Freesurfer Software Update Significantly Impacts Striatal Volumes in the Huntington's Disease Young Adult Study and Will Influence HD-ISS Staging.

Background: The Huntington's Disease Integrated Staging System (HD-ISS) defined disease onset using volumetric cut-offs for caudate and putamen derived from FreeSurfer 6 (FS6). The impact of the latest software update (FS7) on volumes remains unknown. The Huntington's Disease Young Adult Study (HD-YAS) is appropriately positioned to explore differences in FS bias when detecting early atrophy. Objective: Explore the relationships and differences between raw caudate and putamen volumes, calculated total intracranial volumes (cTICV), and adjusted caudate and putamen volumes, derived from FS6 and FS7, in HD-YAS. Methods: Images from 123 participants were segmented and quality controlled. Relationships and differences between volumes were explored using intraclass correlation (ICC) and Bland-Altman analysis. Results: Across the whole cohort, ICC for raw caudate and putamen was 0.99, cTICV 0.93, adjusted caudate 0.87, and adjusted putamen 0.86 (all p < 0.0005). Compared to FS6, FS7 calculated: i) larger raw caudate (+0.8%, p < 0.00005) and putamen (+1.9%, p < 0.00005), with greater difference for larger volumes; and ii) smaller cTICV (-5.1%, p < 0.00005), with greater difference for smaller volumes. The systematic and proportional difference in cTICV was greater than raw volumes. When raw volumes were adjusted for cTICV, these effects compounded (adjusted caudate +7.0%, p < 0.00005; adjusted putamen +8.2%, p < 0.00005), with greater difference for larger volumes. Conclusions: As new software is released, it is critical that biases are explored since differences have the potential to significantly alter the findings of HD trials. Until conversion factors are defined, the HD-ISS must be applied using FS6. This should be incorporated into the HD-ISS online calculator.

Assessment of Perivascular Space Morphometry Across the White Matter in Huntington's Disease Using MRI.

Background: Perivascular spaces (PVS) are fluid-filled cavities surrounding small cerebral blood vessels. There are limited reports of enlarged PVS across the grey matter in manifest Huntington's disease (HD). Little is known about how PVS morphometry in the white matter may contribute to HD. Enlarged PVS have the potential to both contribute to HD pathology and affect the distribution and success of intraparenchymal and intrathecally administered huntingtin-lowering therapies. Objective: To investigate PVS morphometry in the global white matter across the spectrum of HD. Relationships between PVS morphometry and disease burden and severity measures were examined. Methods: White matter PVS were segmented on 3T T2 W MRI brain scans of 33 healthy controls, 30 premanifest HD (pre-HD), and 32 early manifest HD (early-HD) participants from the Vancouver site of the TRACK-HD study. PVS count and total PVS volume were measured. Results: PVS total count slightly increased in pre-HD (p = 0.004), and early-HD groups (p = 0.005), compared to healthy controls. PVS volume, as a percentage of white matter volume, increased subtly in pre-HD compared to healthy controls (p = 0.044), but not in early-HD. No associations between PVS measures and HD disease burden or severity were found. Conclusions: This study reveals relatively preserved PVS morphometry across the global white matter of pre-HD and early-HD. Subtle morphometric abnormalities are implied but require confirmation in a larger cohort. However, in conjunction with previous publications, further investigation of PVS in HD and its potential impact on future treatments, with a focus on subcortical grey matter, is warranted.

Intrapulmonary shunting is a key contributor to hypoxia in COVID-19: An update on the pathophysiology.

BACKGROUND: The pathophysiology of COVID-19 remains poorly understood. We aimed to estimate the contribution of intrapulmonary shunting and ventilation-to-perfusion (VA/Q) mismatch using a mathematical model to construct oxygen-haemoglobin dissociation curves (ODCs). METHODS: ODCs were constructed using transcutaneous pulse oximetry at two different fractions of inspired oxygen (FiO2). 199 patients were included from two large district general hospitals in the South East of England from 1st to 14th January 2021. The study was supported by the National Institute of Health Research (NIHR) Clinical Research Network. RESULTS: Overall mortality was 29%. Mean age was 68.2 years (SEM 1·2) with 46% female. Median shunt on admission was 17% (IQR 8-24.5); VA/Q was 0.61 (IQR 0.52-0.73). Shunt was 37.5% higher in deaths (median 22%, IQR 9-29) compared to survivors (16%, 8-21; p = 0.0088) and was a predictor of mortality (OR 1.04; 95% CI 1.01-1.07). Admission oxygen saturations were more strongly predictive of mortality (OR 0.91, 95% CI 0.87-0.96). There was no difference in VA/Q mismatch between deaths (0.60; IQR 0.50-0.73) and survivors (0.61; IQR 0.52-0.73; p = 0.63) and it was not predictive of mortality (OR 0.68; 95% CI 0.18-2.52; p = 0.55). Shunt negatively correlated with admission oxygen saturation (R -0.533; p<0.0001) whereas VA/Q was not (R 0.1137; p = 0.12). INTERPRETATION: Shunt, not VA/Q mismatch, was associated with worsening hypoxia, though calculating shunt was not of prognostic value. This study adds to our understanding of the pathophysiology of hypoxaemia in COVID-19. Our inexpensive and reliable technique may provide further insights into the pathophysiology of hypoxia in other respiratory diseases.

Magnetic resonance imaging findings in children with Parry-Romberg syndrome and en coup de sabre.

BACKGROUND: The aim of this study was to: (i) describe the abnormalities seen on brain imaging in a group of children with en coup de sabre (EDCS) with/without Parry-Romberg syndrome (PRS); and (ii) identify clinical predictors of brain imaging abnormalities. METHODS: This was a single centre (Great Ormond Street Hospital, London) retrospective case series of patients with ECDS/PRS seen from 2000 to 2018. We identified patients with cutaneous manifestations consistent with the clinical descriptions of ECDS/PRS. Presenting clinical, laboratory, and radiological brain findings are described. Results are expressed as medians and ranges or frequencies and percentages. Fisher's exact test was used to identify clinical associations with magnetic resonance imaging (MRI) abnormalities. RESULTS: Fourteen patients were studied: 6 males and 8 females; median age 14 years (range 3-20). We observed neuroimaging abnormalities in 2/6 ECDS and 5/8 ECDS/PRS patients. White matter signal abnormality, dystrophic calcification, leptomeningeal enhancement, and sulcal crowding were the typical findings on brain imaging. A total of 50% of patients had no MRI abnormality despite some of these patients having neurological symptoms. The presence of seizures was significantly associated with ipsilateral enhanced white matter signalling on MRI (p < 0.05). CONCLUSIONS: In summary, we observed several distinct radiographic patterns associated with ECDS/PRS. Seizure disorder was strongly associated with the presence of ipsilateral enhanced white matter signalling. Improved neuroimaging techniques that combine morphological with functional imaging may improve the detection rate of brain involvement in children with ECDS/PRS in the future.

Characteristics and outcomes of patients with COVID-19 at a district general hospital in Surrey, UK.

BACKGROUND: This retrospective cohort study aims to define the clinical findings and outcomes of every patient admitted to a district general hospital in Surrey with COVID-19 in March 2020, providing a snapshot of the first wave of infection in the UK. This study is the first detailed insight into the impact of frailty markers on patient outcomes and provides the infection rate among healthcare workers. METHODS: Data were obtained from medical records. Outcome measures were level of oxygen therapy, discharge and death. Patients were followed up until 21 April 2020. RESULTS: 108 patients were included. 34 (31%) died in hospital or were discharged for palliative care. 43% of patients aged over 65 died. The commonest comorbidities were hypertension (49; 45%) and diabetes (25; 23%). Patients who died were older (mean difference ±SEM, 13.76±3.12 years; p<0.0001) with a higher NEWS2 score (median 6, IQR 2.5-7.5 vs median 2, IQR 2-6) and worse renal function (median differences: urea 2.7 mmol/L, p<0.01; creatinine 4 µmol/L, p<0.05; eGFR 14 mL/min, p<0.05) on admission compared with survivors. Frailty markers were identified as risk factors for death. Clinical Frailty Scale (CFS) was higher in patients over 65 who died than in survivors (median 5, IQR 4-6 vs 3.5, IQR 2-5; p<0.01). Troponin and creatine kinase levels were higher in patients who died than in those who recovered (p<0.0001). Lymphopenia was common (median 0.8, IQR 0.6-1.2; p<0.005). Every patient with heart failure died (8). 26 (24%) were treated with continuous positive airway pressure (CPAP; median 3 days, IQR 2-7.3) and 9 (8%) were intubated (median 14 days, IQR 7-21). All patients who died after discharge (4; 6%) were care home residents. 276 of 699 hospital staff tested were positive for COVID-19. CONCLUSIONS: This study identifies older patients with frailty as being particularly vulnerable and reinforces government policy to protect this group at all costs.

Localised amyloidosis of the bladder: A rare mimic of urinary tract malignancy (case report and literature review).

INTRODUCTION: Localised amyloidosis of the urinary tract is rare and often presents with haematuria. PRESENTATION OF CASE: A 59 year old male presented with recurrent episodes of frank haematuria exacerbated by anticoagulation after a minor stroke. He had a background of hypertension, hypercholesterolaemia, and Parkinson's disease. Initial investigations did not reveal a cause, but eventual cystoscopic biopsy showed bladder mucosa expanded by deposits of amorphous, pale, eosinophilic, proteinaceous material and immunohistochemical staining revealed the presence of amyloid deposition. Workup for systemic amyloidosis was negative. A diagnosis of primary localised amyloidosis of the bladder was made. Trans-urethral resection was performed and annual cystoscopic surveillance was commenced. He was followed up for 11 years without recurrence. DISCUSSION: A comprehensive literature review revealed 349 published cases of localised amyloidosis of the urinary tract, with a median age of 57 (interquartile range 49-69), and a male preponderance (1.5 to 1). Painless visible haematuria (65%) was the most frequent presenting complaint and the bladder was the most common site of involvement (71%). Transurethral resection was the most common form of management (42%) but a proportion of patients underwent more radical surgery (nephroureterectomy/nephrectomy 9%, cystectomy 1%). Median follow up was 33 months (interquartile range 12-108) and 35% of patients had recurrent disease. This patient represents a typical case of localised amyloidosis of the urinary tract. CONCLUSION: This is the most up to date review of the literature describing localised amyloidosis of the urinary tract. The disease is rare, but salient to the urologist as it invariably mimics urinary tract malignancy.

Corrigendum to "A Critical Review of the Evidence Concerning the HIV Latency Reversing Effect of Disulfiram, the Possible Explanations for Its Inability to Reduce the Size of the Latent Reservoir In Vivo, and the Caveats Associated with Its Use in Practice".

[This corrects the article DOI: 10.1155/2017/8239428.].

A Critical Review of the Evidence Concerning the HIV Latency Reversing Effect of Disulfiram, the Possible Explanations for Its Inability to Reduce the Size of the Latent Reservoir In Vivo, and the Caveats Associated with Its Use in Practice.

Combination antiretroviral therapy (cART) effectively suppresses the replication of human immunodeficiency virus type 1 (HIV-1), improves immune function, and decreases the morbidity of acquired immune deficiency syndrome (AIDS). However, it is unable to eradicate the virus because it does not eliminate latently infected cells. The latent reservoir poses the major barrier to an HIV-1 cure. The "shock and kill" strategy aims to reactivate the virus and destroy latently infected cells. Many latency reversing agents (LRAs) reactivate HIV in vitro, but the absence of damaging side-effects and efficacy in vivo make disulfiram particularly promising. However, in clinical trials to date, disulfiram treatment has not resulted in a reduction in the size of the latent reservoir. In this article I will therefore discuss the evidence for the latency reversing effect of disulfiram, the possible explanations for its inability to reduce the size of the latent reservoir in vivo, and the caveats associated with its use in practice. These considerations will help to inform judgements about the prospect of an HIV cure from disulfiram based treatments.