Clinical value of neuroimaging indicators of intracranial hypertension in patients with cerebral venous thrombosis.

PURPOSE: Intracranial hypertension (IH) frequently complicates cerebral venous thrombosis (CVT). Distinct neuroimaging findings are associated with IH, yet their discriminative power, reversibility and factors favoring normalization in prospective CVT patients are unknown. We determined test performance measures of neuroimaging signs in acute CVT patients, their longitudinal change under anticoagulation, association with IH at baseline and with recanalization at follow-up. METHODS: We included 26 consecutive acute CVT patients and 26 healthy controls. Patients were classified as having IH based on CSF pressure > 25 cmH2O and/or papilledema on ophthalmological examination or ocular MRI. We assessed optic nerve sheath diameter (ONSD), optic nerve tortuousity, bulbar flattening, lateral and IVth ventricle size, pituitary configuration at baseline and follow-up, and their association with IH and venous recanalization. RESULTS: 46% of CVT patients had IH. ONSD enlargement > 5.8 mm, optic nerve tortuousity and pituitary grade ≥ III had highest sensitivity, ocular bulb flattening and pituitary grade ≥ III highest specificity for IH. Only ONSD reliably discriminated IH at baseline. Recanalization was significantly associated with regressive ONSD and pituitary grade. Other neuroimaging signs tended to regress with recanalization. After treatment, 184.9 ± 44.7 days after diagnosis, bulbar flattening resolved, whereas compared with controls ONSD enlargement (p < 0.001) and partially empty sella (p = 0.017), among other indicators, persisted. CONCLUSION: ONSD and pituitary grading have a high diagnostic value in diagnosing and monitoring CVT-associated IH. Given their limited sensitivity during early CVT and potentially persistent alterations following IH, neuroimaging indicators can neither replace CSF pressure measurement in diagnosing IH, nor determine the duration of anticoagulation.

Tangent normalization for somatic copy-number inference in cancer genome analysis.

MOTIVATION: Somatic copy-number alterations (SCNAs) play an important role in cancer development. Systematic noise in sequencing and array data present a significant challenge to the inference of SCNAs for cancer genome analyses. As part of The Cancer Genome Atlas, the Broad Institute Genome Characterization Center developed the Tangent normalization method to generate copy-number profiles using data from single-nucleotide polymorphism (SNP) arrays and whole-exome sequencing (WES) technologies for over 10 000 pairs of tumors and matched normal samples. Here, we describe the Tangent method, which uses a unique linear combination of normal samples as a reference for each tumor sample, to subtract systematic errors that vary across samples. We also describe a modification of Tangent, called Pseudo-Tangent, which enables denoising through comparisons between tumor profiles when few normal samples are available. RESULTS: Tangent normalization substantially increases signal-to-noise ratios (SNRs) compared to conventional normalization methods in both SNP array and WES analyses. Tangent and Pseudo-Tangent normalizations improve the SNR by reducing noise with minimal effect on signal and exceed the contribution of other steps in the analysis such as choice of segmentation algorithm. Tangent and Pseudo-Tangent are broadly applicable and enable more accurate inference of SCNAs from DNA sequencing and array data. AVAILABILITY AND IMPLEMENTATION: Tangent is available at https://github.com/broadinstitute/tangent and as a Docker image (https://hub.docker.com/r/broadinstitute/tangent). Tangent is also the normalization method for the copy-number pipeline in Genome Analysis Toolkit 4 (GATK4). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Incidence and long-term outcome of laser pointer maculopathy in children.

PURPOSE: Single center study to evaluate the incidence and long-term outcome of laser pointer maculopathy (LPM). METHODS: Medical records of 909,150 patients visiting our institution between 2007 and 2020 were screened in our electronic patient record system using the keywords "laserpointer," "laser pointer," and "solar." RESULTS: Eight patients (6/2 male/female, 11 eyes) with a history of LPM were identified by fundoscopy and optical coherence tomography (OCT), all of whom were children (6/2 male/female). Mean age at injury was 12.1 years (range 6-16). Five children (62.5%) were injured between 2019 and 2020, three (37.5%) between 2007 and 2018. Median best-corrected visual acuity (BCVA) of affected eyes at first presentation was 20/25 (range 20/50-20/16). Follow-up examination was performed in seven children (10 eyes) with a median follow-up period of 18 months (range 0.5-96). BCVA improved in 4 children (5 eyes; BCVA at follow-up 20/22.5, range 20/40-20/16). Three of these four children were treated with oral steroids. OCT revealed acute signs such as intraretinal fluid to resolve quickly, while outer retinal disruption persisted until the last follow-up in eight of eleven eyes. These lesions resembled lesions of patients with solar retinopathy of which seven cases (11 eyes) were identified between 2007 and 2020. CONCLUSION: Readily available consumer laser pointers can damage the retina and the underlying retinal pigment epithelium, possibly leading to long-lasting visual impairments. The number of laser pointer injuries has increased over the last years. Therefore, access to laser pointers for children should be strictly controlled.

Pediatric Cataract Surgery: Rate of Secondary Visual Axis Opacification Depending on Intraocular Lens Type.

PURPOSE: To assess the time course of secondary visual axis opacification (VAO) leading to additional surgery after primary intraocular lens (IOL) implantation in children and to describe further surgical outcomes. Comparison of lens types. DESIGN: Single-center, retrospective analysis of children aged 1 to 14 years who underwent cataract surgery with primary IOL implantation. The surgical technique was either in-bag IOL placement with primary posterior capsulotomy and anterior vitrectomy or bag-in-lens IOL placement. We excluded eyes with visually significant ocular comorbidities. PARTICIPANTS: Total of 135 eyes of 95 children. Of these, 64 had received an acrylic 3-piece IOL, 51 had an acrylic single-piece IOL, and 20 had an acrylic single-piece bag-in-lens IOL. The median ages at surgery were 53 months (interquartile range [IQR], 35-75), 52 months (27-65), and 60 months (40-84) in the 3-piece, 1-piece, and bag-in-lens groups, respectively. METHODS: Analysis of medical records. We used the Kaplan-Meier method and a Cox proportional hazards model with predefined adjustments for age at surgery, year of surgery, and the German Index of Socioeconomic Deprivation (score by postal code) to analyze VAO-free survival by lens type. Patients were invited to attend a clinical visit to achieve longer follow-ups. MAIN OUTCOME MEASURES: The rate of survival without VAO that required clearing of the visual axis after cataract surgery with primary IOL implantation. Any other surgical complications. RESULTS: The overall median follow-up was 19 months (IQR, 3-58). There were 13 cases of VAO, occurring at a median of 10 months (IQR, 10-12) after surgery. Of these, 1 eye had a 3-piece in-bag IOL, 10 eyes had 1-piece in-bag IOLs, and 2 eyes had bag-in-lens IOLs. The adjusted hazard ratio was 32.8 (95% confidence interval [CI], 3.3-327, P = 0.003) for 1-piece acrylic IOLs and 19.6 (CI, 1.22-316, P = 0.036) for bag-in-lens IOLs, compared with 3-piece acrylic in-bag IOLs. Two eyes with bag-in-lens surgery (10%) had an iris capture. There was 1 case of endophthalmitis. We found no cases of postoperative retinal detachment or new glaucoma. CONCLUSIONS: Children with secondary VAO who required a procedure to clear the visual axis generally presented within 15 months. Opacification rates were lowest when a 3-piece acrylic IOL was used.

Comparison of two Schwann Cell-Containing Orbital Tumors: Schwannoma and Ganglioneuroma. / Gegenüberstellung zweier Schwann-Zell-haltiger orbitaler Tumoren: Schwannom und Ganglioneurom.

Orbital tumors comprise a variety of diseases, although tumors of the peripheral nerves are rare. Of these, schwannoma is considered the most common entity, consisting histopathologically almost exclusively of Schwann cells. Another benign tumor containing Schwann cells is ganglioneuroma. Here, ganglion cells are histopathologically apparent in addition to the Schwann cell-containing stroma. Ganglioneuroma belongs to the group of neuroblastic tumors and can occur anywhere in the pathway of sympathetic ganglion cells. In this report, we present the disease courses as well as the findings of two patients with different orbital tumors. In both cases, the diagnosis was only confirmed by histopathological examination. The first patient had a schwannoma with cystic degeneration and the second patient had a ganglioneuroma, both tumor entities which occur only rarely in the orbit. Commonalities and differences are discussed.

Thinner temporal peripapillary retinal nerve fibre layer in Stargardt disease detected by optical coherence tomography.

PURPOSE: To evaluate peripapillary retinal nerve fibre layer (RNFL) thickness measured by spectral domain optical coherence tomography (OCT) in patients with Stargardt disease (STGD). METHODS: A cross-sectional, monocentric, observational case-control study. Twenty patients (39 eyes) with ABCA4 mutations graded according to the Fishman STGD classification were included. RNFL measurement was performed using Heidelberg Spectralis SD-OCT. RNFL thickness in STGD patients was compared to age-matched data of healthy individuals provided by the device's manufacturer. A manual readjustment of the optic disc-fovea angle was performed when needed. RESULTS: The mean age at first diagnosis of STGD was 22.9 years (range 9 to 50) and 39.1 years (range 18 to 74) at the time of examination. Thirty-nine percent of eyes (15 eyes) needed manual adjustment of the optic disc-fovea angle due to malfixation of the patients during OCT. The temporal quadrant corresponding to the macula showed a RNFL 16% thinner than controls (mean - 12 µm, 95%CI - 9 to -15 µm). However, global RNFL thickness did not differ from controls due to increased RNFL thickness of 12% in the nasal sectors. Duration and stage of STGD were not correlated to thinner RNFL. CONCLUSION: STGD seems to be associated with thinner peripapillary RNFL in the sector of axons projecting to the degenerated macular area. It is yet unclear as to whether this results from anterograde transneuronal degeneration of direct injury to retinal ganglion cells.

NEGATIVE VESSEL REMODELING IN STARGARDT DISEASE QUANTIFIED WITH VOLUME-RENDERED OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To quantify retinal vasculature changes in Stargardt disease1 (STGD1) with volume-rendered optical coherence tomography angiography. METHODS: Optical coherence tomography angiography volumes from healthy subjects and two subgroups of patients with STGD1 with the presence/absence of definitely decreased autofluorescence areas were compared. Optical coherence tomography angiography vessel surface area and vessel volume were measured in central zones (Z) of 1-, 2-, and 3-mm diameter. RESULTS: Twenty nine eyes of 15 patients with STGD1 (20/9 eyes with/without definitely decreased autofluorescence) and 30 eyes of 15 controls contributed data. An enlarged foveal avascular zone was found in patients with STGD1 without and even more with definitely decreased autofluorescence associated with a vessel rarefication in central and also paracentral zones with unnoticeable autofluorescence. Vessel surface area and vessel volume were reduced in both STGD1 subgroups for all zones (P < 0.0001). Stargardt disease 1 eyes when compared to without definitely decreased autofluorescence showed reduced vessel surface area and vessel volume in Z2+3 (both P < 0.05). CONCLUSION: Volume rendering of optical coherence tomography angiography in STGD1 shows a reduced retinal flow in the central macula. This is most likely secondary to loss of neurosensory tissue with disease progression and therefore not likely be favorably influenced by gene transfer and retinal pigment epithelial transplantation. Retinal blood flow assessed by 3D volume-rendered optical coherence tomography angiography could serve as surrogate marker for vascular changes of the central retina.

Spiroplasma species as a rare cause of congenital cataract and uveitis: a case series.

BACKGROUND: To date, only four cases of ocular spiroplasma infection have been reported in the entire ophthalmic literature. We add two more cases to raise awareness of this sight-threatening congenital disease that manifests as cataract with ocular inflammation. CASE PRESENTATION: Both infants were referred for cataracts associated with ocular inflammation. Case 1, a 3-week-old neonate presented with unilateral cataract, ocular inflammation and elevated intraocular pressure. Case 2 was a 3-month-old infant with bilateral cataract and panuveitis. Lensectomies with or without vitrectomy and subsequent analyses of the specimens were performed. Transmission electron microscopy and multiplex polymerase chain reaction or 16 s rRNA gene polymerase chain reaction revealed spiroplasma species. CONCLUSIONS: Spiroplasma as a very rare cause for congenital cataract might be underdiagnosed. We recommend performing polymerase chain reaction to probe for spiroplasma species in congenital cataracts with an inflammatory component.

Side effects of topical atropine 0.05% compared to 0.01% for myopia control in German school children: a pilot study.

PURPOSE: Based on findings of the Asian low-concentration atropine for myopia progression study, a concentration of 0.05% has been proposed as a good compromise between safety and efficacy for myopia control. However, no data on side effects have been published so far in Caucasian children receiving this dose. METHODS: Prior to commencement of bilateral atropine treatment with 0.05% atropine, 19 myopic children aged 5 to 15 years were treated in only one eye at bedtime leaving the other eye as a control. Pupil size, accommodation amplitude and near visual acuity were measured at 10:00 a.m. the next day and compared to the untreated contralateral control eye. The results were then compared to a cohort of 18 children whose treatment with 0.01% atropine commenced in a similar fashion. RESULTS: Twelve children (63%) reported visual impairment or reading difficulties. Anisocoria was 2.9 ± 1.1 mm. In comparison, 0.01% atropine led to a significantly less anisocoria of 0.8 ± 0.7 mm (p < 0.0001). Accommodation was decreased by - 4.2 ± 3.8 D in 0.05% atropine treated eyes, whereas 0.01% atropine induced hypoaccommodation of - 0.05 ± 2.5 D (p < 0.01). Near visual acuity was not significantly reduced in eyes treated with 0.05% atropine compared to 0.01% atropine (p = 0.26). CONCLUSION: Compared to 0.01%, our data indicate stronger more relevant side effects of 0.05% topical atropine in young Caucasian children with progressive myopia as recently reported in Asian children, potentially compromising acceptance and compliance.

[Telemedicine in maternal health in times of COVID-19: Five national and international projects]. / Télémédecine en santé maternelle en temps de Covid-19 : cinq projets internationaux et nationaux.

Telemedicine in maternal health consists on the use of remote communication to reach, diagnose, treat and follow up patients in the context of pre and post-natal care. Covid-19 has accelerated the use of telemedicine. In the Obstetrics Division of HUG we have developed five projects in Geneva and in low-resource zones of the world with the objective of improving access and quality of care. Based on our experience, the application of telemedicine to maternal health problems has shown three major advantages: improved access to care, standardized procedures and accelerated speed of intervention. However, to be effective, telemedicine requires a health staff with a good level of medical and computer skills as well as fluid communication among all participants and constant follow-up of the information flow.

La télémédecine en santé maternelle consiste à l'utilisation des moyens de communication à distance pour rejoindre, diagnostiquer, traiter et suivre les patientes dans le contexte des soins pré-, per- et postnatals. Le Covid-19 a accéléré l'utilisation de la télémédecine. Dans le Service d'obstétrique des HUG, nous avons développé cinq projets à Genève et dans des régions défavorisées du monde, avec l'objectif d'améliorer l'accès et la qualité des soins. Basée sur notre expérience, l'application de la télémédecine aux problèmes de santé maternelle présente trois avantages essentiels: la facilitation de l'accès aux soins, la standardisation des procédures et la vitesse d'intervention. Mais pour être efficace, elle présuppose un bon niveau de compétence médicale et informatique du staff sanitaire, une communication fluide entre les différents intervenants et un contrôle constant du flux d'informations.

In-situ analysis of continuous cooling precipitation in Al alloys by wide-angle X-ray scattering.

The aim of this work is to investigate quench induced precipitation during continuous cooling in aluminium wrought alloys EN AW-7150 and EN AW-6082 using in situ synchrotron wide-angle X-ray scattering (WAXS). While X-ray diffraction is usually an ex situ method, a variety of diffraction patterns were recorded during the cooling process, allowing in situ analysis of the precipitation process. The high beam energy of about 100 keV allows the beam to penetrate a bulk sample with a 4 mm diameter in a quenching dilatometer. Additionally, the high intensity of a synchrotron source enables sufficiently high time resolution for fast in situ cooling experiments. Reaction peaks could be detected and compared with results from differential scanning calorimetry (DSC) by this method. A methodology is presented in this paper to evaluate WAXS data in a way that is directly comparable to DSC-experiments. The results show a high correlation between both techniques, DSC and WAXS, and can significantly improve continuous cooling precipitation diagrams.

[Corneal Changes in Infancy and Childhood as an Expression of Systemic Metabolic Diseases]. / Hornhautveränderungen im Säuglings- und Kindesalter als Ausdruck systemischer Stoffwechselerkrankungen.

Bilateral corneal opacities can be a leading symptom of different systemic diseases. Especially in childhood, various metabolic diseases, although very rare, should be considered as a possible diagnosis. Since corneal opacities can be among the first clinical symptoms of these diseases, the ophthalmologist plays a central role in initiating early interdisciplinary diagnostics. The early diagnosis is extremely important for further prognosis and the clinical outcome of the affected patients due to the early initiation of therapy.

[Use of the Multidisciplinary Specialised Case Conference at the Freiburg Orbital Centre]. / Inanspruchnahme der multidisziplinären spezialisierten Fallkonferenz im Freiburger Orbitazentrum.

BACKGROUND: The treatment of tumors increasingly takes place in specialised interdisciplinary centres. Therapeutic decisions are usually made at case conferences. Ophthalmologists, oromaximillofacial surgeons, ENT physicians, neurosurgeons, as well as pediatricians, radiotherapists and radiologists are all involved in the treatment of orbital diseases. The aim of this article is to present the concept of a multidisciplinary case conference for orbital diseases and to analyse case numbers, indications, and the influence on the patient's therapy. METHODS: We analysed an anonymized data set of patients who presented in the case conference of the University Hospital Freiburg from 2008 to 2018 with regard to clinical diagnosis, histological diagnoses, number of surgical interventions, and number of interdisciplinary therapy decisions. RESULTS: From 2008 to 2018, 545 patients were presented in a weekly conference. Of these, 453 were available for anonymous evaluation. The median age was 56 years (quartiles 41; 69). The most frequent indication was an orbital tumour of unclear malignancy (n = 52; 11%). Further indications included Grave's orbitopathy (n = 39; 9%), orbital pseudotumour (n = 36; 8%), cranial nerve palsy (n = 22; 5%), and orbital lymphoma (n = 22; 5%). The most frequent histological diagnoses were B-cell lymphoma (n = 10; 2%), venous malformation (cavernoma, n = 8; 2%), marginal zone lymphoma (n = 8; 2%), and squamous cell carcinoma (n = 6; 1%). An interdisciplinary therapeutic approach was defined for 174 patients. CONCLUSION: A high demand for the interdisciplinary case conference was demonstrated. The high rate of primary or secondary interdisciplinary decisions indicates the value of such a conference. Hence, the patient is spared multiple examinations in the individual specialist areas and quick and effective therapy decisions can be achieved.

Swept-source optical coherence tomography angiography alleviates shadowing artifacts caused by subretinal fluid.

PURPOSE: To characterize the choriocapillaris (CC) structure in relation to subretinal fluid (SRF) as a possible systematic error source using spectral domain (SD-OCTA) compared to swept-source optical coherence tomography angiography (SS-OCTA). METHODS: This is a prospective case-control study of 23 eyes. Ten patients with acute central serous chorioretinopathy (CSC), three patients with partial macular-off retinal detachment (RD) and ten healthy, age-matched controls were included. Abnormal CC decorrelation signals were quantitatively compared in CSC and controls by means of custom image processing. To investigate the influence of SRF on CC OCTA signal, the extent of SRF was quantified with a macular heatmap and compared with the corresponding OCTA signal of the CC. RESULTS: SS-OCTA yielded a more homogeneous OCTA signal from the CC than SD-OCTA, offering less signal dispersion and variability in healthy and diseased eyes. Both devices demonstrated CC signal voids in CSC and RD, respectively. In CCS, the voids were predominantly located in the area with SRF. Compared to SD-OCTA, SS-OCTA delivered a more homogenous OCTA signal and reduced signal voids in the CC underneath SRF in both RD and CSC (CSC, 7.6% ± 6.3% vs, 19.7% ± 9.6%, p < 0.01). Despite this significant attenuation of signal voids, SS-OCTA continued to reveal signal voids below SRF and more pixels with reduced OCTA signals in CSC patients compared to controls (7.6% ± 6.3%, 0.1% ± 0.1%, p < 0.0001). CONCLUSION: Understanding OCTA artifacts is critical to ensure accurate clinical evaluations. In this study, we describe the presence of SRF as an important shadow-causing artifact source for CC OCTA analysis which can be mitigated but not completely eliminated by employing SS-OCTA.

Integrative genomic analysis by interoperation of bioinformatics tools in GenomeSpace.

Complex biomedical analyses require the use of multiple software tools in concert and remain challenging for much of the biomedical research community. We introduce GenomeSpace (http://www.genomespace.org), a cloud-based, cooperative community resource that currently supports the streamlined interaction of 20 bioinformatics tools and data resources. To facilitate integrative analysis by non-programmers, it offers a growing set of 'recipes', short workflows to guide investigators through high-utility analysis tasks.

Acute unilateral maculopathy associated with adult onset of hand, foot and mouth disease: a case report.

BACKGROUND: To report the case of a 31-year-old patient with Hand, Foot and Mouth Disease (HFMD) and concurrent acute monocular maculopathy, and to describe multimodal imaging findings never before described including optical coherence tomography angiography (OCT-A). CASE PRESENTATION: Nine days after the onset of clinically highly probable but not laboratory-verified HFMD, a 31-year old male noticed a central scotoma, distorted lines and loss of visual acuity (Snellen visual acuity 20/400) in his right eye. Funduscopy revealed focal alterations in the retinal pigmented epithelium (RPE) and yellow retinal dots corresponding to focal dots of decreased fundus autofluorescence (FAF) surrounded by increased FAF. Spectral domain optical coherence tomography (SD-OCT) demonstrated irregularities in the ellipsoide zone, hyperreflective dots above the RPE and RPE thickening. Fundus fluorescein angiography (FAG) revealed central hypofluorescence in the macular area in the early phase, as well as increasing focal hyperfluorescence in the late phase corresponding with RPE defects observed in FAF. Indocyanine green angiography (ICGA) showed central hypofluorescence in the early and late phase, corresponding with areas of reduced flow in the choroidea and choriocapillaris as apparent in OCT-A. Visual acuity improved within 3 months without any systemic or local therapy. At his three-month follow-up, SD-OCT revealed subtle subretinal fluid that resolved spontaneously over time. No signs of choroidal neovascularization were observed. Twelve months following the onset of symptoms Snellen visual acuity was 400/400. Multimodal imaging revealed subtly changed, decreased FAF while the choroidal architecture recovered completely as demonstrated by OCT-A. CONCLUSIONS: HFMD-associated maculopahty is an uncommon but important differential diagnosis of chorioretinitis with macular involvement. The prognosis can be good and the initially observed morphological pathologies such as impaired perfusion of the choroidal vessels can recover spontaneously over a period lasting 12 months. OCT-A can be employed as a non-invasive tool to detect the reduced perfusion of the choroidal vessels and for monitoring the disease course.

Global action for training in malaria elimination.

The Rethinking Malaria Leadership Forum, held at Harvard Business School in February 2017 with collaboration of the Barcelona Institute for Global Health and the Swiss Tropical and Public Health Institute, identified this training gap as a high priority for both analysis and action. The gap in human resource training for malaria elimination needs to be addressed in order to assure continued progress. This paper identifies major gaps in skills and human resources, suggests institutions that can assist in filling the training gaps, and proposes global actions to implement expanded training for malaria elimination in endemic countries.

"In transition: ensuring the sexual and reproductive health and rights of transgender populations." A roundtable discussion.

This roundtable discussion is the result of a research symposium entitled In Transition: Gender [Identity], Law & Global Health where participants took up the challenge to engage with the question: What will it take to ensure the sexual and reproductive health and rights (SRHR) of transgender populations across the globe? The barriers to overcome are fierce, and include not only lack of access to health services and insurance but also stigma and discrimination, harassment, violence, and violations of rights at every turn. Transgender people must of course lead any sort of initiatives to improve their lives, even as partnerships are needed to build capacity, translate lived experience into usable data, and to make strategic decisions. The SRHR of transgender people can only be addressed with attention to the social, cultural, legal, historical, and political contexts in which people are situated, with social, psychological, medical, and legal gender affirmation as a key priority shaping any intervention. Bringing together nine diverse yet complementary perspectives, our intent is to jumpstart a global and multigenerational conversation among transgender activists, lawyers, policy-makers, programmers, epidemiologists, economists, social workers, clinicians and all other stakeholders to help think through priority areas of focus that will support the needs, rights, and health of transgender populations. Making the changes envisioned here is possible but it will require not only the advocacy, policy, programmatic and research directions presented here but also struggle and action locally, nationally, and globally.