience of the 2020 dental cohort at the University of Sydney was comparable to prior cohorts. Rural clinics were able to compensate for COVID-19 interruptions to clinical training. The number of students in a cohort, if all other variables remain constant, appeared to affect clinical exposure to a greater extent than COVID-19.

Clinical experience improves academic outcomes in dental Oral surgery education.

INTRODUCTION: This paper aimed to determine if the level of a dental student's clinical experience in oral surgery influences the student's oral surgery academic outcomes. MATERIALS AND METHODS: The oral surgery clinical activity and academic outcomes for all students who completed their dental training in 2017, 2018, 2019 and 2020 from the University of Sydney were analysed for correlation. RESULTS: The clinical activity performed by 313 students was recorded. There was a weak, but statistically significant, Pearson correlation between total dental extractions and academic outcomes (r = .243, p = <.001). The total number of dental extractions performed was the only statistically significant variable on academic outcomes with linear regression analysis (ß = .227, p = .005; model R2  = .077). The increase of a student's clinical experience from less than 45 to more than 65 dental extractions raised their oral surgery academic results by an average of 6.4%. There were no academic benefits to earlier clinical experience. CONCLUSION: An increase in experience with dental extractions resulted in an increase in oral surgery academic outcomes, plateauing at 65 dental extractions. There was no academic advantage to dental student's having earlier clinical experience.

Myeloid Sarcoma of the Breast: A Diagnostic Dilemma With Pathologic Correlation.

Myeloid sarcoma (MS) is a rare extramedullary solid tumor arising most often in patients with current or subsequent acute myeloid leukemia (AML). Patients of all ages may present with involvement of the skin, lymph nodes, intestinal tract, bone, and/or central nervous system. Isolated involvement of the breast is rare, and only a small number of cases have been described in the literature. Breast MS may present as a palpable mass on clinical evaluation. In this broad literature review from 2010 to 2022, the most common findings on mammography are either solitary or multiple masses, followed by architectural distortion and, less commonly, no discrete findings. Sonography may demonstrate hypoechoic or mixed echogenicity mass(es) with circumscribed or indistinct, not discrete margins. Myeloid sarcoma may present as an enhancing mass or nonmass enhancement on breast MRI and is typically moderately radiotracer avid on 18F-fluorodeoxyglucose-PET. At histopathology, MS is characterized by myeloid blasts in varying stages of granulocytic or neutrophilic maturation; diagnosis typically requires immunophenotyping. There is no consensus for treatment of MS, although systemic chemotherapy for AML is often used as MS is considered the tissue equivalent of AML. This article will discuss and illustrate imaging and pathology findings when the breast is involved by MS.

Inflammatory Bowel Disease in Children With Systemic Juvenile Idiopathic Arthritis.

OBJECTIVE: The incidence of inflammatory bowel disease (IBD) in juvenile idiopathic arthritis (JIA) is higher than in the general pediatric population. However, reports of IBD in the systemic JIA (sJIA) subtype are limited. We sought to characterize sJIA patients diagnosed with IBD and to identify potential contributing risk factors. METHODS: Using an internationally distributed survey, we identified 16 patients with sJIA who were subsequently diagnosed with IBD (sJIA-IBD cohort). Five hundred twenty-two sJIA patients without IBD were identified from the CARRA Legacy Registry and served as the sJIA-only cohort for comparison. Differences in demographic, clinical characteristics, and therapy were assessed using chi-square test, Fisher exact test, t-test, and univariate and multivariate logistic regression, as appropriate. RESULTS: Of the patients with sJIA-IBD, 75% had a persistent sJIA course and 25% had a history of macrophage activation syndrome. sJIA-IBD subjects were older at sJIA diagnosis, more often non-White, had a higher rate of IBD family history, and were more frequently treated with etanercept or canakinumab compared to sJIA-only subjects. Sixty-nine percent of sJIA-IBD patients successfully discontinued sJIA medications following IBD diagnosis, and sJIA symptoms resolved in 9 of 12 patients treated with tumor necrosis factor-α (TNF-α) inhibitors. CONCLUSION: IBD in the setting of sJIA is a rare occurrence. The favorable response of sJIA symptoms to therapeutic TNF-α inhibition suggests that the sJIA-IBD cohort may represent a mechanistically distinct sJIA subgroup. Our study highlights the importance of maintaining a high level of suspicion for IBD when gastrointestinal involvement occurs in patients with sJIA and the likely broad benefit of TNF-α inhibition in those cases.

Predictors of hospital readmission among older adults with cancer.

OBJECTIVE: Older adults with cancer are at higher risk for costly and potentially dangerous hospital readmissions. Identifying risk factors for readmission in this population is important for future prevention of readmission. MATERIALS AND METHODS: Hospital discharges among patients ≥ 65 years with solid tumors on non-surgical services from 2006-2011 were reviewed in this matched case-control study. We abstracted patient/cancer characteristics; functional status; fall risk; chemotherapy line; comorbidities; laboratory values; discharge parameters; and miscellaneous information (Do Not Resuscitate Order, pain scores) from medical records. Conditional logistic regression was used for univariate and multivariable analysis. RESULTS: This analysis included 184 case-patients readmitted within 30 days after discharge from the index admission and 184 sex- and age-matched control-patients discharged from index admission within three months of the cases with no readmission. Cases and controls had no differences in terms of primary cancer type, treatment, and index admission reason. Cases were more likely to have abnormal hemoglobin, albumin, sodium, and SGOT on discharge. Compared to those with ≤1 abnormal laboratory test, patients with 2 or more abnormal test results were 3 times more likely to be readmitted within 30 days. CONCLUSION: This study demonstrated that older adults with cancer who had at least 2 abnormal laboratory results (hemoglobin, albumin, sodium, and SGOT) at discharge were 3 times more likely to be readmitted within 30 days compared to those with ≤1 abnormal results. These laboratory values may be predictive of the risk of readmission, and should be monitored before discharge to potentially prevent readmission.

Pilot study comparing the childhood arthritis and rheumatology research alliance consensus treatment plans for induction therapy of juvenile proliferative lupus nephritis.

BACKGROUND: To reduce treatment variability and facilitate comparative effectiveness studies, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published consensus treatment plans (CTPs) including one for juvenile proliferative lupus nephritis (LN). Induction immunosuppression CTPs outline treatment with either monthly intravenous (IV) cyclophosphamide (CYC) or mycophenolate mofetil (MMF) in conjunction with one of three corticosteroid (steroid) CTPs: primarily oral, primarily IV or mixed oral/IV. The acceptability and in-practice use of these CTPs are unknown. Therefore, the primary aims of the pilot study were to demonstrate feasibility of adhering to the LN CTPs and delineate barriers to implementation in clinical care in the US. Further, we aimed to explore the safety and effectiveness of the treatments for induction therapy. METHODS: Forty-one patients were enrolled from 10 CARRA sites. Patients had new-onset biopsy proven ISN/RPS class III or IV proliferative LN, were starting induction therapy with MMF or IV CYC and high-dose steroids and were followed for up to 24 months. Routine clinical data were collected at each visit. Provider reasons for CTP selection were assessed at baseline. Adherence to the CTPs was evaluated by provider survey and medication logs. Complete and partial renal responses were reported at 6 months. RESULTS: The majority of patients were female (83%) with a mean age of 14.7 years, SD 2.8. CYC was used more commonly than MMF for patients with ISN/RPS class IV LN (vs. class III), those who had hematuria, and those with adherence concerns. Overall adherence to the immunosuppression induction CTPs was acceptable with a majority of patients receiving the target MMF (86%) or CYC (63%) dose. However, adherence to the steroid CTPs was poor (37%) with large variability in dosing. Renal response endpoints were exploratory and did not show a significant difference between CYC and MMF. CONCLUSIONS: Overall, the immunosuppression CTPs were followed as intended in the majority of patients however, adherence to the steroid CTPs was poor indicating revision is necessary. In addition, our pilot study revealed several sources of treatment selection bias that will need to be addressed in for future comparative effectiveness research.

The Juvenile Psoriatic Arthritis Cohort in the CARRA Registry: Clinical Characteristics, Classification, and Outcomes.

OBJECTIVE: Children with clinically diagnosed juvenile psoriatic arthritis (JPsA) who were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry (CARRA-JPsA) were classified according to pediatric International League of Associations for Rheumatology (ILAR) and adult criteria [Classification criteria for Psoriatic Arthritis (CASPAR)]. Data on demographic and clinical features at baseline and 1-year followup were analyzed and compared. METHODS: Cross-sectional analysis was performed of CARRA-JPsA patients enrolled between May 2010 and December 2013 and stratified according to age at disease onset (≤ or > 4 yrs). Features of patients fulfilling ILAR and CASPAR criteria were compared at baseline and followup using chi square, Fisher's exact, Mann-Whitney-McNemar, Wilcoxon signed rank, and t tests, as appropriate. RESULTS: Among 361 children enrolled as CARRA-JPsA, 72.02% had symptom onset at > 4 years of age, with a male predominance and high prevalence of enthesitis. At followup, statistically significant improvements were reported in arthritis, dactylitis, enthesitis, psoriasis, sacroiliitis, and nail pitting, but not in health questionnaire (HQ) scores. Of the patients, 80.5% fulfilled ILAR criteria for JPsA. Fifty-two patients, whose disease fulfilled CASPAR criteria but had not been included in the JPsA cohort, manifested more enthesitis, sacroiliitis, inflammatory bowel disease and uveitis and less psoriasis. CONCLUSION: The data support division of patients with JPsA into 2 clinical subgroups, according to age at disease onset. Improvement in objective findings did not correlate with changes in HQ scores. Pediatric rheumatologists currently do not diagnose JPsA in all children whose disease manifestations meet CASPAR criteria. Unification of adult and pediatric PsA classification criteria warrants consideration.

Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia and Granulomatous Inflammation Mimicking High-Grade Malignancy on FDG-PET/CT.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare form of preinvasive lung lesion associated with indolent carcinoid tumor formation. This disease is characterized by multiple small pulmonary nodules with low SUVmax on F-FDG PET. Biopsy and immunohistochemical staining for neuroendocrine markers confirm diagnosis. There is no consensus for treatment, which typically involves surgical excision or management of symptoms with steroid-based therapies. We report an unusual case of DIPNECH colocalizing with necrotizing granulomatous inflammation mimicking high-grade aggressive malignancy on FDG-PET and a typical case of DIPNECH for comparison with low FDG avidity.

A novel mutation in NCF2 associated with autoimmune disease and a solitary late-onset infection.

Chronic granulomatous disease (CGD) is typically characterized by recurrent infections, granulomatous disease, and an increased susceptibility to autoimmune disease. We report a novel homozygous mutation in NCF2 that permits residual expression of an alternatively spliced variant in a patient with duodenitis and systemic lupus erythematosus (SLE), followed by a late-onset, single pulmonary infection in the setting of immunosuppressive medications. This report highlights the importance of considering CGD in patients who present initially exclusively with autoimmune disease.

Extension study of participants from the trial of early aggressive therapy in juvenile idiopathic arthritis.

OBJECTIVE: To follow children with juvenile idiopathic arthritis (JIA) who had completed at least 6 months of the TRial of Early Aggressive Therapy (TREAT) clinical study for an additional 2 years, describing safety of early aggressive treatment, disease activity, function, and duration of clinical inactive disease (CID) during followup. METHODS: Children were treated as per provider's discretion. Physician, patient/parent, and laboratory measures of disease status as well as safety information were collected at clinic visits every 3 months for up to 2 years. RESULTS: Forty-eight children were followed for a mean of 28 months (range 12-42) beyond the end of the TREAT study. Half of patients were in CID for > 50% of their followup time. Overall, 88% of patients achieved CID at > 1 study visit and 54% achieved clinical remission while taking medication. Six patients were in CID for the duration of the study, and, of those, 2 achieved a full year of clinical remission while not taking medication. Active disease was mild: mean physician's global assessment 2.4, active joint count 3.5, parent global evaluation 2.4, Childhood Health Assessment Questionnaire 0.32, erythrocyte sedimentation rate 19 mm/h, and morning stiffness 23 min. There were no serious adverse events or adverse events reported at grade 3 or higher of Common Terminology Criteria for Adverse Events. CONCLUSION: Early aggressive therapy in this cohort of patients with polyarticular JIA who had high initial disease activity was associated with prolonged periods of CID in the majority of patients during followup. Those not in CID had low levels of disease activity.

Prenatal food allergen exposures and odds of childhood peanut, tree nut, or sesame seed sensitization.

BACKGROUND: The prevalence of peanut (PN) and tree nut (TN) allergy in children has tripled in the past decade. Prenatal exposures, including maternal diet and medications, may account for some of this increase. In the United States, progesterone for luteal support in assisted reproduction is commonly formulated in PN or sesame seed (SS) oil. OBJECTIVE: To determine whether prenatal exposure to PN or SS oil as progesterone in oil increases the child's odds of PN, TN, or SS allergy. METHODS: Parents of 1,272 children evaluated by allergists from May 2005 through October 2009 completed questionnaires on conception, prenatal exposures, dietary history, and allergic history, with review of the child's medical record and skin prick and specific IgE test results. Odds ratios and 95% confidence intervals were calculated using multivariable adjusted logistic regression models. RESULTS: Children of mothers with a history of infertility, in vitro fertilization, or use of progesterone in oil did not have increased odds of PN, TN, and/or SS sensitization. Maternal consumption of TNs during first 2 trimesters was associated with 60% higher odds of having a PN/TN/SS-sensitized child (95% confidence interval 1.01-2.51), with similarly increased odds with maternal SS ingestion. Odds of PN/TN/SS sensitization were doubled in children with asthma or environmental allergies. CONCLUSION: Neither maternal infertility nor exposure to PN or SS oils through progesterone support during assisted reproduction treatment was associated with increased odds of PN/TN/SS sensitization in the child. However, maternal ingestion of TNs and SS during pregnancy was associated with increased odds of PN/TN/SS sensitization in the child.

T-cell immunoglobulin and mucin domain 1 deficiency eliminates airway hyperreactivity triggered by the recognition of airway cell death.

BACKGROUND: Studies of asthma have been limited by a poor understanding of how nonallergic environmental exposures, such as air pollution and infection, are translated in the lung into inflammation and wheezing. OBJECTIVE: Our goal was to understand the mechanism of nonallergic asthma that leads to airway hyperreactivity (AHR), a cardinal feature of asthma independent of adaptive immunity. METHOD: We examined mouse models of experimental asthma in which AHR was induced by respiratory syncytial virus infection or ozone exposure using mice deficient in T-cell immunoglobulin and mucin domain 1 (TIM1/HAVCR1), an important asthma susceptibility gene. RESULTS: TIM1(-/-) mice did not have airways disease when infected with RSV or when repeatedly exposed to ozone, a major component of air pollution. On the other hand, the TIM1(-/-) mice had allergen-induced experimental asthma, as previously shown. The RSV- and ozone-induced pathways were blocked by treatment with caspase inhibitors, indicating an absolute requirement for programmed cell death and apoptosis. TIM-1-expressing, but not TIM-1-deficient, natural killer T cells responded to apoptotic airway epithelial cells by secreting cytokines, which mediated the development of AHR. CONCLUSION: We defined a novel pathway in which TIM-1, a receptor for phosphatidylserine expressed by apoptotic cells, drives the development of asthma by sensing and responding to injured and apoptotic airway epithelial cells.

Genomic instability and aging-like phenotype in the absence of mammalian SIRT6.

The Sir2 histone deacetylase functions as a chromatin silencer to regulate recombination, genomic stability, and aging in budding yeast. Seven mammalian Sir2 homologs have been identified (SIRT1-SIRT7), and it has been speculated that some may have similar functions to Sir2. Here, we demonstrate that SIRT6 is a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in mouse cells, in association with a role in base excision repair (BER). SIRT6-deficient mice are small and at 2-3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks. We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes.

Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells.

The FcRH4 transmembrane molecule, a member of the Fc receptor homologue family, can potently inhibit B cell receptor (BCR) signaling. We show that cell surface expression of this immunoregulatory molecule is restricted to a subpopulation of memory B cells, most of which lack the classical CD27 marker for memory B cells in humans. The FcRH4+ and FcRH4- memory B cells have undergone comparable levels of immunoglobulin isotype switching and somatic hypermutation, while neither subpopulation expresses the transcription factors involved in plasma cell differentiation. The FcRH4+ memory cells are morphologically distinctive large lymphocytes that express the CD69, CD80, and CD86 cell activation markers. They are also shown to be poised to secrete high levels of immunoglobulins in response to stimulation with T cell cytokines, but they fail to proliferate in response either to BCR ligation or Staphylococcus aureus stimulation. A heightened expression of the CCR1 and CCR5 chemokine receptors may facilitate their preferential localization in lymphoid tissues near epithelial surfaces. Cell surface FcRH4 expression thus marks a unique population of memory B cells with distinctive morphology, functional capabilities, and tissue localization.

The inhibitory potential of Fc receptor homolog 4 on memory B cells.

Fc receptor homolog 4 (FcRH4) is a B cell-specific member of the recently identified family of FcRHs whose intracellular domain contains three potential immunoreceptor tyrosine-based inhibitory motifs (ITIMs). The signaling potential of this receptor, shown here to be preferentially expressed by memory B cells, was compared with the inhibitory receptor FcgammaRIIb in B cells expressing either WT FcgammaRIIb or chimeric proteins in which the intracellular domain of FcRH4 was fused to the transmembrane and extracellular domains of FcgammaRIIb. Coligation of the FcgammaRIIb/FcRH4 chimeric protein with the B cell receptor (BCR) led to tyrosine phosphorylation of the two membrane-distal tyrosines and profound inhibition of BCR-mediated calcium mobilization, whole cell tyrosine phosphorylation, and mitogen-activated protein (MAP)-kinase activation. Mutational analysis of the FcRH4 cytoplasmic region indicated that the two membrane-distal ITIMs are essential for this inhibitory potential. Phosphopeptides corresponding to these ITIMs could bind the Src homology 2 (SH2) domain-containing tyrosine phosphatases SHP-1 and SHP-2, which associated with the WT FcRH4 and with mutants having inhibitory capability. These findings indicate the potential for FcRH4 to abort B cell receptor signaling by recruiting SHP-1 and SHP-2 to its two membrane distal ITIMs.