Interventions in cerebrovascular emergencies among patients with Paroxysmal nocturnal haemoglobinuria - A word of caution.

INTRODUCTION: Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal hematopoietic disorder, where there is deficiency of glycosylphosphatidylinositol (GPI) anchored proteins in the cell membrane, leading to increased complement sensitivity of red blood cells, intravascular hemolysis and vascular inflammation. Arterial and venous strokes in patients with PNH are a rarity posing significant diagnostic and therapeutic challenges. We report our experience with management of PNH patients with cerebrovascular emergencies. METHODS: We report 2 patients with PNH, one who was previously diagnosed with PNH and had arterial stroke, the other had an index presentation of cerebral venous sinus thrombosis (CVT) and was subsequently diagnosed with PNH. We also present the systematic review of literature reporting similar cases, highlighting the challenges in management. RESULTS: Both patients presented to our centre with cerebrovascular emergency. The first patient was a diagnosed with PNH, and presented with left hemispheric infarction caused by thrombosis of middle cerebral artery. He was thrombolysed and underwent mechanical thrombectomy, which was unsuccessful in view of repeated re - thrombosis of the vessel. The patient survived with significant disability. The second patient had severe cerebral venous sinus thrombosis with large right hemispheric hemorrhagic venous infarction. She underwent emergency decompressive hemicraniectomy complicated by massive blood loss and disseminated intravascular coagulation. She subsequently had recurrent life threatening intracranial bleed secondary to platelet transfusions, thrombocytopenia, and use of contrast agents. She progressed to develop Budd Chiari syndrome and was initiated on Eculuzimab. She became transfusion independent, however remained in minimally conscious state and succumbed to sepsis. CONCLUSIONS: Management of arterial and venous strokes is complex in patients with PNH. Invasive procedures and platelet transfusions are to be avoided in acute thrombosis, till robust evidence is available establishing the safety of the same in patients with PNH. Eculuzimab is a promising option, but far from reach for patients in developing countries.

A review of strategies and their effectiveness in reducing indoor airborne transmission and improving indoor air quality.

Airborne transmission arises through the inhalation of aerosol droplets exhaled by an infected person and is now thought to be the primary transmission route of COVID-19. Thus, maintaining adequate indoor air quality levels is vital in mitigating the spread of the airborne virus. The cause-and-effect flow of various agents involved in airborne transmission of viruses has been investigated through a systematic literature review. It has been identified that the airborne virus can stay infectious in the air for hours, and pollutants such as particulate matter (PM10, PM2.5), Nitrogen dioxide (NO2), Sulphur dioxide (SO2), Carbon monoxide (CO), Ozone (O3), Carbon dioxide (CO2), and Total Volatile Organic Compounds (TVOCs) and other air pollutants can enhance the incidence, spread and mortality rates of viral disease. Also, environmental quality parameters such as humidity and temperature have shown considerable influence in virus transmission in indoor spaces. The measures adopted in different research studies that can curb airborne transmission of viruses for an improved Indoor Air Quality (IAQ) have been collated for their effectiveness and limitations. A diverse set of building strategies, components, and operation techniques from the recent literature pertaining to the ongoing spread of COVID-19 disease has been systematically presented to understand the current state of techniques and building systems that can minimize the viral spread in built spaces This comprehensive review will help architects, builders, realtors, and other organizations improve or design a resilient building system to deal with COVID-19 or any such pandemic in the future.

A case of prolidase deficiency in a male patient.

Prolidase deficiency is an extremely rare, autosomal recessive disorder resulting in defective collagen formation. We report a case of prolidase deficiency in a male child, highlighting the dermatologic features. Early diagnosis is important as these patients encounter significant multisystem comorbidities requiring multispecialty care.

Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848.

Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1:2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p.Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect ∼0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.

Outcomes of patients with end stage kidney disease on dialysis with COVID-19 in Abu Dhabi, United Arab Emirates; from PCR to antibody.

BACKGROUND: Individuals with end-stage kidney disease (ESKD) on dialysis are vulnerable to contracting COVID-19 infection, with mortality as high as 31 % in this group. Population demographics in the UAE are dissimilar to many other countries and data on antibody responses to COVID-19 is also limited. The objective of this study was to describe the characteristics of patients who developed COVID-19, the impact of the screening strategy, and to assess the antibody response to a subset of dialysis patients. METHODS: We retrospectively examined the outcomes of COVID19 infection in all our haemodialysis patients, who were tested regularly for COVID 19, whether symptomatic or asymptomatic. In addition, IgG antibody serology was also performed to assess response to COVID-19 in a subset of patients. RESULTS: 152 (13 %) of 1180 dialysis patients developed COVID-19 during the study period from 1st of March to the 1st of July 2020. Of these 81 % were male, average age of 52​ years and 95 % were on in-centre haemodialysis. Family and community contact was most likely source of infection in most patients. Fever (49 %) and cough (48 %) were the most common presenting symptoms, when present. Comorbidities in infected individuals included hypertension (93 %), diabetes (49 %), ischaemic heart disease (30 %). The majority (68 %) developed mild disease, whilst 13 % required critical care. Combinations of drugs including hydroxychloroquine, favipiravir, lopinavir, ritonavir, camostat, tocilizumab and steroids were used based on local guidelines. The median time to viral clearance defined by two negative PCR tests was 15 days [IQR 6-25]. Overall mortality in our cohort was 9.2 %, but ICU mortality was 65 %. COVID-19 IgG antibody serology was performed in a subset (n = 87) but 26 % of PCR positive patients (n = 23) did not develop a significant antibody response. CONCLUSIONS: Our study reports a lower mortality in this patient group compared with many published series. Asymptomatic PCR positivity was present in 40 %. Rapid isolation of positive patients may have contributed to the relative lack of spread of COVID-19 within our dialysis units. The lack of antibody response in a few patients is concerning.

De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.

PURPOSE: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. METHODS: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. RESULTS: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. CONCLUSION: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.

A systematic review of economic evaluations of local authority commissioned preventative public health interventions in overweight and obesity, physical inactivity, alcohol and illicit drugs use and smoking cessation in the United Kingdom.

Background: Since 2013, local authorities in England have been responsible for commissioning preventative public health interventions. The aim of this systematic review was to support commissioning by collating published data on economic evaluations and modelling of local authority commissioned public health preventative interventions in the UK. Methods: Following the PRISMA protocol, we searched for economic evaluations of preventative intervention studies in four different areas: overweight and obesity, physical inactivity, alcohol and illicit drugs use and smoking cessation. The systematic review identified studies between January 1994 and February 2015, using five databases. We synthesized the studies to identify the key methods and examined results of the economic evaluations. Results: The majority of the evaluations related to cost-effectiveness, rather than cost-benefit analyses or cost-utility analyses. These analyses found preventative interventions to be cost effective, though the context of the interventions differed between the studies. Conclusions: Preventative public health interventions in general are cost-effective. There is a need for further studies to support justification of continued and/or increased funding for public health interventions. There is much variation between the types of economically evaluated preventative interventions in our review. Broader studies incorporating different contexts may help support funding for local authority-sponsored public health initiatives.

Molecular and clinical analyses of 16q24.1 duplications involving FOXF1 identify an evolutionarily unstable large minisatellite.

BACKGROUND: Point mutations or genomic deletions of FOXF1 result in a lethal developmental lung disease Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. However, the clinical consequences of the constitutively increased dosage of FOXF1 are unknown. METHODS: Copy-number variations and their parental origin were identified using a combination of array CGH, long-range PCR, DNA sequencing, and microsatellite analyses. Minisatellite sequences across different species were compared using a gready clustering algorithm and genome-wide analysis of the distribution of minisatellite sequences was performed using R statistical software. RESULTS: We report four unrelated families with 16q24.1 duplications encompassing entire FOXF1. In a 4-year-old boy with speech delay and a café-au-lait macule, we identified an ~15 kb 16q24.1 duplication inherited from the reportedly healthy father, in addition to a de novo ~1.09 Mb mosaic 17q11.2 NF1 deletion. In a 13-year-old patient with autism and mood disorder, we found an ~0.3 Mb duplication harboring FOXF1 and an ~0.5 Mb 16q23.3 duplication, both inherited from the father with bipolar disorder. In a 47-year old patient with pyloric stenosis, mesenterium commune, and aplasia of the appendix, we identified an ~0.4 Mb duplication in 16q24.1 encompassing 16 genes including FOXF1. The patient transmitted the duplication to her daughter, who presented with similar symptoms. In a fourth patient with speech and motor delay, and borderline intellectual disability, we identified an ~1.7 Mb FOXF1 duplication adjacent to a large minisatellite. This duplication has a complex structure and arose de novo on the maternal chromosome, likely as a result of a DNA replication error initiated by the adjacent large tandem repeat. Using bioinformatic and array CGH analyses of the minisatellite, we found a large variation of its size in several different species and individuals, demonstrating both its evolutionarily instability and population polymorphism. CONCLUSIONS: Our data indicate that constitutional duplication of FOXF1 in humans is not associated with any pediatric lung abnormalities. We propose that patients with gut malrotation, pyloric or duodenal stenosis, and gall bladder agenesis should be tested for FOXF1 alterations. We suggest that instability of minisatellites greater than 1 kb can lead to structural variation due to DNA replication errors.

Self-motion induced environmental kinetopsia and pop-out illusion - Insight from a single case phenomenology.

Stable visual perception, while we are moving, depends on complex interactions between multiple brain regions. We report a patient with damage to the right occipital and temporal lobes who presented with a visual disturbance of inward movement of roadside buildings towards the centre of his visual field, that occurred only when he moved forward on his motorbike. We describe this phenomenon as "self-motion induced environmental kinetopsia". Additionally, he was identified to have another illusion, in which objects displayed on the screen, appeared to pop out of the background. Here, we describe the clinical phenomena and the behavioural tasks specifically designed to document and measure this altered visual experience. Using the methods of lesion mapping and lesion network mapping we were able to demonstrate disrupted functional connectivity in the areas that process flow-parsing such as V3A and V6 that may underpin self-motion induced environmental kinetopsia. Moreover, we suggest that altered connectivity to the regions that process environmental frames of reference such as retrosplenial cortex (RSC) might explain the pop-out illusion. Our case adds novel and convergent lesion-based evidence to the role of these brain regions in visual processing.

The SOAR stroke score predicts inpatient and 7-day mortality in acute stroke.

BACKGROUND AND PURPOSE: An accurate prognosis is useful for patients, family, and service providers after acute stroke. METHODS: We validated the Stroke subtype, Oxfordshire Community Stroke Project Classification, Age, and prestroke Rankin stroke score in predicting inpatient and 7-day mortality using data from 8 National Health Service hospital trusts in the Anglia Stroke and Heart Clinical Network between September 2008 and April 2011. RESULTS: A total of 3547 stroke patients (ischemic, 92%) were included. An incremental increase of inpatient and 7-day mortality was observed with increase in Stroke subtype, Oxfordshire Community Stroke Project Classification, Age, and prestroke Rankin stroke score. Using a cut-off of ≥3, the area under the receiver operator curves values for inpatient and 7-day mortality were 0.80 and 0.82, respectively. CONCLUSIONS: A simple score based on 4 easily obtainable variables at the point of care may potentially help predict early stroke mortality.

Fractures in children with neurofibromatosis type 1 from two NF clinics.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with osseous abnormalities occurring in up to one-third of patients. Several studies have documented osteopenia in both children and adults with NF1; however, the significance of lower bone mineral density (BMD) in relationship to fracture incidence is not well elucidated in NF1, particularly in children. We undertook a retrospective study to determine prevalence and location of fractures in children and adolescents with NF1, ages 5-20 years, using a standardized questionnaire. We surveyed 256 individuals with NF1 from two multidisciplinary NF centers and 178 controls without NF1 of similar ages and sex. Participants with known long bone dysplasia (LBD) were analyzed separately. Data collected included numbers and location of fractures, dietary calcium intake, and physical activity levels. There was no difference in prevalence of ever having a fracture between the NF1 group without LBD (22%) and the control group (25%); median number of fractures also did not differ. There were significant differences in fracture location with a higher frequency of fractures of the lower extremities in NF1 individuals without LBD compared to controls. Both NF1 cohorts had lower rates of physical activity than controls (P < 0.0001). Our data demonstrate that the likelihood of having had a fracture is not higher in young NF1 individuals without LBD in comparison to healthy controls. The lower physical activity level may have a "protective effect" for those with NF1, thus keeping their fracture incidence lower than expected for their relative degree of osteopenia.

Implementing the English health inequalities agenda: addressing challenges to person-level, cross-sectoral data linkage, access and routine use for local authority public health.

Local authorities are central to the implementation of English Integrated Care Systems' health inequalities agendas, embedding public health into population health management planning. They work with partners to deliver a range of 'health determinant' services and facilities for people in a defined geographic area. This work is substantially premised on the use of cross-sectoral data that is linked at the individual level, readily available, longitudinal and contemporaneous. However, multiple challenges exist to such data availability. This paper elaborates upon these challenges to local authority public health systems and their potential solutions.

Embedding OR modelling as decision support in health capacity planning: insights from an evaluation.

Literature reviews over five decades have reported the paucity of examples of OR methods being routinely used to support decision-making in health and social care. This paper presents insights from an independent evaluation of a project intended to overcome some of the barriers to implementation by establishing a "community of practice" in Kent (England). The project itself was undertaken by practitioners, and had two main aims: providing training in system dynamics modelling to analysts, and making senior managers aware of the benefits of modelling. The findings largely confirmed previous studies, but also raised issues about style of training delivery and selection of problems to be modelled. Project leaders fully understood the barriers to embedding OR modelling skills, and made considerable efforts to avoid them, but nevertheless the main barrier, pressures on people's time, remained an obstacle. The paper concludes with general reflections and advice.

Planning for healthcare services during the COVID-19 pandemic in the Southeast of England: a system dynamics modelling approach.

OBJECTIVES: To develop, test, validate and implement a system dynamics model to simulate the pandemic progress and the impact of various interventions on viral spread, healthcare utilisation and demand in secondary care. DESIGN: We adopted the system dynamics model incorporating susceptible, exposed, infection and recovery framework to simulate the progress of the pandemic and how the interventions for the COVID-19 response influence the outcomes with a focus on secondary care. SETTING: This study was carried out covering all the local health systems in Southeast of England with a catchment population of six million with a specific focus on Kent and Medway system. PARTICIPANTS: Six local health systems in Southeast of England using Kent and Medway as a case study. INTERVENTIONS: Short to medium 'what if' scenarios incorporating human behaviour, non-pharmaceutical interventions and medical interventions were tested using the model with regular and continuous feedback of the model results to the local health system leaders for monitoring, planning and rapid response as needed. MAIN OUTCOME MEASURES: Daily output from the model which included number infected in the population, hospital admissions needing COVID-19 care, occupied general beds, continuous positive airway pressure beds, intensive care beds, hospital discharge pathways and deaths. RESULTS: We successfully implemented a regional series of models based on the local population needs which were used in healthcare planning as part of the pandemic response. CONCLUSIONS: In this study, we have demonstrated the utility of system dynamics modelling incorporating local intelligence and collaborative working during the pandemic to respond rapidly and take decisions to protect the population. This led to strengthened cooperation among partners and ensured that the local population healthcare needs were met.

Nuclear lamina strain states revealed by intermolecular force biosensor.

Nuclear lamins have been considered an important structural element of the nucleus. The nuclear lamina is thought both to shield DNA from excessive mechanical forces and to transmit mechanical forces onto the DNA. However, to date there is not yet a technical approach to directly measure mechanical forces on nuclear lamins at the protein level. To overcome this limitation, we developed a nanobody-based intermolecular tension FRET biosensor capable of measuring the mechanical strain of lamin filaments. Using this sensor, we were able to show that the nuclear lamina is subjected to significant force. These forces are dependent on nuclear volume, actomyosin contractility, functional LINC complex, chromatin condensation state, cell cycle, and EMT. Interestingly, large forces were also present on nucleoplasmic lamins, indicating that these lamins may also have an important mechanical role in the nucleus. Overall, we demonstrate that the nanobody-based approach allows construction of biosensors for complex protein structures for mechanobiology studies.

Cerebral venous sinus thrombosis: changing trends in the incidence, age and gender (findings from the CMC Vellore CVT registry).

BACKGROUND: Multiple cerebral venous sinus thrombosis (CVT) registries from various geographical regions indicate that female gender, the use of contraceptive pills, pregnancy and puerperium are important risk factors. In this study, we report the changes in the epidemiology of patients with CVT managed over the past 26 years. METHODS: The CMC Vellore CVT registry is a prospectively maintained database at the Christian Medical College, Vellore since January 1995. Stata software was used to analyse the data and assess the changes in the incidence, age and gender distribution over the previous 26 years. RESULTS: Among 1701 patients treated during the study period, 908 (53%) were women and 793 (47%) were men. The mean incidence of CVT was 49 per 100 000 admissions before 2010, which increased to 96 per 100 000 after 2010. Male gender had a higher odds of developing CVT (OR - 2.07 (CI 1.68 to 2.55, p<0.001). This could be attributed to the declining incidence of postpartum CVT after 2010 compared with the decade before 2010 (50% vs 20%). The mean age at presentation had increased from 24.5 to 33.2 years in the last decade. CONCLUSIONS: There was a clear change in the gender pattern from being a condition with female preponderance, to one where equal or more men are being affected. Lower incidence of postpartum CVT cases could be the driving factor. An increase in the overall incidence of CVT cases was noted, probably due to a higher index of clinical suspicion and better diagnostic imaging modalities.

Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites.

Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' untranslated region (3'UTR), introns, or exons. Most studies focus on APA within the 3'UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3'UTR APA and are up-regulated. This suggests that, under healthy conditions, cells toggle between internal and 3'UTR APA to modulate protein expression.

Tetrasomy 15q25.2→qter identified with SNP microarray in a patient with multiple anomalies including complex cardiovascular malformation.

We report on a male neonate with prenatally diagnosed mosaicism for a supernumerary marker chromosome and multiple congenital anomalies. Prenatal ultrasound imaging revealed a heart defect, pleural effusion, clubbed feet, and absent right kidney. Clinical cytogenetic analysis of amniocytes identified a marker chromosome present in 10 out of 15 cells analyzed. Clinical evaluation of the neonate revealed distinct facial features, complex heart defects, solitary left kidney, and arachnodactyly. Chromosome analysis of lymphocytes demonstrated an abnormal male karyotype with a marker chromosome present in all 24 cells examined. To identify the marker chromosome, SNP microarray analysis was performed which detected the presence of a two copy gain of 17.7 Mb of DNA from the distal long arm of chromosome 15 (15q25.2-qter). FISH analysis using a probe specific to the 15q26.3 region showed one signal on each normal 15q and two signals, one on each arm of the marker chromosome resulting in four copies. Distal tetrasomy 15q is rare. Only 11 cases have been described in the literature, all due to a supernumerary analphoid marker chromosome consisting of an inverted duplication of the distal long arm of chromosome 15. We report on a unique patient with tetrasomy 15q with complex cardiovascular malformation (CVM) involving progressive diffuse pulmonary vein stenosis (PVS). We propose overexpression of three genes, ADAMTSL3, MESP1, and MESP2 as a potential mechanism for cardiac and vessel malformations associated with tetrasomy 15q. Finally, we believe cardiac defects with this genetic syndrome are a poor prognostic finding associated with high mortality.

Fostering disaster mitigation through community participation- case of Kochi residents following the Kerala floods of 2018 and 2019.

Community participation has grown in prominence in mitigating disasters globally. It involves the active involvement in search and rescue to reconstruction that people affected by disasters undertake unsolicited. Predictive power in disaster recovery has further increased its relevance. However, quantitative analysis that community participation has on disaster mitigation measures is scant. The study analyses community participation's impact on disaster mitigation measures following the Kochi flood of 2018 and 2019 in India. We use a Multivariate Probit Regression model with a sample size of 750 to analyse the relationship between disaster mitigation measures (namely, disaster event planning, previous experience, following disaster-related news closely, and neighbourhood relationship) and community participation. The results show participants who were active in community events were 23% more likely to adopt all the disaster mitigation measures than those who did not. In addition, households with special needs members were more likely to be prepared for an unanticipated event. The results also showed higher education levels directly correlated to implementing more significant disaster mitigation measures. Implications for government policy formation include schemes to enhance community rehabilitation and promote social participation to mitigate future disaster events.