Evolution of white matter hyperintensity segmentation methods and implementation over the past two decades; an incomplete shift towards deep learning.

This systematic review examines the prevalence, underlying mechanisms, cohort characteristics, evaluation criteria, and cohort types in white matter hyperintensity (WMH) pipeline and implementation literature spanning the last two decades. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, we categorized WMH segmentation tools based on their methodologies from January 1, 2000, to November 18, 2022. Inclusion criteria involved articles using openly available techniques with detailed descriptions, focusing on WMH as a primary outcome. Our analysis identified 1007 visual rating scales, 118 pipeline development articles, and 509 implementation articles. These studies predominantly explored aging, dementia, psychiatric disorders, and small vessel disease, with aging and dementia being the most prevalent cohorts. Deep learning emerged as the most frequently developed segmentation technique, indicative of a heightened scrutiny in new technique development over the past two decades. We illustrate observed patterns and discrepancies between published and implemented WMH techniques. Despite increasingly sophisticated quantitative segmentation options, visual rating scales persist, with the SPM technique being the most utilized among quantitative methods and potentially serving as a reference standard for newer techniques. Our findings highlight the need for future standards in WMH segmentation, and we provide recommendations based on these observations.

Multi-Tracer Studies of Brain Oxygen and Glucose Metabolism Using a Time-of-Flight Positron Emission Tomography - Computed Tomography Scanner.

The authors have developed a paradigm using positron emission tomography (PET) with multiple radiopharmaceutical tracers that combines measurements of cerebral metabolic rate of glucose (CMRGlc), cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and cerebral blood volume (CBV), culminating in estimates of brain aerobic glycolysis (AG). These in vivo estimates of oxidative and non-oxidative glucose metabolism are pertinent to the study of the human brain in health and disease. The latest positron emission tomography-computed tomography (PET-CT) scanners provide time-of-flight (TOF) imaging and critical improvements in spatial resolution and reduction of artifacts. This has led to significantly improved imaging with lower radiotracer doses. Optimized methods for the latest PET-CT scanners involve administering a sequence of inhaled 15O-labeled carbon monoxide (CO) and oxygen (O2), intravenous 15O-labeled water (H2O), and 18F-deoxyglucose (FDG)-all within 2-h or 3-h scan sessions that yield high-resolution, quantitative measurements of CMRGlc, CMRO2, CBF, CBV, and AG. This methods paper describes practical aspects of scanning designed for quantifying brain metabolism with tracer kinetic models and arterial blood samples and provides examples of imaging measurements of human brain metabolism.

Accuracy of TrUE-Net in comparison to established white matter hyperintensity segmentation methods: An independent validation study.

White matter hyperintensities (WMH) are nearly ubiquitous in the aging brain, and their topography and overall burden are associated with cognitive decline. Given their numerosity, accurate methods to automatically segment WMH are needed. Recent developments, including the availability of challenge data sets and improved deep learning algorithms, have led to a new promising deep-learning based automated segmentation model called TrUE-Net, which has yet to undergo rigorous independent validation. Here, we compare TrUE-Net to six established automated WMH segmentation tools, including a semi-manual method. We evaluated the techniques at both global and regional level to compare their ability to detect the established relationship between WMH burden and age. We found that TrUE-Net was highly reliable at identifying WMH regions with low false positive rates, when compared to semi-manual segmentation as the reference standard. TrUE-Net performed similarly or favorably when compared to the other automated techniques. Moreover, TrUE-Net was able to detect relationships between WMH and age to a similar degree as the reference standard semi-manual segmentation at both the global and regional level. These results support the use of TrUE-Net for identifying WMH at the global or regional level, including in large, combined datasets.

Heterozygous COL17A1 variants are a frequent cause of amelogenesis imperfecta.

BACKGROUND: Collagen XVII is most typically associated with human disease when biallelic COL17A1 variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically heterogeneous, mucocutaneous blistering disease with amelogenesis imperfecta (AI), a developmental enamel defect. Despite recognition that heterozygous carriers in JEB families can have AI, and that heterozygous COL17A1 variants also cause dominant corneal epithelial recurrent erosion dystrophy (ERED), the importance of heterozygous COL17A1 variants causing dominant non-syndromic AI is not widely recognised. METHODS: Probands from an AI cohort were screened by single molecule molecular inversion probes or targeted hybridisation capture (both a custom panel and whole exome sequencing) for COL17A1 variants. Patient phenotypes were assessed by clinical examination and analyses of affected teeth. RESULTS: Nineteen unrelated probands with isolated AI (no co-segregating features) had 17 heterozygous, potentially pathogenic COL17A1 variants, including missense, premature termination codons, frameshift and splice site variants in both the endo-domains and the ecto-domains of the protein. The AI phenotype was consistent with enamel of near normal thickness and variable focal hypoplasia with surface irregularities including pitting. CONCLUSION: These results indicate that COL17A1 variants are a frequent cause of dominantly inherited non-syndromic AI. Comparison of variants implicated in AI and JEB identifies similarities in type and distribution, with five identified in both conditions, one of which may also cause ERED. Increased availability of genetic testing means that more individuals will receive reports of heterozygous COL17A1 variants. We propose that patients with isolated AI or ERED, due to COL17A1 variants, should be considered as potential carriers for JEB and counselled accordingly, reflecting the importance of multidisciplinary care.

Pakistani healthcare professionals' perceptions of communication with patients and their relatives about hereditary breast cancer: a qualitative study in a LMIC.

Pakistan has the highest incidence and mortality rates of breast cancer in Asia, with high numbers of patients diagnosed at a young age suggesting the possibility of an inherited cancer syndrome. Communication of hereditary breast cancer (HBC) risk information with patients could enable earlier detection of the condition in relatives and reduce mortality rates. This study aimed to explore perceptions of healthcare professionals (HCPs) in Pakistan about communication with patients and their relatives about HBC. Semi-structured qualitative interviews were conducted with eighteen HCPs during March to May 2020 in Lahore. Thematic analysis shows the HCPs were generally supportive of informing patients themselves about HBC, but believed it was the patients' role to inform their relatives. HCPs also highlighted important barriers to communication with patients about HBC, including (i) patients' low socioeconomic status and educational attainment; (ii) high prevalence of the social stigma of breast cancer; and (iii) lack of health resources and facilities to provide genetic testing for HBC. In conclusion, HCPs would value the development of interventions to support communication between HCPs and patients. They also highlighted the need for interventions to support intrafamilial communication about HBC. Much research and political support are needed to address patient, social, and systemic-level barriers to facilitate communication about HBC.

Understanding the mental health impact and needs of public healthcare professionals during COVID-19 in Pakistan : a qualitative study.

OBJECTIVES: A dearth of qualitative studies constrains in-depth understanding of health service providers' perspectives and experiences regarding the impact of COVID-19 on their mental health. This study explored the mental health impact and needs of of public sector healthcare workers during COVID-19 who working in secondary-level and tertiary-level healthcare settings of Pakistan. DESIGN: An exploratory qualitative study. SETTING: Twenty-five secondary-level and eight tertiary-level public hospitals of Sindh and Punjab provinces of Pakistan. PARTICIPANTS: In-depth interviews were conducted with 16 health service providers and 40 administrative personnel. Study data were analysed on NVivo V.11 using the conventional content analysis technique. RESULTS: The study identified three overarching themes: (1) mental health impact of COVID-19 on health service providers that included the fear of acquiring the infection and transmitting it to their family members, fear of social isolation and stigma, anxiety related to the uncertainty of COVID-19, nervousness due to media exaggeration and stress associated with excessive workload; (2) mental health needs of health service providers involved in the COVID-19 crisis and available support from the healthcare system, including the expression of the need for counselling services and safe working conditions, the need for paid rest periods, and the need for appreciation and motivation to work in the pandemic; and (3) suggestions to address mental health needs of healthcare workers, including provision of specialised mental healthcare/services, formal training of health managers on managing mental health needs of health facility staff, and assessment and addressing of these needs of the health workforce. CONCLUSION: The study emphasises the need to strengthen health system preparedness for recognising and addressing the needs of healthcare professionals. At the system level, there is a need for a specialised unit to provide mental health services and better communication strategies. At the staff level, continuous motivation and appreciation should be given to healthcare professionals either through monetary incentives or formal acknowledgement of their performance.

Novel SIX6 mutations cause recessively inherited congenital cataract, microcornea, and corneal opacification with or without coloboma and microphthalmia.

Purpose: To investigate the molecular basis of recessively inherited congenital cataract, microcornea, and corneal opacification with or without coloboma and microphthalmia in two consanguineous families. Methods: Conventional autozygosity mapping was performed using single nucleotide polymorphism (SNP) microarrays. Whole-exome sequencing was completed on genomic DNA from one affected member of each family. Exome sequence data were also used for homozygosity mapping and copy number variation analysis. PCR and Sanger sequencing were used to confirm the identification of mutations and to screen further patients. Evolutionary conservation of protein sequences was assessed using CLUSTALW, and protein structures were modeled using PyMol. Results: In family MEP68, a novel homozygous nucleotide substitution in SIX6 was found, c.547G>C, that converts the evolutionarily conserved aspartic acid residue at the 183rd amino acid in the protein to a histidine, p.(Asp183His). This residue mapped to the third helix of the DNA-binding homeobox domain in SIX6, which interacts with the major groove of double-stranded DNA. This interaction is likely to be disrupted by the mutation. In family F1332, a novel homozygous 1034 bp deletion that encompasses the first exon of SIX6 was identified, chr14:g.60975890_60976923del. Both mutations segregated with the disease phenotype as expected for a recessive condition and were absent from publicly available variant databases. Conclusions: Our findings expand the mutation spectrum in this form of inherited eye disease and confirm that homozygous human SIX6 mutations cause a developmental spectrum of ocular phenotypes that includes not only the previously described features of microphthalmia, coloboma, and congenital cataract but also corneal abnormalities.

Healthcare professionals' perceptions of implementing a decision support intervention for cascade screening for beta-thalassemia in Pakistan.

Counselling relatives of individuals with ßeta-Thalassaemia Major (ß-TM) about cascade screening is the role of field officers (FOs) in the Punjab Thalassaemia Prevention Project (PTPP). This paper presents FOs' views about using a 'decision support intervention for relatives' (DeSIRe) to facilitate informed decision making, and their perception of its implementation and sustainability. Semi-structured qualitative interviews were conducted with nine FOs (June to July 2021) in seven cities in the Punjab province (Lahore, Sheikhupura, Nankana Sahab, Kasur, Gujranwala, Multan, and Faisalabad) following its use in routine clinical practice. Thematic analysis shows that the FOs were overwhelmingly supportive of the DeSIRe, expressing enthusiasm and identifying benefits of its use, both for their own practice and for relatives. They supported the aim of the intervention to enable them to facilitate relatives' decision-making about cascade screening, and advocated its use more widely within the PTPP and the other provinces of Pakistan. Overall, the DeSIRe was valued by the FOs for use in routine practice. These findings suggest the DeSIRe is highly likely to be implemented by healthcare professionals more widely in the PTPP and, therefore, is worth evaluating to prove its efficacy. Further research is needed on the extent to which the DeSIRe could be adapted for use by other healthcare professionals with similar responsibilities in the other provinces of Pakistan, and in other low-middle income countries.

Cascade screening for beta-thalassaemia in Pakistan: relatives' experiences of a decision support intervention in routine practice.

Low uptake of cascade screening for ßeta-thalassaemia major (ß-TM) in the 'Punjab Thalassaemia Prevention Project' (PTPP) in Pakistan led to the development of a 'decision support intervention for relatives' (DeSIRe). This paper presents the experiences of relatives of children with ß-TM of the DeSIRe following its use by PTPP field officers (FOs) in routine clinical practice. Fifty-four semi-structured qualitative interviews were conducted (April to June 2021) with relatives in seven cities in the Punjab province (Lahore, Sheikhupura, Nankana Sahab, Kasur, Gujranwala, Multan and Faisalabad). Thematic analysis shows that participants were satisfied with the content of the DeSIRe and its delivery by the FOs in a family meeting. They understood that the main purpose of the DeSIRe was to improve their knowledge of ß-TM and its inheritance, and to enable them to make decisions about thalassaemia carrier testing, particularly before marriage. Participants also raised concerns about the stigma of testing positive; however, they believed the DeSIRe was an appropriate intervention, which supported relatives to make informed decisions. Our findings show that the DeSIRe is appropriate for use by healthcare professionals in routine practice in a low-middle income country, and has the potential to facilitate shared decision making about cascade screening for thalassaemia. Further research is needed to prove the efficacy of the DeSIRe.