Nipah Virus Outbreak in Kerala State, India Amidst of COVID-19 Pandemic.

We report here a Nipah virus (NiV) outbreak in Kozhikode district of Kerala state, India, which had caused fatal encephalitis in a 12-year-old boy and the outbreak response, which led to the successful containment of the disease and the related investigations. Quantitative real-time reverse transcription (RT)-PCR, ELISA-based antibody detection, and whole genome sequencing (WGS) were performed to confirm the NiV infection. Contacts of the index case were traced and isolated based on risk categorization. Bats from the areas near the epicenter of the outbreak were sampled for throat swabs, rectal swabs, and blood samples for NiV screening by real-time RT-PCR and anti-NiV bat immunoglobulin G (IgG) ELISA. A plaque reduction neutralization test was performed for the detection of neutralizing antibodies. Nipah viral RNA could be detected from blood, bronchial wash, endotracheal (ET) secretion, and cerebrospinal fluid (CSF) and anti-NiV immunoglobulin M (IgM) antibodies from the serum sample of the index case. Rapid establishment of an onsite NiV diagnostic facility and contact tracing helped in quick containment of the outbreak. NiV sequences retrieved from the clinical specimen of the index case formed a sub-cluster with the earlier reported Nipah I genotype sequences from India with more than 95% similarity. Anti-NiV IgG positivity could be detected in 21% of Pteropus medius (P. medius) and 37.73% of Rousettus leschenaultia (R. leschenaultia). Neutralizing antibodies against NiV could be detected in P. medius. Stringent surveillance and awareness campaigns need to be implemented in the area to reduce human-bat interactions and minimize spillover events, which can lead to sporadic outbreaks of NiV.

Obstructive sleep apnoea in women with idiopathic intracranial hypertension: a sub-study of the idiopathic intracranial hypertension weight randomised controlled trial (IIH: WT).

OBJECTIVE: Obesity is a risk factor for idiopathic intracranial hypertension (IIH) and obstructive sleep apnoea (OSA). We aimed to determine the prevalence of OSA in IIH and evaluate the diagnostic performance of OSA screening tools in IIH. Additionally, we evaluated the relationship between weight loss, OSA and IIH over 12 months. METHODS: A sub-study of a multi-centre, randomised controlled parallel group trial comparing the impact of bariatric surgery vs. community weight management intervention (CWI) on IIH-related outcomes over 12 months (IIH:WT). OSA was assessed using home-based polygraphy (ApneaLink Air, ResMed) at baseline and 12 months. OSA was defined as an apnoea-hypopnoea index (AHI) ≥ 15 or ≥ 5 with excessive daytime sleepiness (Epworth Sleepiness Scale ≥11 ). RESULTS: Of the 66 women in the IIH: WT trial, 46 were included in the OSA sub-study. OSA prevalence was 47% (n = 19). The STOP-BANG had the highest sensitivity (84%) compared to the Epworth Sleepiness Scale (69%) and Berlin (68%) to detect OSA. Bariatric surgery resulted in greater reductions in AHI vs. CWI (median [95%CI] AHI reduction of - 2.8 [ - 11.9, 0.7], p = 0.017). Over 12 months there was a positive association between changes in papilloedema and AHI (r = 0.543, p = 0.045), despite adjustment for changes in the body mass index (R2 = 0.522, p = 0.017). CONCLUSION: OSA is common in IIH and the STOP-BANG questionnaire was the most sensitive screening tool. Bariatric surgery improved OSA in patients with IIH. The improvement in AHI was associated with improvement in papilloedema independent of weight loss. Whether OSA treatment has beneficial impact on papilloedema warrants further evaluation. TRIAL REGISTRATION NUMBER: IIH: WT is registered as ISRCTN40152829 and on ClinicalTrials.gov as NCT02124486 (28/04/2014).

Effectiveness of Bariatric Surgery vs Community Weight Management Intervention for the Treatment of Idiopathic Intracranial Hypertension: A Randomized Clinical Trial.

Importance: Idiopathic intracranial hypertension (IIH) causes headaches, vision loss, and reduced quality of life. Sustained weight loss among patients with IIH is necessary to modify the disease and prevent relapse. Objective: To compare the effectiveness of bariatric surgery with that of a community weight management (CWM) intervention for the treatment of patients with active IIH. Design, Setting, and Participants: This 5-year randomized clinical trial (Idiopathic Intracranial Hypertension Weight Trial) enrolled women with active IIH and a body mass index (calculated as weight in kilograms divided by height in meters squared) of 35 or higher at 5 National Health Service hospitals in the UK between March 1, 2014, and May 25, 2017. Of 74 women assessed for eligibility, 6 did not meet study criteria and 2 declined to participate; 66 women were randomized. Data were analyzed from November 1, 2018, to May 14, 2020. Interventions: Bariatric surgery (n = 33) or CWM intervention (Weight Watchers) (n = 33). Main Outcomes and Measures: The primary outcome was change in intracranial pressure measured by lumbar puncture opening pressure at 12 months, as assessed in an intention-to-treat analysis. Secondary outcomes included lumbar puncture opening pressure at 24 months as well as visual acuity, contrast sensitivity, perimetric mean deviation, and quality of life (measured by the 36-item Short Form Health Survey) at 12 and 24 months. Because the difference in continuous outcomes between groups is presented, the null effect was at 0. Results: Of the 66 female participants (mean [SD] age, 32.0 [7.8] years), 64 (97.0%) remained in the clinical trial at 12 months and 54 women (81.8%) were included in the primary outcome analysis. Intracranial pressure was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, -6.0 [1.8] cm cerebrospinal fluid [CSF]; 95% CI, -9.5 to -2.4 cm CSF; P = .001) and at 24 months (adjusted mean [SE] difference, -8.2 [2.0] cm CSF; 95% CI, -12.2 to -4.2 cm CSF; P < .001) compared with the CWM arm. In the per protocol analysis, intracranial pressure was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, -7.2 [1.8] cm CSF; 95% CI, -10.6 to -3.7 cm CSF; P < .001) and at 24 months (adjusted mean [SE] difference, -8.7 [2.0] cm CSF; 95% CI, -12.7 to -4.8 cm CSF; P < .001). Weight was significantly lower in the bariatric surgery arm at 12 months (adjusted mean [SE] difference, -21.4 [5.4] kg; 95% CI, -32.1 to -10.7 kg; P < .001) and at 24 months (adjusted mean [SE] difference, -26.6 [5.6] kg; 95% CI, -37.5 to -15.7 kg; P < .001). Quality of life was significantly improved at 12 months (adjusted mean [SE] difference, 7.3 [3.6]; 95% CI, 0.2-14.4; P = .04) and 24 months (adjusted mean [SE] difference, 10.4 [3.8]; 95% CI, 3.0-17.9; P = .006) in the bariatric surgery arm. Conclusions and Relevance: In this randomized clinical trial, bariatric surgery was superior to a CWM intervention in lowering intracranial pressure. The continued improvement over the course of 2 years shows the impact of this intervention with regard to sustained disease remission. Trial Registration: ClinicalTrials.gov Identifier: NCT02124486.

Erenumab for headaches in idiopathic intracranial hypertension: A prospective open-label evaluation.

OBJECTIVE: To determine the effectiveness of erenumab in treating headaches in idiopathic intracranial hypertension (IIH) in whom papilledema had resolved. BACKGROUND: Disability in IIH is predominantly driven by debilitating headaches with no evidence for the use of preventative therapies. Headache therapy in IIH is an urgent unmet need. METHODS: A prospective, open-label study in the United Kingdom was conducted. Adult females with confirmed diagnosis of IIH now in ocular remission (papilledema resolved) with chronic headaches (≥15 days a month) and failure of ≥3 preventative medications received erenumab 4-weekly (assessments were 3-monthly). The primary end point was change in monthly moderate/severe headache days (MmsHD) from baseline (30-day pretreatment period) compared to 12 months. RESULTS: Fifty-five patients, mean (SD) age 35.3 (9) years and mean duration of headaches 10.4 (8.4) years with 3.7 (0.9) preventative treatment failures, were enrolled. Mean baseline MmsHD was 16.1 (4.7) and total monthly headache days (MHD) was (29) 2.3. MmsHD reduced substantially at 12 months by mean (SD) [95% CI] 10.8 (4.0) [9.5, 11.9], p < 0.001 and MHD reduced by 13.0 (9.5) [10.2, 15.7], p < 0.001. Crystal clear days (days without any head pain) increased by 13.1 (9.5) [9.6, 15.3], p < 0.001, headache severity (scale 0-10) fell by 1.3 (1.7) [0.9, 1.9], p < 0.001, and monthly analgesic days reduced by 4.3 (9.2) [1.6, 6.9], p = 0.002. All these measures had improved significantly by 3 months, with a consistent significant response to 12 months. Headache impact test-6 score and quality of life Short Form-36 Health Survey significantly improved at 12 months. Sensitivity analysis revealed similar results for patients with and without a prior migraine diagnosis (28/55 (52%) patients) or those with or without medication overuse (27/55 (48%) patients). CONCLUSIONS: This study provides evidence for the effectiveness of erenumab to treat headaches in IIH patients with resolution of papilledema. It provides mechanistic insights suggesting that calcitonin gene-related peptide is likely a modulator driving headache and a useful therapeutic target.

Instrumented Analysis of the Sit-to-Stand Movement for Geriatric Screening: A Systematic Review.

The Sit-to-Stand (STS) is a widely used test of physical function to screen older people at risk of falls and frailty and is also one of the most important components of standard screening for sarcopenia. There have been many recent studies in which instrumented versions of the STS (iSTS) have been developed to provide additional parameters that could improve the accuracy of the STS test. This systematic review aimed to identify whether an iSTS is a viable alternative to a standard STS to identify older people at risk of falling, frailty, and sarcopenia. A total of 856 articles were found using the search strategy developed, with 12 articles retained in the review after screening based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Six studies evaluated the iSTS in fallers, five studies in frailty and only one study in both fallers and frailty. The results showed that power and velocity parameters extracted from an iSTS have the potential to improve the accuracy of screening when compared to a standard STS. Future work should focus on standardizing the segmentation of the STS into phases to enable comparison between studies and to develop devices integrated into the chair used for the test to improve usability.

Using Optical Coherence Tomography as a Surrogate of Measurements of Intracranial Pressure in Idiopathic Intracranial Hypertension.

Importance: There is an unmet need for noninvasive biomarkers of intracranial pressure (ICP), which manifests as papilledema that can be quantified by optical coherence tomography (OCT) imaging. Objective: To determine whether OCT of the optic nerve head in papilledema could act as a surrogate measure of ICP. Design, Setting, and Participants: This longitudinal cohort study used data collected from 3 randomized clinical trials that were conducted between April 1, 2014, and August 1, 2019. Participants who were female and had active idiopathic intracranial hypertension were enrolled from 5 National Health Service hospitals in the UK. Automated perimetry and OCT imaging were followed immediately by ICP measurement on the same day. Cohort 1 used continuous sitting telemetric ICP monitoring (Raumedic Neurovent P-tel device) on 1 visit. Cohort 2 was evaluated at baseline and after 3, 12, and 24 months and underwent lumbar puncture assessment of ICP. Main Outcomes and Measures: Optical coherence tomography measures of the optic nerve head and macula were correlated with ICP levels, Frisén grading, and perimetric mean deviation. The OCT protocol included peripapillary retinal nerve fiber layer, optic nerve head, and macular volume scans (Spectralis [Heidelberg Engineering]). All scans were validated for quality and resegmented manually when required. Results: A total of 104 women were recruited. Among cohort 1 (n = 15; mean [SD] age, 28.2 [9.4] years), the range of OCT protocols was evaluated, and optic nerve head central thickness was found to be most closely associated with ICP (right eye: r = 0.60; P = .02; left eye: r = 0.73; P = .002). Subsequently, findings from cohort 2 (n = 89; mean [SD] age, 31.8 [7.5] years) confirmed the correlation between central thickness and ICP longitudinally (12 and 24 months). Finally, bootstrap surrogacy analysis noted a positive association between central thickness and change in ICP at all points (eg, at 12 months, a decrease in central thickness of 50 µm was associated with a decrease in ICP of 5 cm H2O). Conclusions and Relevance: In this study, optic nerve head volume measures on OCT (particularly central thickness) reproducibly correlated with ICP and surrogacy analysis demonstrated its ability to inform ICP changes. These data suggest that OCT has the utility to not only monitor papilledema but also noninvasively prognosticate ICP levels in idiopathic intracranial hypertension.

Reviewing the Recent Developments in Idiopathic Intracranial Hypertension.

There is increasing evidence and appreciation of idiopathic intracranial hypertension (IIH) in medicine. The pathological processes underlying raised intracranial pressure are being studied, with new insights found in both hormonal dysregulation and the metabolic neuroendocrine axis. These will potentially lead to novel therapeutic targets for IIH. The first consensus guidelines have been published on the investigation and management of adult IIH, and the International Headache Society criteria for headache attributable to IIH have been modified to reflect our evolving understanding of IIH. Randomized clinical trials have been published, and a number of studies in this disease area are ongoing.

Calcitonin gene related peptide monoclonal antibody treats headache in patients with active idiopathic intracranial hypertension.

BACKGROUND: Headache is the dominant factor for quality of life related disability in idiopathic intracranial hypertension (IIH) and typically has migraine-like characteristics. There are currently no evidence-based therapeutics for headache in IIH, and consequently this is an important unmet clinical need. CASE SERIES: We report a series of seven patients in whom headaches were the presenting feature of IIH and the headaches had migraine-like characteristics, as is typical in many IIH patients. Papilloedema settled (ocular remission) but headaches continued. These headaches responded markedly to erenumab, a monoclonal antibody targeted against the calcitonin gene related peptide (CGRP) receptor. Of note, there was a recurrence of raised ICP, as evidenced by a return of the papilloedema, however the headaches did not recur whilst treated with erenumab. CONCLUSIONS: Those with prior IIH who have their headaches successfully treated with CGRP therapy, should remain under close ocular surveillance (particularly when weight gain is evident) as papilloedema can re-occur in the absence of headache. These cases may suggest that CGRP could be a mechanistic driver for headache in patients with active IIH.

Detecting and predicting neutralization of alemtuzumab responses in MS.

OBJECTIVE: To test the hypothesis that antidrug antibodies (ADAs) against alemtuzumab could become relevant after repeated treatments for some individuals, possibly explaining occasional treatment resistance. METHODS: Recombinant alemtuzumab single-chain variable fragment antibody with a dual tandem nanoluciferase reporter linker was made and used to detect binding ADAs. Alemtuzumab immunoglobulin G Alexa Fluor 488 conjugate was used in a competitive binding cell-based assay to detect neutralizing ADAs. The assays were used to retrospectively screen, blinded, banked serum samples from people with MS (n = 32) who had received 3 or more cycles of alemtuzumab. Lymphocyte depletion was measured between baseline and about 1 month postinfusion. RESULTS: The number of individuals showing limited depletion of lymphocytes increased with the number of treatment cycles. Lack of depletion was also a poor prognostic feature for future disease activity. ADA responses were detected in 29/32 (90.6%) individuals. Neutralizing antibodies occurred before the development of limited depletion in 6/7 individuals (18.8% of the whole sample). Preinfusion, ADA levels predicted limited, postinfusion lymphocyte depletion. CONCLUSIONS: Although ADAs to alemtuzumab have been portrayed as being of no clinical significance, alemtuzumab-specific antibodies appear to be clinically relevant for some individuals, although causation remains to be established. Monitoring of lymphocyte depletion and the antidrug response may be of practical value in patients requiring additional cycles of alemtuzumab. ADA detection may help to inform on retreatment or switching to another treatment.

A Comparison of Four Approaches to Evaluate the Sit-to-Stand Movement.

The sit-to-stand test (STS) is a simple test of function in older people that can identify people at risk of falls. The aim of this study was to develop two novel methods of evaluating performance in the STS using a low-cost RGB camera and another an instrumented chair containing load cells in the seat of the chair to detect center of pressure movements and ground reaction forces. The two systems were compared to a Kinect and a force plate. Twenty-one younger subjects were tested when performing two 5STS movements at self-selected slow and normal speeds while 16 older fallers were tested when performing one 5STS at a self-selected pace. All methods had acceptable limits of agreement with an expert for total STS time for younger subjects and older fallers, with smaller errors observed for the chair (-0.18 ± 0.17 s) and force plate (-0.19 ± 0.79 s) than for the RGB camera (-0.30 ± 0.51 s) and the Kinect (-0.38 ± 0.50 s) for older fallers. The chair had the smallest limits of agreement compared to the expert for both younger and older participants. The new device was also able to estimate movement velocity, which could be used to estimate muscle power during the STS movement. Subsequent studies will test the device against opto-electronic systems, incorporate additional sensors, and then develop predictive equations for measures of physical function.

A Pilot Study to Detect Balance Impairment in Older Adults Using an Instrumented One-Leg Stance Test.

The aim of this study was to investigate whether parameters from an instrumented one-leg stance (OLS) on a force plate could provide relevant information related to fall risk in older people. Forty-two community dwelling older people including 17 fallers and 25 nonfallers, and 25 young subjects performed a OLS while standing on a force plate, with parameters related to transferring weight onto one leg and postural sway in singe-leg stance evaluated. No differences were observed between older fallers and nonfallers and the younger participants for any of the weight transfer parameters. The younger participants were able to reduce their postural sway during the OLS test after the first 0-2 s period, unlike older participants who swayed the same amount throughout the test. The older fallers swayed significantly more than both nonfallers and younger participants throughout the 10-s of OLS evaluated. When the tests were used to classify older participants as fallers, the instrumented OLS achieved 100% accuracy, compared to 69.0% classification accuracy for the five times sit-to-stand test, 61.9% for the standard OLS, and 47.6% for the timed-up-and-go test. These findings suggest that the standard OLS test might not be suitable to detect fall risk. In contrast, an instrumented version of the OLS could provide valuable additional information that could identify older fallers. Future work will include a prospective study of the instrumented OLS in a larger population of older people.

Guide to preclinical models used to study the pathophysiology of idiopathic intracranial hypertension.

Idiopathic intracranial hypertension (IIH) is characterised by raised intracranial pressure (ICP) and papilloedema in the absence of an identifiable secondary cause typically occurring in young women with obesity. The impact is considerable with the potential for blindness, chronic disabling headaches, future risk of cardiovascular disease and marked healthcare utilisation. There have been marked advances in our understanding the pathophysiology of IIH including the role of androgen excess. Insight into pathophysiological underpinnings has arisen from astute clinical observations, studies, and an array of preclinical models. This article summarises the current literature pertaining to the pathophysiology of IIH. The current preclinical models relevant to gaining mechanistic insights into IIH are then discussed. In vitro and in vivo models which study CSF secretion and the effect of potentially pathogenic molecules have started to glean important mechanistic insights. These models are also useful to evaluate novel therapeutic targets to abrogate CSF secretion. Importantly, in vitro CSF secretion assays translate into relevant changes in ICP in vivo. Models of CSF absorption pertinent to IIH, are less well established but highly relevant and of future interest. There is no fully developed in vivo model of IIH but this remains an area of importance. Progress is being made to improve our understanding of the underlying aetiology in IIH including the characterisation of disease biomarkers and their mechanistic role in driving disease pathology. Preclinical models, used to evaluate IIH mechanisms are yielding important mechanistic insights. Further work to refine these techniques will provide translatable insights into disease aetiology.

Novel advances in monitoring and therapeutic approaches in idiopathic intracranial hypertension.

PURPOSE OF REVIEW: The current article appraises the recent developments in idiopathic intracranial hypertension (IIH), with particular attention to novel therapeutic avenues and advanced clinical assessment and monitoring with optical coherence tomography and telemetric intracranial pressure devices. RECENT FINDINGS: The incidence of IIH is increasing. The first consensus guidelines for IIH have been published detailing investigation and management algorithms for adult IIH. Improved understanding, clinical assessment and monitoring are emerging with the use of optical coherence tomography. Intracranial pressure telemetry is providing unique insights into the physiology of raised intracranial pressure in IIH. There are now an increasing number of ongoing clinical trials evaluating weight loss methods and novel targeted therapies, such as 11ß-HSD1 inhibition and Glucagon-like peptide 1 (GLP-1) receptor agonists. SUMMARY: Several studies are evaluating new therapies for IIH. Monitoring techniques are advancing, aiding diagnosis and allowing the clinician to accurately evaluate changes in papilloedema and intracranial pressure.

The new study leave and study budget system for trainees: what you need to know.

On 1 April 2018, Health Education England launched a new system for study leave and study budget, following concerns raised by trainees regarding the previous system. This article reviews these significant changes, highlighting the reasons provided for this overhaul, and looks ahead to the potential benefits and drawbacks of this new system.

Lesson of the month 1: Lemierre's syndrome: a reminder of the 'forgotten disease'.

Lemierre's syndrome is a condition characterised by suppurative thrombophlebitis of the internal jugular (IJ) vein following a recent oropharyngeal infection, with resulting septicaemia and metastatic lesions. It is strongly associated with Fusobacterium necrophorum, a Gram-negative bacilli. Key to early diagnosis is awareness of the classical history and course of this illness, and therefore to ask about a history of recent oropharyngeal infections when a young patient presents with fever and rigors. Diagnosis can be confirmed by showing thrombophlebitis of the IJ vein, culturing F necrophorum from normally sterile sites or demonstrating metastatic lesions in this clinical setting. The cornerstone of management is draining of purulent collection where possible and prolonged courses of appropriate antibiotics. In this article, we review a case study of a young man with Lemierre's syndrome and discuss the condition in more detail.

Vascular calcification and bone mineral density in recurrent kidney stone formers.

BACKGROUND AND OBJECTIVES: Recent epidemiologic studies have provided evidence for an association between nephrolithiasis and cardiovascular disease, although the underlying mechanism is still unclear. Vascular calcification (VC) is a strong predictor of cardiovascular morbidity and the hypothesis explored in this study is that VC is more prevalent in calcium kidney stone formers (KSFs). The aims of this study were to determine (1) whether recurrent calcium KSFs have more VC and osteoporosis compared with controls and (2) whether hypercalciuria is related to VC in KSFs. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a retrospective, matched case-control study that included KSFs attending an outpatient nephrology clinic of the Royal Free Hospital (London, UK) from 2011 to 2014. Age- and sex-matched non-stone formers were drawn from a list of potential living kidney donors from the same hospital. A total of 111 patients were investigated, of which 57 were KSFs and 54 were healthy controls. Abdominal aortic calcification (AAC) and vertebral bone mineral density (BMD) were assessed using available computed tomography (CT) imaging. The prevalence, severity, and associations of AAC and CT BMD between KSFs and non-stone formers were compared. RESULTS: Mean age was 47±14 years in KSFs and 47±13 in non-stone formers. Men represented 56% and 57% of KSFs and non-stone formers, respectively. The prevalence of AAC was similar in both groups (38% in KSFs versus 35% in controls, P=0.69). However, the AAC severity score (median [25th percentile, 75th percentile]) was significantly higher in KSFs compared with the control group (0 [0, 43] versus 0 [0, 10], P<0.001). In addition, the average CT BMD was significantly lower in KSFs (159±53 versus 194 ±48 Hounsfield units, P<0.001). A multivariate model adjusted for age, sex, high BP, diabetes, smoking status, and eGFR confirmed that KSFs have higher AAC scores and lower CT BMD compared with non-stone formers (P<0.001 for both). Among stone formers, the association between AAC score and hypercalciuria was not statistically significant (P=0.86). CONCLUSIONS: This study demonstrates that patients with calcium kidney stones suffer from significantly higher degrees of aortic calcification than age- and sex-matched non-stone formers, suggesting that VC may be an underlying mechanism explaining reported associations between nephrolithiasis and cardiovascular disease. Moreover, bone demineralization is more prominent in KSFs. However, more data are needed to confirm the possibility of potentially common underlying mechanisms leading to extraosseous calcium deposition and osteoporosis in KSFs.