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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., Competing Interests: Declarations. Ethics approval: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Conflicts of interest: The authors declare that there are no conflicts of interest regarding the publication of this paper. This declaration is made to confirm that there has been no financial or personal relationship with other people or organizations that could inappropriately influence or bias the work presented in this manuscript. This includes, but is not limited to, employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding., (© 2024. The Author(s).)

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 15 O-labeled carbon monoxide (CO) and oxygen (O2), intravenous 15 O-labeled water (H2O), and 18 F-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.

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Mapping 3D plasma membrane topology in live cells can bring unprecedented insights into cell biology. Widefield-based super-resolution methods such as 3D-structured illumination microscopy (3D-SIM) can achieve twice the axial ( ~ 300 nm) and lateral ( ~ 100 nm) resolution of widefield microscopy in real time in live cells. However, twice-resolution enhancement cannot sufficiently visualize nanoscale fine structures of the plasma membrane. Axial interferometry methods including fluorescence light interference contrast microscopy and its derivatives (e.g., scanning angle interference microscopy) can determine nanoscale axial locations of proteins on and near the plasma membrane. Thus, by combining super-resolution lateral imaging of 2D-SIM with axial interferometry, we developed multi-angle-crossing structured illumination microscopy (MAxSIM) to generate multiple incident angles by fast, optoelectronic creation of diffraction patterns. Axial localization accuracy can be enhanced by placing cells on a bottom glass substrate, locating a custom height-controlled mirror (HCM) at a fixed axial position above the glass substrate, and optimizing the height reconstruction algorithm for noisy experimental data. The HCM also enables imaging of both the apical and basal surfaces of a cell. MAxSIM with HCM offers high-fidelity nanoscale 3D topological mapping of cell plasma membranes with near-real-time ( ~ 0.5 Hz) imaging of live cells and 3D single-molecule tracking., (© 2023. Springer Nature Limited.)

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., (© 2023. The Author(s).)

Compensatory endocytosis keeps the membrane surface area of secretory cells constant following exocytosis. At chemical synapses, clathrin-independent ultrafast endocytosis maintains such homeostasis. This endocytic pathway is temporally and spatially coupled to exocytosis; it initiates within 50 ms at the region immediately next to the active zone where vesicles fuse. However, the coupling mechanism is unknown. Here, we demonstrate that filamentous actin is organized as a ring, surrounding the active zone at mouse hippocampal synapses. Assuming the membrane area conservation is due to this actin ring, our theoretical model suggests that flattening of fused vesicles exerts lateral compression in the plasma membrane, resulting in rapid formation of endocytic pits at the border between the active zone and the surrounding actin-enriched region. Consistent with model predictions, our data show that ultrafast endocytosis requires sufficient compression by exocytosis of multiple vesicles and does not initiate when actin organization is disrupted, either pharmacologically or by ablation of the actin-binding protein Epsin1. Our work suggests that membrane mechanics underlie the rapid coupling of exocytosis to endocytosis at synapses., (© 2023. The Author(s).)

Objectives: The existing literature regarding the mental health consequences of COVID-19 among healthcare workers revolves predominantly around specialised hospital settings, while neglecting primary healthcare workers (PHCW) who are the first point of contact for patients. In view of negligible evidence, this study explored the mental health impact of COVID-19 and health system response, and sought suggestions and recommendations from the PHCWs to address their mental health needs during the pandemic crisis., Design: We employed a qualitative exploratory design., Setting: A total of 42 primary healthcare facilities across 15 districts in Sindh and Punjab provinces of Pakistan., Participants: We telephonically conducted 47 in-depth interviews with health service providers and hospital managers. A combination of inductive and deductive approach was used for data analyses using NVivo V.11.0., Results: There was immense fear, stress and anxiety among PHCWs being infected and infecting their families at the beginning of this outbreak and its peak which tapered off over time. It was triggered by lack of information about the virus and its management, false rumours, media hype, lack of personal protective measures (personal protective equipment, PPE) and non-cooperation from patients and community people. Trainings on awareness raising and the PPEs provided by the healthcare system, with emotional support from coworkers and supervisors, were instrumental in addressing their mental health needs. Additionally, they recommended appreciation and recognition, and provision of psychosocial support from mental health professionals., Conclusion: Primary healthcare system should be prepared to provide timely informational (eg, continuous updates in training and guidelines), instrumental (eg, provision of PPE, appreciation and recognition), organisational (eg, safe and conducive working environment) and emotional and psychosocial support (eg, frequent or needs-based session from mental health professionals) to PHCWs in order to mitigate the mental health impact of pandemic crisis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Counselling relatives of individuals with βeta-Thalassaemia Major (β-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., (© 2022. The Author(s).)

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 183 rd 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., (Copyright © 2022 Molecular Vision.)

Low uptake of cascade screening for βeta-thalassaemia major (β-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 β-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 β-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., (© 2021. The Author(s).)

The government-funded 'Punjab Thalassaemia Prevention Project' (PTPP) in Pakistan includes cascade screening for biological relatives of children with beta-Thalassaemia Major (β-TM). However, there is low uptake of cascade screening. This paper presents the (i) development of a paper-based 'decision support intervention for relatives' (DeSIRe) to enable PTPP Field Officers to facilitate informed decision making about carrier testing, and (ii) assessment of the feasibility and acceptability of the DeSIRe. The intervention was developed using the International Patient Decision Aids Standards quality criteria and Ottawa Decision Support Framework. Twelve focus groups were conducted (September and October 2020) to explore the views of healthcare professionals (HCPs) and relatives of children with β-TM, in six cities. The focus groups were attended by 117 participants (60 HCPs and 57 relatives). Thematic analysis showed that the DeSIRe was considered acceptable for supporting relatives to make informed decisions about cascade screening, and potentially feasible for use in clinical practice. Suggestions for changing some words, the structure and adding information about how carrier testing relates to consanguineous marriages will enable further development of the DeSIRe. Participants generally welcomed the DeSIRe; however, they highlighted the perceived need to use more directive language, hence showed a cultural preference for directive genetic counselling. The findings highlight challenges for researchers using western theories, frameworks, policies and clinical guidelines to develop decision support interventions for implementation more globally. Future research is needed to evaluate the use of the DeSIRe in routine practice and whether it enables relatives to make informed decisions., (© 2021. The Author(s).)

Respiratory failure and chronic ventilator dependence in tetraplegics following cervical injuries located high on the spine (C1-C3) constitute significant challenges in the rehabilitation of patients given the occurrence of repeated hospitalizations and an ever-increasing financial burden. A 30-year-old man presented with posttraumatic tetraplegia following an unstable injury at the C1-C2 level with cord compression; he was managed by posterior stabilization and decompression followed by ventilator dependence and no rehabilitation until 6 months postinjury. We implanted phrenic nerve stimulator electrodes bilaterally for indirect diaphragm pacing by an implantable pulse generator that allowed for weaning from mechanical ventilation and spontaneous ventilator-free breathing at 20 weeks post-implantation and which facilitated post-tetraplegia rehabilitation. At 36 months after implantation, the patient is ventilator-free without any procedure-related complications or respiratory infections. Diaphragm pacing with phrenic nerve stimulation may be a way forward for ventilator-dependent tetraplegics in developing countries to pursue effective rehabilitation and improved quality of life.

Background: There are few evidence-based non-pharmacological interventions adapted for people with dementia (PwD) in lower- and middle-income countries (LMIC). Thus, there is value in culturally adapting existing interventions from other settings. One such intervention for PwD involves hearing rehabilitation, which may improve dementia-related outcomes. Objective: To culturally adapt and evaluate the feasibility and acceptability of a multi-faceted hearing support intervention to enhance quality of life in PwD for a LMIC setting, Pakistan. Design: This was a study in three phases: (1) training and capacity building to deliver the study, including Patient and Public Involvement (PPI); (2) cultural adaptation of the intervention; and (3) delivery of a single-group feasibility study with a pre-test post-test design. Setting: Home-based intervention, in two cities of Pakistan. Participants: Adults aged ≥ 60 with mild-moderate dementia and uncorrected or partially corrected hearing impairment, and their study partners ( n = 14). Intervention: An adapted hearing support intervention (HSI) comprising a full assessment of hearing function, fitting of hearing aids, and home-based support from a "hearing support practitioner." Outcomes: Ratings of the feasibility of the study procedures, and acceptability/tolerability of the adapted intervention were ascertained through questionnaires, participant diaries, therapist logbooks and semi-structured interviews. A signal of effectiveness of the intervention was also explored using a battery of dementia-related outcome measures. Results: Following cultural adaptation and capacity building for study conduct and delivery, we successfully implemented all intervention components in most participants, which were well-received and enacted by participant dyads. Acceptability (i.e., understanding, motivation, sense of achievement) and tolerability (i.e., effort, fatigue) ratings and safety of the intervention were within a priori target ranges. Recruitment and retention targets required improvement, due to the COVID-19 pandemic outbreak, as well as the lack of a clear clinical diagnostic pathway for dementia in both sites. Areas for future modification were clearly identified, including: the assessment/delivery logistics circuit; procedures for arranging visits; communication among referring clinicians and the study team. Conclusion: This is the first study in a LMIC of sensory enhancement to improve dementia outcomes. Positive feasibility, acceptability and tolerability findings suggest that a full-scale effectiveness trial, with certain modifications is warranted., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sheikh, Tofique, Zehra, Amjad, Rasheed, Usman, Lal, Hooper, Miah, Husain, Jafri, Chaudhry and Leroi.)

Background: Although an integral part of ethical and quality health care, little is known about the informed decision making of Chinese women with different socioeconomic backgrounds within the context of antenatal testing., Methods: To explore women's viewpoints on informed decision making regarding antenatal screening, a Q-methodology study that combines both quantitative factor analysis and interviews was conducted between June 2016 and February 2017 in Shanghai and Duyun. A total of 169 women (84 Shanghai and 85 Duyun) participated in the study of 41 ranked statements along a Q-sorting grid., Results: Using by-person factor analysis, five distinct viewpoints are identified: (a) choice is shared with the partner/husband, but the mother has the right to make the final decision; (b) having antenatal tests is not about choice but about a mother's responsibility; (c) choice is a shared decision led primarily by the partner/husband and secondarily by the doctors; (d) choice should be made using the advice of doctors, but the decision should be made with the partner/husband; and (e) choice is a responsibility shared with the partner, family and doctors., Conclusions: The study reveals that women with better education and higher incomes demonstrate more autonomy than those with less education. The nuclear family clearly emerges as the main decision makers in health-care services in China., Patient and Public Contribution: The 169 participants shared their views and stories for at least an hour. They were debriefed after the interviews and contributed their thoughts on our study design and interpretation of the data., (© 2020 The Authors Health Expectations published by John Wiley & Sons Ltd.)

The World Health Organization (WHO) undertook the development of a rapid guide on the use of chest imaging in the diagnosis and management of coronavirus disease 2019 (COVID-19). The rapid guide was developed over 2 months by using standard WHO processes, except for the use of "rapid reviews" and online meetings of the panel. The evidence review was supplemented by a survey of stakeholders regarding their views on the acceptability, feasibility, impact on equity, and resource use of the relevant chest imaging modalities (chest radiography, chest CT, and lung US). The guideline development group had broad expertise and country representation. The rapid guide includes three diagnosis recommendations and four management recommendations. The recommendations cover patients with confirmed or who are suspected of having COVID-19 with different levels of disease severity, throughout the care pathway from outpatient facility or hospital entry to home discharge. All recommendations are conditional and are based on low certainty evidence ( n = 2), very low certainty evidence ( n = 2), or expert opinion ( n = 3). The remarks accompanying the recommendations suggest which patients are likely to benefit from chest imaging and what factors should be considered when choosing the specific imaging modality. The guidance offers considerations about implementation, monitoring, and evaluation, and also identifies research needs. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Waldenstrom macroglobulinemia (WM) is a lymphoplasmacytic lymphoma associated with a monoclonal immunoglobulin M protein. Extranodal involvement in WM is not very common. In this article, we present a rare case of WM with kidney and central nervous system involvement. Bing-Neel syndrome is a distinct complication of WM where lymphoplasmacytic cells involve the central nervous system (CNS). Our patient was initially treated with dialysis and steroids with improvement in his kidney function. He was then started on systemic treatment with rituximab, cyclophosphamide, and dexamethasone with stable kidney function but persistent CNS symptoms. Due to rarity of cases, there is no standard treatment for Bing-Neel syndrome. His treatment was switched to ibrutinib with dramatic improvement in his CNS symptoms as well as radiological findings on magnetic resonance imaging.

Follicular lymphoma, the third most common lymphoid malignancy, is considered indolent but incurable non-Hodgkin lymphoma. Isolated cutaneous relapse from follicular lymphoma is very uncommon, and very few cases have been reported in the literature. In this article, we present a case of an adult patient with a history of treated follicular lymphoma who presented with a skin lesion on his face and scalp. Further workup, including biopsy, led to the diagnosis of relapsed follicular lymphoma with no progression of disease elsewhere. We reviewed cases of follicular lymphoma, which relapsed with isolated cutaneous involvement. Treatment options for relapsed follicular lymphoma include observation, anti-CD 20 antibody alone, or in combination with chemotherapy, radio-immunotherapy, and stem cell transplantation in selected patients. Increased awareness of disease evolution and prompt diagnosis of this form of relapse from follicular lymphoma will improve the effectiveness and outcome of its management.

Objective: To determine the perinatal outcome of pregnancies complicated by Rh-alloimmunisation, requiring intrauterine blood transfusion., Study Design: Observational study., Place and Duration of Study: Feto-maternal Unit of Gene Tech Laboratory, Lahore, from 2007 to 2019., Methodology: A retrospective analysis was done on the data of cases of intrauterine, intravascular blood transfusion given to at-risk foetuses to correct foetal anaemia due to Rh-alloimmunisation or parvovirus B19. All cases, who were eligible to receive IUBT were included in the study. Cases where historic data was not available have been excluded., Results: A total of 305 intrauterine blood transfusion (IUBT) procedures were performed on 127 foetuses. The gestational age ranged from 18-32 weeks at the time of referral. Infra-hepatic part of umbilical vein was preferred for transfusion, but in some cases of anterior placenta, the cord insertion was approached with exception of only two cases where intra-cardiac route was employed. In this study, 71.6% of the babies survived, 14.2% were loss to follow and 14.2% died., Conclusion: IUBT is a safe procedure, especially when performed by experienced hands, and helps save the foetuses at risk. Mothers with Rh-alloimmunisation should be referred before developing hydrops fetalis for better outcome. Key Words: Red cell alloimmunisation, Intrauterine intravascular blood transfusion, Foetal anaemia.

In vitro eradication of the C. albicans and S. mutans mixed biofilms by eugenol alone and in combination with the antimicrobial drugs. Previously characterized strains of C. albicans (CAJ-01 and CAJ-12) and S. mutans MTCC497 were used to evaluate the eradication of biofilms using XTT reduction assay, viability assay, time dependent killing assay and scanning electron microscopy (SEM). Synergistic interaction was assessed by checkerboard method. Sessile MIC (SMIC) of eugenol was equivalent to the planktonic MIC (PMIC) against C. albicans and S. mutans mixed biofilms. SMIC of fluconazole and azithromycin was increased upto 1000-folds over PMIC. Eradication of single or mixed biofilms was evident from the viability assay and SEM. At 1 × MIC of eugenol, log 10 CFU count of C. albicans cells were decreased from 6.3 to 4.2 and 3.8 (p < 0.05) in single and mixed biofilms, respectively. SEM studies revealed the eradication of C. albicans and S. mutans cells from glass surface at 800 µg/mL concentration of eugenol. Time dependent killing assay showed dose dependent effect of eugenol on pre-formed CAJ-01, CAJ-12 and S. mutans biofilm cells. Eugenol was highly synergistic with fluconazole (FICI = 0.156) against CAJ-12 single biofilms. However, the combination of eugenol and azithromycin showed maximum synergy (FICI = 0.140) against pre-formed C. albicans and S. mutans mixed biofilms. These findings highlighted the promising efficacy of eugenol in the eradication of biofilms of two oral pathogens (C. albicans and S. mutans) in vitro and could also be exploited in synergy with fluconazole and azithromycin in controlling oral infections.

Objective: Despite combined antiretroviral therapy, neuroinflammation may persist in persons living with HIV (PLWH) and contribute to cognitive impairment in this population. Positron emission tomography (PET) imaging targeting 18 kDa translocator protein (TSPO) has been used to localize neuroinflammation. We aimed to use TSPO-PET imaging to evaluate neuroinflammation in PLWH., Design: Twenty-four virologically suppressed PLWH on combined antiretroviral therapy and 13 HIV-negative (HIV-) controls completed TSPO-PET imaging using the radiotracer [C]PBR28. Because of tracer complexity and differing procedures used in previous studies, we employed an expansive methodological approach, using binding potential (BP) and standard uptake value ratio and multiple different reference regions to estimate [C]PBR28 binding., Methods: [C]PBR28 binding was measured in 30 cortical and subcortical regions and compared between PLWH and HIV- controls. Pearson correlation evaluated the association between [C]PBR28 binding and cognition and clinical measures of HIV., Results: Analyses conducted using multiple reference regions and measures of tracer uptake revealed no significant differences between [C]PBR28 binding in PLWH compared with HIV- controls. In addition, [C]PBR28 binding in PLWH was not significantly associated with clinical measures of HIV or plasma biomarkers of inflammation. [C]PBR28 binding was not significantly elevated in cognitively impaired PLWH compared with unimpaired PLWH, but there were inverse relationships between cognitive performance (executive and global function) and [C]PBR28 binding in PLWH., Conclusions: Our results suggest that neuroinflammation may play a role in cognitive deficits, but overall neuroinflammatory levels as measured by TSPO-PET imaging in PLWH are not significantly different from those seen in HIV- controls.

Role of biofilm in disease development and enhance tolerance to antifungal drugs among Candida species has necessitated search for new anti-fungal treatment strategy. Interference in pathogenic biofilm development by new antifungal compounds is considered as an attractive anti-infective strategy. Therefore, the objective of this study was to evaluate Thymus vulgaris essential oil and its major active compound, thymol for their potential to inhibit and eradicate biofilms alone and in combination with antifungal drugs against Candida spp. with especial reference to Candida tropicalis. Anti-candidal efficacy of T. vulgaris and thymol in terms of minimum inhibitory concentration (MIC) was first determined to select the sub-MICs against C. albicans and C. tropicalis. Biofilm formation in the presence and absence of test agents was determined in 96-well microtiter plate by XTT reduction assay and effect of essential oils at sub-MICs of the test agents on biofilm development on glass surface was analysed by light and scanning electron microscopy. Synergistic interaction between essential oils and antifungal drugs were studied by checkerboard method. Effect of sub-MIC of T. vulgaris (0.5×MIC) and thymol (0.5×MIC) on biofilm formation showed a significant reduction (P<0.05) in biofilms. Light microscopy and SEM studies revealed disaggregation and deformed shape of C. albicans biofilm cells and reduced hyphae formation in C. tropicalis biofilm cells at sub-MICs of thymol. Significant effect of T. vulgaris and thymol was also recorded on pre-formed biofilms of both C. albicans and C. tropicalis. T. vulgaris and thymol also showed synergy with fluconazole against both in planktonic and biofilm mode of growth of C. albicans and C. tropicalis. However, synergy with amphotericin B is clearly evident only in planktonic Candida cells. Thyme oil and thymol alone or in combination with antifungal drugs can act as promising antibiofilm agent against drug resistant strains of Candida species and needs further in vivo study to synergise its therapeutic efficacy., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

This is a case of 49-year-old white woman who presented with a rapidly growing right sided breast mass. A subsequent punch biopsy confirmed grade 3 invasive mammary carcinoma of no special type which was negative for oestrogen receptor, progesterone receptor and Her-2 neu overexpression. She was a carrier of folliculin gene mutation that is characteristic of Birt-Hogg-Dubé syndrome (BHDS), a condition known to cause skin lesions, renal cancers and pneumothoraces. Family history revealed patient's mother, grandmother and maternal aunt developed renal cell carcinomas during their lifetime and were positive for the same germ line mutation. Tumour tissue was positive for TP53 mutation and negative for BRCA1, BRCA2 and other genes commonly associated with breast cancer. We report a patient with BHDS presenting with breast cancer that showed dramatic response to neoadjuvant chemotherapy prior to bilateral mastectomy, local chest wall radiation and 6 months of adjuvant capecitabine., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The aim of the present study was to characterize the clinical pathways that people with dementia (PwD) in different countries follow to reach specialized dementia care., Methods: We recruited 548 consecutive clinical attendees with a standardized diagnosis of dementia, in 19 specialized public centres for dementia care in 15 countries. The WHO "encounter form," a standardized schedule that enables data concerning basic socio-demographic, clinical, and pathways data to be gathered, was completed for each participant., Results: The median time from the appearance of the first symptoms to the first contact with specialist dementia care was 56 weeks. The primary point of access to care was the general practitioners (55.8%). Psychiatrists, geriatricians, and neurologists represented the most important second point of access. In about a third of cases, PwD were prescribed psychotropic drugs (mostly antidepressants and tranquillizers). Psychosocial interventions (such as psychological counselling, psychotherapy, and practical advice) were delivered in less than 3% of situations. The analyses of the "pathways diagram" revealed that the path of PwD to receiving care is complex and diverse across countries and that there are important barriers to clinical care., Conclusions: The study of pathways followed by PwD to reach specialized care has implications for the subsequent course and the outcome of dementia. Insights into local differences in the clinical presentations and the implementation of currently available dementia care are essential to develop more tailored strategies for these patients, locally, nationally, and internationally., (© 2019 John Wiley & Sons, Ltd.)

The paper [Prasongkit et al. , RSC Adv. , 2016, 64 , 59299] by Prasongkit and Rocha calculates the binding energy of gas molecules attached to 1-8-biphenyl-dithiol (BPDT) molecules. We find from our calculations, that the binding energies calculated for the NO 2 molecules are too low, most likely due to lacking optimization of the site at which the gas molecule binds to the BPDT. Though not shown explicitly here, the same statement might apply to the other gas molecules used in this paper., Competing Interests: The group of K. Leifer working in Electron Microscopy and Nano-Engineering at Uppsala University, Sweden, has carried out gas sensor measurements since 2009 starting with measurements on graphene.5 On the background of the gas sensing work on graphene, Leifer proposed in 2011 to build a nanoMoED (nanomolecular electronics) device functionalized with BPDT and try to carry out gas sensing experiments with environmental gases. This idea was nourished by the interdisciplinary centre at Uppsala University, U3MEC (Uppsala University Unimolecular Electronics Centre). After successful initial results, in 2013, we gathered again with the colleagues from theory to discuss possible DFT calculations of the gas sensing effects in uni-molecular devices. At this time, J. Prasongkit was a guest researcher at Uppsala University and our theory colleagues invited her to the meetings., (This journal is © The Royal Society of Chemistry.)

Antimicrobial development for children remains challenging due to multiple barriers to conducting randomised clinical trials (CTs). There is currently considerable heterogeneity in the design and conduct of paediatric antibiotic studies, hampering comparison and meta-analytic approaches. The board of the European networks for paediatric research at the European Medicines Agency (EMA), in collaboration with the Paediatric European Network for Treatments of AIDS-Infectious Diseases network (www.penta-id.org), recently developed a Working Group on paediatric antibiotic CT design, involving academic, regulatory and industry representatives. The evidence base for any specific criteria for the design and conduct of efficacy and safety antibiotic trials for children is very limited and will evolve over time as further studies are conducted. The suggestions being put forward here are based on the adult EMA guidance, adapted for neonates and children. In particular, this document provides suggested guidance on the general principles of harmonisation between regulatory and strategic trials, including (1) standardised key inclusion/exclusion criteria and widely applicable outcome measures for specific clinical infectious syndromes (CIS) to be used in CTs on efficacy of antibiotic in children; (2) key components of safety that should be reported in paediatric antibiotic CTs; (3) standardised sample sizes for safety studies. Summarising views from a range of key stakeholders, specific criteria for the design and conduct of efficacy and safety antibiotic trials in specific CIS for children have been suggested. The recommended criteria are intended to be applicable to both regulatory and clinical investigator-led strategic trials and could be the basis for harmonisation in the design and conduct of CTs on antibiotics in children. The next step is further discussion internationally with investigators, paediatric CTs networks and regulators., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To produce a strategic roadmap for supporting the development of dementia research in Pakistan., Background: While global research strategies for dementia research already exist, none is tailored to the specific needs and challenges of low- and middle-income countries (LMIC) like Pakistan., Methods: We undertook an iterative consensus process with lay and professional experts to develop a Theory of Change-based strategy for dementia research in Pakistan. This included Expert Reference Groups (ERGs), strategic planning techniques, a "research question" priority survey, and consultations with Key Opinion Leaders., Results: We agreed on ten principles to guide dementia research in Pakistan, emphasizing pragmatic, resource sparing, real-world approaches to support people with dementia, both locally and internationally. Goals included capacity/capability building. Priority research topics included raising awareness and understanding of dementia, and improving quality of life., Conclusion: This roadmap may be a model for other LMIC health ecosystems with emerging dementia research cultures., (© 2019 The Authors.)

The size of oocytes was previously reported to be smaller in obese women with polycystic ovary syndrome (PCOS). In the present prospective cohort study, we sought to determine whether oocyte size and morphology are associated with patient characteristics in non-PCOS women. Oocyte and oolemmal diameter were measured, enlarged perivitelline space (PVS) and ooplasmic granulation were assessed in 308 MII oocytes from 77 IVF/ICSI couples. Statistical analysis was undertaken using SAS version 9.4 (SAS institute Inc., USA). Continuous values are presented as mean ± SD and compared using a two-sample t-test or Mann-Whitney U test as appropriate. Categorical parameters are presented as proportions and compared using a Fisher exact test. Logistic and linear regression models were used to control for the effect of age for categorical and continuous variables respectively. P-value < 0.05 was considered statistically significant. Patients presented with a mean age of 40.3±5.0 years, had a BMI of 25.1±6.1 kg/m2, median AMH levels of 0.6 ng/ml and produced a median of 4 oocytes. Mean total oocyte diameter was 163.2±7.4 μm (range 145.8-182.1 μm), while oolemmal diameter was 109.4±4.1 μm (range 98.5-122.3 μm). After adjusting for age and ovarian reserve increasing BMI was associated with decreased total oocyte diameter (p<0.05). Total oocyte diameter was also inversely associated with AMH levels (p = 0.03) and oocyte yield (p = 0.04). In contrast to total oocyte diameter, oolemmal diameter was not related to patient characteristics. Younger women and those with large oocyte yields demonstrated fewer oocytes with ooplasmic granulation (p<0.05 and p = 0.01). After adjustments for age, ooplasmic granulation was also less frequently observed in oocytes from women with higher AMH (p = 0.03) and increasing BMI (p<0.01). Fertilization was more likely in oocytes with larger oolemmal diameter (p = 0.008). Embryos from oocytes with larger total and ooplasmic diameters were more likely to be transferred or frozen (p = 0.004 and p = 0.01). In non-PCOS infertile women, BMI and ovarian function relate to total oocyte diameter. These results expand on previously observed associations between oocyte size and BMI in women with PCOS. They indicate the importance of detailed oocyte assessments, which may aid the currently used criteria for embryo selection and help to better understand how oocyte status is associated with later embryo development., Competing Interests: Author AW: As visiting Associate Scientist at the Center for Human Reproduction AW is entitled to full access to all data and materials of this facility and adheres to safety and confidentiality regulations. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Prenatal genetic technologies now are being implemented in LMICs, and while there is much research on the ethical, legal and social implications of such technologies in Western countries, there is a paucity of such research in LMICs, which have diverse cultural, religious, political, financial and health service contexts. This study aimed to explore views about women's autonomous decision-making for antenatal screening held by women, men and healthcare professionals (HCPs) in Pakistan. A Q-methodology study was conducted during June 2016 to January 2018 in Lahore, Pakistan. A total of 137 participants (60 women, 57 men, 20 HCPs) rank-ordered 41 statements. Following by-person factor analysis, four distinct viewpoints were identified. Three of these represent views held by women and men only: autonomous decision-making requires directive advice from doctors; autonomous decision-making requires the husband's involvement, where independent decision-making by the woman is considered culturally inappropriate; and opting for antenatal screening is a foregone decision. One contrasting viewpoint represents predominantly HCPs: autonomous decision-making is the couple's responsibility. These findings highlight that Western approaches to facilitating women's autonomy for antenatal screening are unlikely to be suitable for use in Pakistan. Instead, culturally appropriate practice guidelines are needed in LMICs to enable HCPs to adopt shared decision-making approaches in a way that enables them to facilitate active and joint decision-making by couples, while ensuring women exercise their autonomy.

Objective: Delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH) may result in focal neurological deficits and cerebral infarction, believed to result from critical regional rather than global impairments in cerebral blood flow (CBF). However, the burden of such regional hypoperfusion has not been evaluated by gold-standard voxel-by-voxel CBF measurements. Specifically, the authors sought to determine whether the proportion of brain affected by hypoperfusion was greater in patients with DCI than in SAH controls without DCI and whether the symptomatic hemisphere (in those with lateralizing deficits) exhibited a greater cerebral hypoperfusion burden., Methods: Sixty-one patients with aneurysmal SAH underwent 15O PET to measure regional CBF during the period of risk for DCI (median 8 days after SAH, IQR 7-10 days). Regions of visibly abnormal brain on head CT studies, including areas of hemorrhage and infarction, were excluded. Burden of hypoperfusion was defined as the proportion of PET voxels in normal-appearing brain with CBF < 25 ml/100 g/min. Global CBF and hypoperfusion burden were compared between patients with and those without DCI at the time of PET. For patients with focal impairments from DCI, the authors also compared average CBF and hypoperfusion burden in symptomatic versus asymptomatic hemispheres., Results: Twenty-three patients (38%) had clinical DCI at the time of PET. Those with DCI had higher mean arterial pressure (MAP; 126 ± 14 vs 106 ± 12 mm Hg, p < 0.001) and 18 (78%) were on vasopressor therapy at the time of PET study. While global CBF was not significantly lower in patients with DCI (mean 39.4 ± 11.2 vs 43.0 ± 8.3 ml/100 g/min, p = 0.16), the burden of hypoperfusion was greater (20%, IQR 12%-23%, vs 12%, 9%-16%, p = 0.006). Burden of hypoperfusion performed better than global CBF as a predictor of DCI (area under the curve 0.71 vs 0.65, p = 0.044). Neither global CBF nor hypoperfusion burden differed in patients who responded to therapy compared to those who had not improved by the time of PET. Although hemispheric CBF was not lower in the symptomatic versus contralateral hemisphere in the 13 patients with focal deficits, there was a trend toward greater burden of hypoperfusion in the symptomatic hemisphere (21% vs 18%, p = 0.049)., Conclusions: The burden of hypoperfusion was greater in patients with DCI, despite hemodynamic therapies, higher MAP, and equivalent global CBF. Similarly, hypoperfusion burden was greater in the symptomatic hemisphere of DCI patients with focal deficits even though the average CBF was similar to that in the contralateral hemisphere. Evaluating the proportion of the brain with critical hypoperfusion after SAH may better capture the extent of DCI than averaging CBF across heterogenous brain regions.

Objectives: MEDI3902 is a bivalent, bispecific human immunoglobulin G1κ monoclonal antibody that binds to both the Pseudomonas aeruginosa PcrV protein involved in host cell cytotoxicity and the Psl exopolysaccharide involved in P. aeruginosa colonization and tissue adherence. MEDI3902 is being developed for the prevention of nosocomial P. aeruginosa pneumonia in high-risk patients., Methods: This phase 1 dose-escalation study (NCT02255760) evaluated the safety, pharmacokinetics, antidrug antibody (ADA) responses and ex vivo anticytotoxicity and opsonophagocytic killing activities of MEDI3902 after a single intravenous infusion in healthy adults aged 18 to 60 years. Fifty-six subjects were randomized in a 3:1 ratio to receive 250, 750, 1500 or 3000 mg of MEDI3902 or placebo and followed for 60 days afterwards., Results: Treatment-emergent adverse events (TEAEs) were mild or moderate in severity; no serious TEAEs were observed. The most common TEAEs were infusion-related reactions. MEDI3902 exhibited approximately linear pharmacokinetics across the 250, 750 and 1500 mg doses and nonlinear pharmacokinetics between the 1500 and 3000 mg doses. One subject in the 3000 mg group tested positive for ADA on day 61 and had a lower MEDI3902 serum concentration from days 43 to 61 than ADA-negative subjects. Serum anticytotoxicity antibody concentrations and opsonophagocytic killing activity were correlated with MEDI3902 serum concentrations across all doses., Conclusions: Phase 1 study results of MEDI3902 in healthy subjects support further evaluation of its safety and efficacy in subjects at risk for P. aeruginosa pneumonia., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Candida albicans is frequently associated with mixed infections of Streptococcus mutans in plaque biofilms. These pathogens under chemical interactions resulting in mixed biofilm development have turned it into a prevalent and costly oral disease, which is not successfully being treated by existing chemotherapeutics., Hypothesis: Considering the need for newer drugs to overcome this challenge, the present study was aimed to investigate the efficacy of eugenol in inhibiting single and mixed biofilms of C. albicans and S. mutans., Methods: The broth dilution assay was used to determine drug resistance in the test strains. Biofilm formation on polystyrene microtiter plate was studied by XTT reduction assay whereas biofilm development on glass coverslips was assessed using 0.1% crystal violet and visualised under light microscope. Single and mixed biofilms formed on glass coverslips in the presence and absence of eugenol was analysed by scanning electron microscopy., Results: In our study, all the thirteen strains of C. albicans were resistant to fluconazole, itraconazole, ketoconazole, amphotericin B except C. albicans (CAJ-01) and C. albicans MTCC3017 which were sensitive to fluconazole. S. mutans MTCC497 was resistant to ampicillin, azithromycin, ceftriaxone and vancomycin. Among all the strains of C. albicans, CAJ-01, C. albicans ATCC90028 and C. albicans MTCC3017 formed strong biofilms and rest of the strains considered as moderate to weak biofilm formers. S. mutans MTCC497 was also formed strong biofilms. Eugenol showed concentration dependent anti-biofilm activity against single and mixed biofilms of C. albicans (CAJ-01) and S. mutans MTCC497. At sub-MIC of eugenol (100 μg/ml), the biofilm formation was 36.37% and 29.72% in CAJ-01 and S. mutans MTCC497, respectively, whereas 52.65% in mixed biofilms. The cell viability assay showed significant reduction (p < 0.05) in the log 10 CFU/ml from 6.3 to 4.8 at 200 μg/ml of eugenol for CAJ-01, whereas, from 6.4 to 3.8 and 5.3 for S. mutans MTCC497 strains in single and mixed biofilms, respectively. Scanning electron microscopy showed the disruption of cell membrane and matrix structure in both single and mixed biofilms., Conclusions: Eugenol at sub-MICs effectively inhibited single and mixed biofilms formed by the drug resistant strains of two oral pathogens, C. albicans and S. mutans through multiple mode of action., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Background and Purpose: Impaired cerebrovascular reactivity has been associated with decreased cortical thickness in patients with arterial occlusive diseases. This study tests the hypothesis that severe hemodynamic impairment, indicated by increased oxygen extraction fraction ratios on positron-emission tomography with 15 O tracers, is associated with decreased cortical thickness in patients with Moyamoya phenomenon., Materials and Methods: Patients with unilateral or bilateral idiopathic Moyamoya phenomenon were recruited. Oxygen extraction fraction ratio maps were generated from cerebral images of O[ 15 O] counts divided by H 2 [ 15 O] counts with normalization by corresponding cerebellar counts. The normal range of the oxygen extraction fraction ratio was estimated from historically available healthy control subjects. Cortical thickness was estimated from T1-weighted MR imaging and FreeSurfer. Regional samples of oxygen extraction fraction ratios and cortical thicknesses were drawn using FreeSurfer parcellations, retaining only parcellations from the vascular territory of the middle cerebral artery., Results: Complete MR imaging and PET datasets were available in 35 subjects, including 23 women; the mean age at scanning was 44 years. Patients with Moyamoya phenomenon had a significantly increased regional oxygen extraction fraction ratio compared with 15 healthy control subjects ( P < .001). Regional oxygen extraction fraction ratio and age were significant predictors of cortical thickness ( P < .001 for each) in a generalized linear mixed-effects model. Using hemisphere averages and patient averages, we found that only age was a significant predictor of cortical thickness ( P < .001)., Conclusions: Chronic hemodynamic impairment, as indicated by a higher regional oxygen extraction fraction ratio, was significantly predictive of reduced cortical thickness in mixed-effects analysis of FreeSurfer regions. This phenomenon may be related to reversible metabolic down-regulation., (© 2018 by American Journal of Neuroradiology.)

Research of the human brain metabolism in vivo has largely focused on total glucose use (via fluorodeoxyglucose positron emission tomography) and, until recently, did not examine the use of glucose outside oxidative phosphorylation, which is known as aerobic glycolysis (AG). AG supports important functions including biosynthesis and neuroprotection but decreases dramatically with aging. This multitracer positron emission tomography study evaluated the relationship between AG, total glucose use (CMRGlc), oxygen metabolism (CMRO 2 ), tau, and amyloid deposition in 42 individuals, including those at preclinical and symptomatic stages of Alzheimer's disease. Our findings demonstrate that in individuals with amyloid burden, lower AG is associated with higher tau deposition. No such correlation was observed for CMRGlc or CMRO 2 . We suggest that aging-related loss of AG leading to decreased synaptic plasticity and neuroprotection may accelerate tauopathy in individuals with amyloid burden. Longitudinal AG and Alzheimer's disease pathology studies are needed to verify causality., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background Functional status has been previously shown in the elderly cancer population to predict both mortality as well as treatment tolerance. The goal of this study was to determine if there are certain subsets of the elderly breast cancer population that are at higher risk of experiencing functional decline following treatment. Methods Patient charts from the Edwards Comprehensive Cancer Center in Huntington, West Virginia, from January 2006 - January 2016 were reviewed. Relevant inclusion criteria included patients of 65 years of age and older with a new diagnosis of Stage 0-III breast cancer. Functional decline was defined as an increase of at least one point in Eastern Cooperative Oncology Group (ECOG) scores within one year of diagnosis. ECOG performance status was subjectively determined by the physician. Fisher's exact test and Pearson's Chi-squared test were initially utilized to assess potential factors associated with functional decline such as pretreatment ECOG score, age at diagnosis, stage, hormone receptor status, type of surgery received, whether radiation therapy, chemotherapy, or hormonal therapy was received, medical comorbidities, body mass index (BMI), complaints of weakness at diagnosis, and ambulatory status. Factors that were found to be significant were further assessed via multivariate logistic regressions. Results Three-hundred and fourteen patients were identified as meeting inclusion criteria. At one-year follow-up, 45 patients (14.3% of the cohort) had documented functional decline. On initial analysis, factors associated with functional decline included Stage III disease (p=0.002) and complaints of weakness at diagnosis (p=0.004). Following multivariate analysis, Stage III disease (p = 0.02), complaints of weakness at diagnosis (p = 0.04), and bilateral mastectomy (p = 0.03) were significantly associated with functional decline. Conclusion Patients who were diagnosed with Stage III breast cancer, had complaints of weakness at time of diagnosis, or had bilateral mastectomies were more likely to have a decline in functional status at one-year follow-up. Awareness of factors associated with functional decline in the elderly Appalachian population with Stage 0-III breast cancer will be useful during discussions regarding patient expectations, treatment, and goals of care. Elderly breast cancer patients for whom bilateral prophylactic mastectomies are not indicated may be better served by lumpectomy alone (based on patient age, hormone receptor status, and tumor size), lumpectomy followed by radiation therapy, or unilateral mastectomy to maximize the likelihood of functional preservation following treatment., Competing Interests: The authors have declared that no competing interests exist.

Experience results in long-lasting changes in dendritic spine size, yet how the molecular architecture of the synapse responds to plasticity remains poorly understood. Here a combined approach of multicolor stimulated emission depletion microscopy (STED) and confocal imaging in rat and mouse demonstrates that structural plasticity is linked to the addition of unitary synaptic nanomodules to spines. Spine synapses in vivo and in vitro contain discrete and aligned subdiffraction modules of pre- and postsynaptic proteins whose number scales linearly with spine size. Live-cell time-lapse super-resolution imaging reveals that NMDA receptor-dependent increases in spine size are accompanied both by enhanced mobility of pre- and postsynaptic modules that remain aligned with each other and by a coordinated increase in the number of nanomodules. These findings suggest a simplified model for experience-dependent structural plasticity relying on an unexpectedly modular nanomolecular architecture of synaptic proteins.

The concept of informed choice for antenatal screening consists of Western ideologies, encapsulating individualistic approaches, and may be valued differently by people from countries with more collectivist cultures. This study aimed to explore perceptions of informed choice in antenatal screening in women from China, Hong Kong and Pakistan. A Q-methodology study was conducted during June 2016 to February 2017, in China (Shanghai and Duyun), Hong Kong and Pakistan (Lahore). A total of 299 women rank ordered 41 statements. Following by-person factor analysis, five distinct viewpoints were identified: choice as a maternal responsibility entrusted to doctors; choice as a shared decision led by the mother; choice as a shared decision led by the partner; choice as a responsibility delegated to the partner and doctors; and choice within a religious discourse. The findings highlight ethical dilemmas for healthcare professionals in facilitating informed choice for antenatal screening where policy and practice guidelines adapt predominantly individualistic approaches. Women's preferences for decision-making with health professionals and/or their partner, with minimal emphasis on individual rights, suggest the need for clarification of the role of health professionals in supporting and facilitating decision-making to enhance women's autonomy. Policy and practice guidelines need to be (re)framed to facilitate decision-making processes for antenatal screening using relational approaches to autonomy.

Metaplastic breast cancer (MBC) in men is an extremely rare entity. MBC is typically very aggressive with a poor prognosis. In men, it has only been reported three times in the literature. We report a 47-year-old man who presented with right-sided breast erythema and nipple inversion. Mammogram revealed a 2.4 cm spiculated mass. Initial pathology was inconclusive; however, right-sided simple mastectomy showed invasive metaplastic carcinoma with adenosquamous histology. He received adjuvant chemotherapy with 4 cycles of dose dense Adriamycin and cyclophosphamide followed by 12 weeks of paclitaxel and chest wall radiation. Although oestrogen receptor status was 1%, tamoxifen was not given due to recent diagnosis of pulmonary embolism. Two years after treatment, he is currently living with no signs of recurrence. This case will serve as a useful addition to the current literature discussing successful diagnosis, treatment and prognosis of a man with MBC., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Triple synchronous primary malignant neoplasms are rare. The exact aetiology is unknown; however, risk factors include older age, family history, genetic aberrations, prolonged exposure to carcinogens and smoking. We describe a previously healthy 48-year-old woman who presented with abdominal pain and a palpable abdominal mass. Imaging revealed a complex cystic, solid pelvic mass and another mass in the right upper quadrant. She received an extensive abdominal surgery including exploratory laparotomy, pelvic mass resection, total abdominal hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymphadenectomy, omentectomy and right adrenalectomy. During surgery, a mass in the distal sigmoid colon was noted and subsequent sigmoidectomy was performed. The surgical specimen revealed three different primary tumours with three different histologies, a granulosa cell tumour of the ovary, adrenocortical carcinoma and adenocarcinoma of the colon. She received six cycles of adjuvant chemotherapy for colon cancer with 5-fluorourocil, leucovorin and oxaliplatin and is currently living with no recurrence., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background and Purpose: The purpose was to test the hypothesis that increased oxygen extraction fraction (OEF), a marker of severe hemodynamic impairment measured by positron emission tomography, is an independent risk factor for subsequent ischemic stroke in this population., Methods: Adults with idiopathic moyamoya phenomena were recruited between 2005 and 2012 for a prospective, multicenter, blindly adjudicated, longitudinal cohort study. Measurements of OEF were obtained on enrollment. Subjects were followed up for the occurrence of ipsilateral ischemic stroke at 6-month intervals. Patients were censored at the time of surgical revascularization or at last follow-up. The primary analysis was time to ischemic stroke in the territory of the occlusive vasculopathy., Results: Forty-nine subjects were followed up during a median of 3.7 years. One of 16 patients with increased OEF on enrollment had an ischemic stroke and another had an intraparenchymal hemorrhage. Three of 33 patients with normal OEF had an ischemic stroke. On a per-hemisphere basis, 21 of 79 hemispheres with moyamoya vasculopathy had increased OEF at baseline. No ischemic strokes and one hemorrhage occurred in a hemisphere with increased OEF (n=21). Sixteen patients (20 hemispheres), including 5 with increased OEF at enrollment, were censored at a mean of 5.3 months after enrollment for revascularization surgery., Conclusions: The risk of new or recurrent stroke was lower than expected. The low event rate, low prevalence of increased OEF, and potential selection bias introduced by revascularization surgery limit strong conclusions about the association of increased OEF and future stroke risk., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00629915., (© 2017 American Heart Association, Inc.)

Objectives: Stakeholders' views are essential for informing implementation strategies for non-invasive prenatal testing (NIPT). Little is known about such views in developing countries. We explored attitudes towards NIPT among obstetricians in Pakistan, a developing, Islamic country., Methods: A 35-item questionnaire was distributed and collected at eight events (a national conference and seven workshops in five cities) for obstetric professionals on advances in fetal medicine., Results: Responses from 113 obstetrician show positive attitudes towards implementation of NIPT: 95% agreed prevention of genetic conditions was a necessity, and 97% agreed public hospitals should provide prenatal screening tests. However, participants also agreed the availability of NIPT would increase social pressure on women to have prenatal screening tests and to terminate an affected pregnancy (53% and 63%, respectively). Most participants would not offer NIPT for sex determination (55%), although 31% would. The most valued aspects of NIPT were its safety, followed by its utility and then accuracy., Conclusion: Participants generally supported the implementation of NIPT but raised concerns about social implications. Therefore, national policy is needed to regulate the implementation of NIPT, and pretest information and post-test genetic counselling are needed to mitigate social pressure and support parents to make informed decisions. © 2017 John Wiley & Sons, Ltd., (© 2017 John Wiley & Sons, Ltd.)

F4 fimbriae are protein filaments found in enterotoxigenic Escherichia coli cells and are implicated in the process of bacterial infection due to their function as bacterial adhesins. These filaments are comprised from several proteins, but the bacterial adhesin FaeG, which is a lactose-binding protein, is the major subunit comprising F4 fimbriae. Crystal structures for three variants of the FaeG protein were recently solved, including the ad variant of FaeG that was crystallized in complex with lactose. However, the dynamics of the FaeG protein bound to lactose have not been explored previously using molecular dynamics simulations. Therefore, in order to study the dynamical interactions between the FaeG ad variant and lactose, we have carried out the first all-atom molecular dynamics simulations of this system. We have also probed the role of crystallographic water molecules on the stability of lactose in the FaeG binding site, and have simulated seven FaeG mutants to probe the influence of amino acid substitutions on the ability of FaeG to bind lactose effectively. Our simulations agree well with experimental results for the influence of mutations on lactose binding, provide dynamical insights into the interactions of FaeG with lactose, and also suggest the possibility of additional regions of the FaeG protein that may act as secondary lactose binding sites., (Copyright © 2016 Elsevier Inc. All rights reserved.)