Imaging Pathway of a Pediatric Patient with Succinate Dehydrogenase B-Deficient Paraganglioma.

Pheochromocytoma and paraganglioma are rare in children, at only 1 in every 50,000 cases. Even though some cases are sporadic, they have been connected to syndromes such as von Hippel-Lindau, multiple endocrine neoplasia types IIa and IIb, neurofibromatosis type 1, and hereditary pheochromocytoma-paraganglioma syndromes. A genetic mutation causes around 60% of pheochromocytomas and paragangliomas in children under 18. Methods: A 15-y-old child with a 6-y history of back discomfort is presented. The justification for using 2 functional imaging modalities, 68Ga-DOTATATE PET/CT and 123I-meta-iodobenzylguanidine SPECT/CT, is examined in this case study. We reviewed the patients' journey since the first referral for imaging. Results: Delaying the molecular imaging modalities has affected patients' overall diagnosis and applied treatment outcomes. Conclusion: This case study investigates the potential for the earlier use of various diagnostic modalities in conjunction with diagnostic testing to facilitate an earlier diagnosis. However, since this study is based solely on imaging and lacks access to the patient's clinical or family history, factors such as potential inequities in health-care facilities, health literacy, and socioeconomic status are not addressed. It is essential to acknowledge these influences as they contribute to the inequitable access to health-care settings in New Zealand.

Improving Red Reflex Screening in a Level III NICU Through a Quality Improvement-based Approach.

BACKGROUND: Red reflex is a routine part of newborn examination in most high-income countries. It is an inexpensive, noninvasive method of detecting serious ocular abnormalities like cataracts, retinoblastoma, vitreous masses, etc. The American Academy of Pediatrics recommends red reflex examination before discharge from newborn nursery. However, the current rate of red reflex examination in the NICUs in the United States is unknown. We noted a low rate of documentation (19%) in our level III NICU, prompting us to initiate this quality improvement project to improve this rate. METHODS: We created a key-driver diagram and summarized possible interventions to achieve our aim to increase the documentation rate to >80%. We implemented various interventions over 4 plan-do-study-act cycles. Over 19 months, we educated the nurses and the providers regarding the importance of red reflex assessment, placed visual reminders to check red reflex, implemented discharge checklist for the residents, and improved the accessibility to ophthalmoscope. RESULTS: Infants discharged from our NICU during a 25-month period included 1168 infants who an ophthalmologist did not formally examine. The rate of red reflex documentation improved significantly from a baseline of 19% (6 months before the first plan-do-study-act cycle) to 89.5% (during the 19-month intervention period). One abnormal red reflex was detected during this study. CONCLUSIONS: Implementation of this project has led to a culture change at our institution, which will help prevent us from missing the diagnosis of serious visual abnormalities in the future.

Diagnosis and localization of parathyroid adenomas using 16-slice SPECT/CT: A clinicopathological correlation.

INTRODUCTION: This study aimed to evaluate a new 16-slice SPECT/CT scanner at Auckland City Hospital for its use in the detection and localization of parathyroid adenomas in patients with primary, secondary and tertiary hyperparathyroidism. The secondary outcome was to compare findings from SPECT/CT with ultrasound and operative findings. METHODS: One hundred patients who underwent a SPECT/CT scan for primary/secondary/tertiary hyperparathyroidism were included in this study. Of these patients, 45 received surgery. SPECT/CT and ultrasound findings were collated for each patient, and of those who received surgery, operative and pathological findings were compared with those on SPECT/CT. RESULTS: The sensitivity of diagnosis and localization was 86.5% (95% CI: 71.2-95.5%). Specificity was 25.0% (95% CI: 3.2-65.1%). Comparison between SPECT/CT and ultrasound findings demonstrated a kappa coefficient of 0.203 (95% CI: -0.036 to 0.442), correlating with fair agreement. These figures are in line with other published series. CONCLUSION: The SPECT/CT scanner (and associated reporters) at Auckland City Hospital demonstrates high sensitivity in the detection and localization of parathyroid adenomas and is an effective first-line investigation in patients with primary/secondary/tertiary hyperparathyroidism.

Risk of acute respiratory infection and acute cardiovascular events following acute respiratory infection among adults with increased cardiovascular risk in England between 2008 and 2018: a retrospective, population-based cohort study.

BACKGROUND: Although acute respiratory infections can lead to cardiovascular complications, the effect of underlying cardiovascular risk on the incidence of acute respiratory infections and cardiovascular complications following acute respiratory infection in individuals without established cardiovascular disease is unknown. We aimed to investigate whether cardiovascular risk is associated with increased risk of acute respiratory infection and acute cardiovascular events after acute respiratory infection using 10 years of linked electronic health record (EHR) data in England. METHODS: In this retrospective, population-based cohort study we used EHRs from primary care providers registered on the Clinical Practice Research Datalink (CPRD) GOLD and Aurum databases in England. Eligible individuals were aged 40-64 years, did not have established cardiovascular disease or a chronic health condition that would make them eligible for influenza vaccination, were registered at a general practice contributing to the CPRD, and had linked Hospital Episode Statistics Admitted Patient Care data in England from Sept 1, 2008, to Aug 31, 2018. We classified cardiovascular risk on the basis of diagnosed hypertension and overall predicted cardiovascular risk, estimated by use of the QRISK2 risk-prediction tool (comparing a score of ≥10% [increased risk] with a score of <10% [low risk]). Using multivariable Poisson regression models, we calculated incidence rate ratios (IRRs) for systemic acute respiratory infection. Among individuals who had an acute respiratory infection, we used multivariable Cox regression to calculate hazard ratios (HRs) for the risk of acute cardiovascular events within 1 year of infection. FINDINGS: We identified 6 075 321 individuals aged 40-64 years with data in the CPRD and linked data in the Hospital Episode Statistics Admitted Patient Care database between Sept 1, 2008, and Aug 31, 2018. Of these individuals, 4 212 930 (including 526 480 [12·5%] with hypertension and 607 087 [14·4%] with a QRISK2 score of ≥10%) were included in the assessment of the incidence of acute respiratory infection. After adjusting for confounders (age, sex, ethnicity, socioeconomic status, body-mass index, alcohol consumption, smoking status, and consultation frequency in the hypertension analysis; and alcohol consumption and consultation frequency in the QRISK2 analysis), the incidence of acute respiratory infection was higher in individuals with hypertension than those without (IRR 1·04 [95% CI 1·03-1·05]) and higher in those with a QRISK2 score of 10% or higher than in those with a QRISK2 score of less than 10% (1·39 [1·37-1·40]). Of the 442 408 individuals who had an acute respiratory infection, 4196 (0·9%) had an acute cardiovascular event within 1 year of infection. After adjustment (for age, sex, ethnicity, socioeconomic status, body-mass index, alcohol consumption, and smoking status in the hypertension analysis; and for alcohol consumption in the QRISK2 analysis), hypertension (HR 1·98 [95% CI 1·83-2·15]) and a QRISK2 score of 10% or higher (3·65 [3·42-3·89]) were associated with a substantially increased risk of acute cardiovascular events after acute respiratory infection. INTERPRETATION: People with increased cardiovascular risk but without diagnosed cardiovascular disease, measured by diagnosed hypertension or overall predicted cardiovascular risk, could benefit from influenza and pneumococcal vaccine prioritisation to reduce their risk of both acute respiratory infection and cardiovascular complications following an acute respiratory infection. FUNDING: British Heart Foundation and the Wellcome Trust.

Environmentally-induced parental or developmental conditioning influences coral offspring ecological performance.

The persistence of reef building corals is threatened by human-induced environmental change. Maintaining coral reefs into the future requires not only the survival of adults, but also the influx of recruits to promote genetic diversity and retain cover following adult mortality. Few studies examine the linkages among multiple life stages of corals, despite a growing knowledge of carryover effects in other systems. We provide a novel test of coral parental conditioning to ocean acidification (OA) and tracking of offspring for 6 months post-release to better understand parental or developmental priming impacts on the processes of offspring recruitment and growth. Coral planulation was tracked for 3 months following adult exposure to high pCO2 and offspring from the second month were reciprocally exposed to ambient and high pCO2 for an additional 6 months. Offspring of parents exposed to high pCO2 had greater settlement and survivorship immediately following release, retained survivorship benefits during 1 and 6 months of continued exposure, and further displayed growth benefits to at least 1 month post release. Enhanced performance of offspring from parents exposed to high conditions was maintained despite the survivorship in both treatments declining in continued exposure to OA. Conditioning of the adults while they brood their larvae, or developmental acclimation of the larvae inside the adult polyps, may provide a form of hormetic conditioning, or environmental priming that elicits stimulatory effects. Defining mechanisms of positive acclimatization, with potential implications for carry over effects, cross-generational plasticity, and multi-generational plasticity, is critical to better understanding ecological and evolutionary dynamics of corals under regimes of increasing environmental disturbance. Considering environmentally-induced parental or developmental legacies in ecological and evolutionary projections may better account for coral reef response to the chronic stress regimes characteristic of climate change.

Metastatic Osseous Disease Masquerading as Infection, Diagnosed on Bone Scintigraphy and SPECT/CT.

We present a 72-y-old woman with an osseous metastasis to the spine that had an atypical appearance on both nuclear medicine and radiologic modalities and was misdiagnosed as an abscess. We discuss the pitfalls of bone scintigraphy and the causes of photopenic metastatic lesions.

Synthesis of multi-omic data and community metabolic models reveals insights into the role of hydrogen sulfide in colon cancer.

Multi-omic data and genome-scale microbial metabolic models have allowed us to examine microbial communities, community function, and interactions in ways that were not available to us historically. Now, one of our biggest challenges is determining how to integrate data and maximize data potential. Our study demonstrates one way in which to test a hypothesis by combining multi-omic data and community metabolic models. Specifically, we assess hydrogen sulfide production in colorectal cancer based on stool, mucosa, and tissue samples collected on and off the tumor site within the same individuals. 16S rRNA microbial community and abundance data were used to select and inform the metabolic models. We then used MICOM, an open source platform, to track the metabolic flux of hydrogen sulfide through a defined microbial community that either represented on-tumor or off-tumor sample communities. We also performed targeted and untargeted metabolomics, and used the former to quantitatively evaluate our model predictions. A deeper look at the models identified several unexpected but feasible reactions, microbes, and microbial interactions involved in hydrogen sulfide production for which our 16S and metabolomic data could not account. These results will guide future in vitro, in vivo, and in silico tests to establish why hydrogen sulfide production is increased in tumor tissue.

Reduction in tuberculosis incidence in the UK from 2011 to 2015: a population-based study.

BACKGROUND: Following nearly two decades of increasing tuberculosis in the UK, TB incidence decreased by 32% from 2011 to 2015. Explaining this reduction is crucial to informing ongoing TB control efforts. METHODS: We stratified TB cases notified in the UK and TB cases averted in the UK through pre-entry screening (PES) between 2011 and 2015 by country of birth and time since arrival. We used population estimates and migration data to establish denominators, and calculated incidence rate ratios (IRRs) between 2011 and 2015. We calculated the contribution of changing migrant population sizes, PES and changes in TB rates to the reduction in TB notifications. RESULTS: TB IRRs fell in all non-EU migrant and UK-born populations between 2011 and 2015 (0.61; 95% CI 0.59 to 0.64 and 0.78; 0.73 to 0.83 respectively), with the greatest decrease in recent non-EU migrants (0.54; 0.48 to 0.61). 61.9% of the reduction in TB notifications was attributable to decreases in TB rates, 33.4% to a fall in the number of recent/mid-term non-EU migrants and 11.4% to PES. A small increase in notifications in EU-born migrants offset the reduction by 6.6%. CONCLUSIONS: Large decreases in TB rates in almost all populations accounted for the majority of the reduction in TB notifications, providing evidence of the impact of recent interventions to improve UK TB control. The particularly large decrease in TB rates in recent non-EU migrants provides evidence of the effectiveness of screening interventions that target this population. These findings will inform ongoing improvements to TB control.

Ocular axial growth in pseudophakic eyes of patients operated for monocular infantile cataract: a comparison of operated and fellow eyes measured at surgery and 5 or more years later.

PURPOSE: To report the change in axial length (AL) over time and to compare the percentage of AL growth of pseudophakic eyes operated on for monocular cataract to that of the unoperated fellow eyes. METHODS: The medical records of children operated on by a single surgeon for monocular congenital cataract before 7 months of age were retrospectively reviewed. Inclusion criteria were corneal diameter of ≥9 mm and availability of AL data for >5 years' follow-up after cataract surgery and >1 year after IOL implantation (in case of secondary IOL). Cataract with persistent fetal vasculature causing stretching of the ciliary processes, diagnosis of glaucoma or glaucoma suspect, and eyes with aphakia were excluded. Globe AL was measured by immersion ultrasound at surgery and 5 or more years later. RESULTS: A total of 24 children were identified. Average age at cataract surgery was 2.6 ± 2.1 months. Age at last follow-up was 8.4 ± 2.8 years and duration of follow-up was 8.2 ± 2.8 years. 13 eyes received a primary IOL and 11 eyes received a secondary IOL. AL was significantly different between operative and fellow eyes, preoperatively (18.1 mm vs 18.7 mm, P = 0.004), and at the final follow-up (22.2 mm vs 23.0 mm, P = 0.03). Differences in AL growth of operated and fellow eyes were not significant (4.1 mm vs 4.4 mm, P = 0.4). Similarly, percentage of AL growth of operated and fellow eyes was also not significantly different (23% vs 23.6%, P = 0.7). CONCLUSIONS: Eyes operated for monocular cataract have similar axial growth to that of fellow unoperated eyes, despite having a shorter AL at the time of surgery.

High-grade transformation of acinic cell carcinoma: an inadequately treated entity?

OBJECTIVE: Acinic cell carcinoma (AcCC) is an uncommon salivary gland malignancy. We aim to characterize the clinical and pathologic characteristics of AcCC with and without high-grade transformation (HGT). Importantly, cases of mammary analogue secretory carcinoma, a recently described histologic mimic of AcCC, have been excluded by using cytogenetics and molecular studies. STUDY DESIGN: Archival surgical pathology material was obtained for patients diagnosed with AcCC at Mayo Clinic Rochester between 1990 and 2010. Tumors harboring the ETV6-NTRK3 fusion transcript were excluded from analysis by using cytogenetics and molecular studies. Tumors with HGT were characterized by areas with an infiltrative growth pattern, nuclear anaplasia, prominent nucleoli, brisk mitotic activity, geographic necrosis, and stromal desmoplasia. Demographic and clinical data were extracted from the medical records. RESULTS: AcCC with HGT was seen in 8 of 48 cases (17%). Patients with AcCC with HGT were significantly older than patients without HGT (median 69 vs 54 years; P = .04). Angiolymphatic invasion was more common in AcCC with HGT (P = .02). Relapse-free survival and overall survival were significantly worse for cases of AcCC with HGT (hazard ratio 10.4 and 9.3, respectively; P < .0001 for both comparisons). Locoregional recurrence-free survival was not significantly different (P = .12), but distant metastases-free survival was significantly worse in patients with HGT compared with non-HGT patients (P < .0001). CONCLUSIONS: Prognosis for overall survival and distant relapse for AcCC patients with HGT is significantly worse than that for patients without HGT.

The effectiveness of the Spot Vision Screener in detecting amblyopia risk factors.

PURPOSE: To evaluate the updated Spot Vision Screener (PediaVision, Welch Allyn, Skaneateles Falls, NY) in detecting amblyopia risk factors using 2013 guidelines of American Association for Pediatric Ophthalmology and Strabismus (AAPOS). METHODS: In this prospective study, patients seen from June 2012 to November 2013 were tested with the Spot prior to examination by a pediatric ophthalmologist who was masked to test results. The following data were analyzed: age, subject testability, examination findings, and systemic and ocular pathology. Children were divided into three age groups to determine gold standard results according to the AAPOS guidelines. RESULTS: A total of 444 children (average age, 72 months) were included. Compared to the ophthalmologist's examination, the Spot sensitivity was 87.7% and the specificity was 75.9% in detecting amblyopia risk factors. Sensitivity did not differ significantly between age groups, although the positive predictive value improved in the older age groups. CONCLUSIONS: In our study cohort, the Spot provided good specificity and sensitivity in detecting amblyopia risk factors according 2013 AAPOS criteria, with minor improvements with updated versions.

Transoral robotic surgery using the thulium:YAG laser: a prospective study.

OBJECTIVE: To compare thulium:YAG laser-assisted transoral robotic surgery (TY:TORS) and conventional electrocautery-equipped TORS (EC:TORS) in patients undergoing transoral resection of upper aerodigestive tract malignant neoplasms. DESIGN: Prospective matched cohort study. SETTING: Tertiary academic referral center. PATIENTS: Fifteen patients undergoing TY:TORS were matched on the basis of tumor site, clinical T stage, sex, and age with 30 control subjects undergoing EC:TORS. MAIN OUTCOME MEASURES: The primary outcome was a comparison between the feasibility of TY:TORS compared with EC:TORS. The secondary outcome was a comparison between the safety and functional outcome of TY:TORS compared with EC:TORS in patients undergoing resection of upper aerodigestive tract malignant neoplasms. RESULTS: All the tumors underwent complete excision with negative margins. Estimated blood loss was minimal (<150 mL) for 87% of TY:TORS patients (13 of 15) and 63% of EC:TORS controls (19 or 30). Intraoperative pharyngotomy was reported in 8% of TY:TORS patients (1 of 13) and 42% of EC:TORS controls (11 of 30) (P = .03). Postoperative pain was greater in EC:TORS compared with TY:TORS (P = .02). No statistically significant differences were noted in hemostasis, postoperative bleeding rates, or other complications. CONCLUSIONS: Compared with EC:TORS, TY:TORS seems feasible and safe. In addition, TY:TORS resulted in fewer intraoperative pharyngotomies and less postoperative pain than did EC:TORS, which may be because of decreased collateral thermal damage, improved visualization, and finer cutting using the thulium laser.

Prophylactic and therapeutic mastectomy in BRCA mutation carriers: can the nipple be preserved?

BACKGROUND: Use of nipple-sparing mastectomy (NSM) is increasing. We sought to look at the role of NSM in BRCA mutation carriers. METHODS: Tissue from women with a BRCA1 or BRCA2 mutation who underwent mastectomy between March 1987 and June 2009 at a single institution was reviewed. The entire nipple-areolar complex (NAC) was excised and histologically evaluated. The presence of terminal duct lobular units (TDLUs) and premalignant or malignant lesions in the NAC was noted. RESULTS: Sixty-two NACs from 33 women (25 BRCA1, 8 BRCA2) were studied. TDLUs were present in 15 (24%) NAC specimens. No evidence of atypical hyperplasia, carcinoma in situ, or invasive carcinoma was found in any of the 33 prophylactic mastectomy specimens. Among the 29 breasts with cancer and available tissue, 2 (7%) had malignant findings and 1 (3%) had atypia in the NAC. One woman who underwent bilateral mastectomy for bilateral invasive carcinoma had one nipple with tumor within lymphatics, and her contralateral nipple had atypical lobular hyperplasia. A second woman had ductal carcinoma in situ involving a single major lactiferous duct. CONCLUSIONS: The probability of nipple involvement by premalignant or malignant lesions in the NAC of BRCA mutation carriers is low at time of prophylactic mastectomy, but higher (10%) in women undergoing therapeutic mastectomy. NSM may be appropriate and oncologically safe for selected women with BRCA mutations. However, 24% of NACs contained TDLUs, with only 8% found in the nipple papilla; the significance of this for long-term risk is unknown.

Use of intrathecal urokinase in repeated shunt and external ventricular drain blockage from high CSF protein due to an optic pathway glioma.

INTRODUCTION: High cerebrospinal fluid (CSF) protein is a recognised association of optic pathway gliomas. This can occlude ventriculoperitoneal (VP) shunt catheters or external ventricular drains (EVD). CASE REPORT: We describe an 8-year-old boy with an optic pathway glioma, who had frequent episodes of a blocked VP shunt and EVD due to high CSF protein level. This responded favourably to repeated urokinase instillation into the catheter lumen. We present the course of treatment and the method of administration and review the literature behind thrombolytic therapy for occluded catheter devices. CONCLUSION: Intrathecal urokinase was effective in unblocking the EVD and lysing the protein clots within the ventricle. We found no previously published cases of intrathecal urokinase for this problem. This novel intervention seemed promising as a safe and effective means of maintaining EVD patency in cases complicated by excessive protein loads in CSF and hydrocephalus.

Pre-morbid skin changes in patients with cancer: Using 'Welam's sign' as a new prognostic marker?

Identification of the imminently dying patient can be a complex and difficult process, especially in a frail and elderly population with malignancy. The Liverpool Care Pathway utilizes a number of identification criteria for end-of-life care, but additional prognostic physical signs may be useful. This article describes specific skin changes not previously featured in the literature in four patients at end of life with malignancy, and discusses the potential use of this as a prognostic indicator.

Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro.

BACKGROUND: Toll-like receptor 9 (TLR9) recognizes microbial DNA. In addition to immune cells, TLR9 expression has been detected in various cancer cells. We showed recently that TLR9 agonistic CpG-oligonucleotides (CpG-ODNs) induce matrix metalloproteinase-13 (MMP-13)-mediated invasion in TLR9-expressing (TLR9(+)) breast cancer cells. We investigated here TLR9 expression and function in human prostate cancer (CaP) cells. METHODS: TLR9 expression was detected with Western blotting and immunohistochemistry. Invasion was studied with Matrigel-assays. MMP-13 was assayed with ELISA. RESULTS: Human CaP cell lines and clinical samples exhibit various levels of TLR9 expression. Treatment of TLR9(+), but not TLR9(-) CaP cells with CpG-ODNs or bacterial DNA increased their invasion, which was inhibited with chloroquine. CpG-ODN-treatment also increased MMP-13 activity and neutralizing anti-MMP-13 antibody prevented CpG-ODN-induced invasion in TLR9(+) CaP cells. Estradiol up-regulated TLR9 expression in LnCaP cells. CONCLUSIONS: TLR9-mediated invasion may represent a novel mechanism through which infections promote prostate cancer.

Separation of adeno-associated virus type 2 empty particles from genome containing vectors by anion-exchange column chromatography.

Adeno-associated virus (AAV) empty capsids typically co-purify with genome containing AAV2 vectors purified by column chromatography. This study describes a method to remove empty capsids from genome containing vector particles by anion exchange chromatography. The separation is based on the slightly less anionic character of empty particles compared to vectors. Detailed methods to achieve AAV2 vector purification and particle separation using cation exchange resin POROS 50HS followed by anion exchange resin Q-Sepharose(xl) are described. Chromatographic separation of AAV2 particles was achieved using gradients based on sodium acetate and ammonium acetate, and was optimal at pH 8.5. Efficient removal of particle surface nucleic acid impurities was found to be important to achieve good particle separation. In a large scale experiment performed using partially purified vector containing a mixture of 1.56 x 10(14)vg and 2.52 x 10(15) empty capsids as a starting material, the optimized anion exchange chromatography method resulted in a vector peak of 1.15 x 10(14)vg containing 0.25 x 10(14) empty capsids, corresponding to 74% vector yield and 86-fold reduction in empty capsids in the vector product.