Echocardiographic and clinical findings in patients with Fabry disease during long-term enzyme replacement therapy: a nationwide Danish cohort study

Objectives: In patients with Fabry disease (FD), left ventricular hypertrophy and arrhythmias are frequently observed and cardiac involvement is the leading cause of death. Long-term efficacy of enzyme replacement therapy (ERT) on cardiac involvement is unclear. We assessed and compared long-term progression of cardiac involvement according to ERT and non-ERT. Methods: We retrospectively assessed and compared long-term progression of cardiac involvement in adult patients with FD in the nationwide Danish cohort. We followed clinical signs, symptoms and findings by echocardiography, electrocardiography and Holter-monitoring. Results: We included 66 patients; 47 patients (27 women) received ERT (ERT group) and 19 patients (15 women) did not (non-ERT group). The groups were followed for a median of 8 [0–12] years and 6 [0–13] years, respectively. Comparison between ERT and non-ERT receiving patients by left ventricular mass (echocardiographic assessment) and Sokolow-Lyon voltage- and Cornell product criteria (electrocardiographic assessment) revealed no significant differences. In the ERT group, we observed no change in left ventricular mass but a decrease in Sokolow-Lyon voltage- and Cornell product criteria from baseline to follow-up; 30?mm [15–53] vs. 25?mm [3–44], p?p?Discussion: We raise concerns regarding the efficacy and benefit of ERT on cardiac involvement in Fabry disease and stress the need for further research.     

Reproducibility of 18F-FDG PET uptake measurements in head and neck squamous cell carcinoma on both PET/CT and PET/MR

Objective:

To investigate reproducibility of fluorine-18 fludeoxyglucose (¹⁸F-FDG) uptake on ¹⁸F-FDG positron emission tomography (PET)/CT and ¹⁸F-FDG PET/MR scans in patients with head and neck squamous cell carcinoma (HNSCC).

Methods:

30 patients with HNSCC were included in this prospective study. The patients were scanned twice before radiotherapy treatment with both PET/CT and PET/MR. Patients were scanned on the same scanners, 3 days apart and according to the same protocol. Metabolic tumour activity was measured by the maximum and peak standardized uptake value (SUV_max and SUV_peak, respectively), and total lesion glycolysis from the metabolic tumour volume defined from ≥50% SUV_max. Bland–Altman analysis with limits of agreement, coefficient of variation (CV) from the two modalities were performed in order to test the reproducibility. Furthermore, CVs from SUV_max and SUV_peak were compared. The area under the curve from cumulative SUV–volume histograms were measured and tested for reproducibility of the distribution of ¹⁸F-FDG uptake.

Results:

24 patients had two pre-treatment PET/CT scans and 21 patients had two pre-treatment PET/MR scans available for further analyses. Mean difference for SUV_max, peak and mean was approximately 4% for PET/CT and 3% for PET/MR, with 95% limits of agreement less than ±20%. CV was small (5–7%) for both modalities. There was no significant difference in CVs between PET/CT and PET/MR (p = 0.31). SUV_max was not more reproducible than SUV_peak (p = 0.09).

Conclusion:

¹⁸F-FDG uptake in PET/CT and PET/MR is highly reproducible and we found no difference in reproducibility between PET/CT and PET/MR.

Advances in knowledge:

This is the first report to test reproducibility of PET/CT and PET/MR.Functional imaging with fluorine-18 fludeoxyglucose positron emission tomography combined with CT (¹⁸F-FDG PET/CT) has been shown to be useful for prognostication of head and neck squamous cell carcinoma (HNSCC),^1–3 and the use of ¹⁸F-FDG PET/CT has also been shown to reduce interobserver variability in target delineation for radiotherapy.^4,5 Furthermore, ¹⁸F-FDG PET/CT can identify regions of the tumour with a high risk of relapse, leading to the idea that ¹⁸F-FDG uptake might be a target for dose painting.^6,7 Finally, ¹⁸F-FDG PET/CT may be used in response evaluation.^8,9 Maximum standardized uptake value (SUV_max) has for many years been the main uptake measurement in prognostic studies for various malignancies. More recent studies have focused on demonstrating prognostic value of PET/CT-based volumetric parameters such as metabolic tumour volume (MTV) and total lesion glycolysis (TLG). MTV is the sum of the volume of voxels with standard uptake value (SUV) exceeding a certain threshold value in a tumour, and TLG is calculated by multiplying MTV and the mean standardized uptake value (SUV_mean) of the MTV. These volume-based PET parameters have increasingly gained interest and have been reported to be significant prognostic factors for various malignancies including HNSCC.^{10–13 18}F-FDG PET/CT is currently not routinely recommended as a diagnostic tool in HNSCC except in very specific situations,¹⁴ but reproducibility of the ¹⁸F-FDG signal is a prerequisite for a more widespread use of ¹⁸F-FDG PET for the above-mentioned indications. Yet, only a few studies of the reproducibility of ¹⁸F-FDG PET/CT exist^8,15–21 and none of these studies includes patients with HNSCC.MRI is gaining acceptance as an imaging modality for oncology as it offers superior soft-tissue contrast compared with CT alone, and it has been suggested that information from PET/CT and MR is complementary in head and neck cancer.²² The introduction of the integrated PET/MR scanner offers a unique opportunity to combine the high soft-tissue contrast of MR with the functional imaging from PET within a single imaging session. PET/MR is still in its infancy, but the combined modality imaging is potentially useful in the management of patients with HNSCC.^22–28 However, the same criteria of reproducibility as with PET/CT should be upheld by this new modality. The purpose of this prospective test–retest study is to assess the reproducibility of both ¹⁸F-FDG PET/CT and ¹⁸F-FDG PET/MR in a homogenous cohort of patients with HNSCC.     

Successful use of sacral neuromodulation after failed bladder augmentation

Sacral neuromodulation has become a standard minimally invasive therapy for refractory urinary urge/frequency and urge incontinence. Prior to the widespread use of sacral neuromodulation, augmentation cystoplasty was a standard treatment for refractory overactive bladder (OAB). The use of sacral neuromodulation following bladder augmentation has not been previously reported in the literature. We report 2 cases of successful sacral neuromodulation in patients with OAB refractory to bladder augmentation.     

Characterization of a Novel Chimeric Swine Enteric Coronavirus from Diseased Pigs in Central Eastern Europe in 2016

During a severe outbreak of diarrhoea and vomiting in a pig herd in Central Eastern Europe, faecal samples were tested positive for porcine epidemic diarrhoea virus (PEDV) and negative for transmissible gastroenteritis virus (TGEV) using a commercial RT‐qPCR assay that can detect both of these coronaviruses. However, further analyses, using other TGEV‐ and PEDV‐specific RT‐qPCR assays, provided results inconsistent with infection by either of these viruses. Sequencing of an amplicon (ca. 1.6 kb), generated by an RT‐PCR specific for the PEDV S‐gene, indicated a very close similarity (ca. 99% identity) to recently described chimeric viruses termed swine enteric coronaviruses (SeCoVs). These viruses (with an RNA genome of ca. 28 kb) were first identified in Italy in samples from 2009 but have not been detected there since 2012. A closely related virus was detected in archived samples in Germany from 2012, but has not been detected subsequently. Building on the initial sequence data, further amplicons were generated and over 9 kb of sequence corresponding to the 3′‐terminus of the new SeCoV genome was determined. Sequence comparisons showed that the three known SeCoVs are ≥98% identical across this region and contain the S‐gene and 3a sequences from PEDV within a backbone of TGEV, but the viruses are clearly distinct from each other. It is demonstrated, for the first time, that pigs from within the SeCoV‐infected herd seroconverted against PEDV but tested negative in a TGEV‐specific ELISA that detects antibodies against the S protein. These results indicate that SeCoV is continuing to circulate in Europe and suggest it can cause a disease that is very similar to PED. Specific detection of the chimeric SeCoVs either requires development of a new diagnostic RT‐qPCR assay or the combined use of assays targeting the PEDV S‐gene and another part of the TGEV genome.     

The clinical and pathological characteristics of Chinese patients with pauci-immune crescent golmerulonephritis

Objective　To investigate the clinical and pathological characteristics of pauci-immune crescent glomerulo～nephritis (PICGN) in Chinese patients. Methods　During 13 years (1985-1998), 6400 patients underwent non-transplanting renal biopsy. Twenty-four patients were diagnosed as PICGN. All clinical and laboratory data of these patients were collected from the patients’ records and used for detailed analysis. The diagnosis is based on clinico-pathologic findings. Results　Of the 24 patients, 16 were females and 8 were males, with median age of 33 years (ranged 10-76 years). Microscopic polyarteritis (MPA) (33.3%) and systemic vasculitis (8.3%) were the secondary diseases. The incidence of PICGN was 0.38% in renal biopsies and 22.9% in crescentic glomerulonephritis. Clinically, most patients (75.0%) showed rapidly progressive nephritis with enlarged kidneys. At onset, gross hematuria was noted in 58.3% of patients, hypertension in 45.8%, nephrotic syndrome in 41.7%, and oliguria in 25.0%. However, systemic symptoms were rare except for anemia. Pathologically, necrosis of glomerular capillaries (62.5%), infiltration of monocytes and neutrophil cells in glomeruli (66.7%), and vasculitis in the interstitium (53.3%) were observed. In addition, glomerulosclerosis was noted in 45.8%, severe tubular atrophy in 83.3% and interstitial fibrosis in 75.0%. Anti-neutrophil cytoplasmic antibodies (ANCAs) were positive in 52.2%. All patients except two received intensively immunosuppressive therapy. Sixteen patients were available for long-term follow up (median 29.8 months, range 8-92 months). Twelve of them had life-sustaining renal function, four had normal serum creatinine (<124?μmol/L) and only 4 patients were dialysis-dependent. Conclusion　PICGN is not rare in China. Early diagnosis and administration of immunosuppressive therapy, particularly in patients with rapidly progressive glomerulonephritis (RPGN), are important for good prognosis.     

Cervical Spine Clearance in Trauma Patients with an Unreliable Physical Examination

Background

The objective of this study was to describe and compare the timing of cervical spine clearance in trauma patients with an unreliable physical examination.

Methods

We prospectively included adult trauma patients admitted with a cervical collar and an unreliable clinical examination (as defined by the NEXUS criteria) at two level 1 trauma centers: one in the USA (US) and one in Denmark (DK). We excluded patients with cervical spine injuries requiring a collar or surgery as treatment and patients with a collar placed after hospital arrival. The primary outcome was time from emergency department (ED) arrival to collar removal. Secondary outcomes included time to CT of the cervical spine (CTCS). At the US trauma center, an institutional protocol allowing cervical spine clearance exclusively by CTCS was in place. At the Danish trauma center, cervical spine clearance was based on a clinical evaluation by an orthopedic surgeon, usually after CTCS.

Results

A total of 113 patients were included (US: n = 56; DK: n = 57). The median age was 47 years, and 68% were males. The main reasons for an unreliable physical examination were a Glasgow Coma Scale score below 14 (35%), distracting injuries (26%), cervical spine tenderness (13%) and intoxication (13%). The injury severity score at the US trauma center was higher than at the DK trauma center (median: 17 vs. 11, p = 0.03). Both time to CTCS (median: 41 vs. 18 min, p < 0.0001) and time to collar removal (median: 1042 vs. 49 min, p < 0.0001) were significantly greater at the US trauma center.

Conclusions

Time to collar removal was significantly greater in a trauma center utilizing a cervical spine clearance protocol based on CTCS. As patients may develop complications related to the collar, future studies should clarify how early removal can be implemented without increasing the risk of morbidity.

     

Massive infection and loss of CD4+ T cells occurs in the intestinal tract of neonatal rhesus macaques in acute SIV infection

Rapid, profound, and selective depletion of memory CD4+ T cells has now been confirmed to occur in simian immunodeficiency virus (SIV)-infected adult macaques and human immunodeficiency virus (HIV)-infected humans. Within days of infection, marked depletion of memory CD4+ T cells occurs primarily in mucosal tissues, the major reservoir for memory CD4+ T cells in adults. However, HIV infection in neonates often results in higher viral loads and rapid disease progression, despite the paucity of memory CD4+ T cells in the peripheral blood. Here, we examined the immunophenotype of CD4+ T cells in normal and SIV-infected neonatal macaques to determine the distribution of naive and memory T-cell subsets in tissues. We demonstrate that, similar to adults, neonates have abundant memory CD4+ T cells in the intestinal tract and spleen and that these are selectively infected and depleted in primary SIV infection. Within 12 days of SIV infection, activated (CD69+), central memory (CD95+CD28+) CD4+ T cells are marked and persistently depleted in the intestine and other tissues of neonates compared with controls. The results in dicate that "activated" central memory CD4+ T cells are the major target for early SIV infection and CD4+ T cell depletion in neonatal macaques.     

Severity of postoperative hypophosphatemia in relation to glucose administration and renal handling of phosphate

Major surgery is associated with fall in the concentration of inorganic phosphate in serum, as is intravenous infusion of glucose. Hypophosphatemia during different forms of postoperative dextrose administration was evaluated in patients who had undergone colorectal surgery. They were randomized to two groups. All patients received standardized intravenous fluids on the first 3 postoperative days, but one group had constant infusion of a solution containing glucose (4%), sodium (40 mmol/l) and potassium (20 mmol/l) throughout the observation period, while the other group had a 5-hour infusion of 10% glucose daily, with potassium and sodium solution in between. The amounts of administered glucose and electrolytes were the same in both groups. The serum phosphate levels were significantly lower in the group with constant glucose infusion, due to intergroup difference in renal handling of phosphate. Significantly less phosphate was reabsorbed in the proximal tubules when glucose was given as 24-hour infusion than in the group with 5-hour infusion.     

Severe hypoglycaemia in 1076 adult patients with type 1 diabetes: influence of risk markers and selection

BACKGROUND: Differences between studies in rates of severe hypoglycaemia in type 1 diabetic cohorts are common and poorly understood. The purpose of this study was to assess the frequency of severe hypoglycaemia in unselected patients treated in different secondary care centres and to evaluate the influence of risk markers, clinical setting and selection. METHODS: Cross-sectional Danish-British multicentre survey of 1076 consecutive adult patients with clinical type 1 diabetes who completed a detailed questionnaire on hypoglycaemia and related issues. Key variable was the self-reported rate of severe hypoglycaemia during the preceding year. RESULTS: The overall rate of severe hypoglycaemia in the preceding year was 1.3 episodes/patient-year and episodes were reported by 36.7% of subjects. The distribution was highly skewed with 5% of subjects accounting for 54% of all episodes. There were no significant differences between countries or centres. Reduced hypoglycaemia awareness, peripheral neuropathy and smoking were the only significant risk markers of severe hypoglycaemia in a stepwise multivariate analysis. In a subgroup selected to be similar to the Diabetes Control and Complications Trial (DCCT) cohort, the rate of severe hypoglycaemia was 0.35 episodes/patient-year and only retinopathy was a significant risk marker together with state of awareness. CONCLUSION: Severe hypoglycaemia remains a significant clinical problem in type 1 diabetes. The rate of severe hypoglycaemia and the influence of risk markers are very sensitive to selection and differences in rates between centres or studies seem to disappear after correction for differences in clinical characteristics. Smoking is a novel overall risk marker of severe hypoglycaemia.