Healthcare innovations: Enhancing patient privacy and security in the digital era.

Technology integration in the healthcare industry has resulted in unparalleled efficiency and accessibility to healthcare services. However, this digital transformation has also created new vulnerabilities, particularly in cyberattacks, which pose significant patient safety and privacy threats. To address this issue, healthcare providers must proactively safeguard patient data and mitigate cybersecurity risks. This includes implementing robust security protocols, adhering to established privacy regulations, and selecting digital health solutions from vendors prioritizing privacy and security. By doing so, the healthcare industry can ensure that patients' personal and personal health information remains private and secure while maintaining the efficiency and accessibility of healthcare services.

Development of wafer-scale multifunctional nanophotonic neural probes for brain activity mapping.

Optical techniques, such as optogenetic stimulation and functional fluorescence imaging, have been revolutionary for neuroscience by enabling neural circuit analysis with cell-type specificity. To probe deep brain regions, implantable light sources are crucial. Silicon photonics, commonly used for data communications, shows great promise in creating implantable devices with complex optical systems in a compact form factor compatible with high volume manufacturing practices. This article reviews recent developments of wafer-scale multifunctional nanophotonic neural probes. The probes can be realized on 200 or 300 mm wafers in commercial foundries and integrate light emitters for photostimulation, microelectrodes for electrophysiological recording, and microfluidic channels for chemical delivery and sampling. By integrating active optical devices to the probes, denser emitter arrays, enhanced on-chip biosensing, and increased ease of use may be realized. Silicon photonics technology makes possible highly versatile implantable neural probes that can transform neuroscience experiments.

Monolithically integrated, broadband, high-efficiency silicon nitride-on-silicon waveguide photodetectors in a visible-light integrated photonics platform.

Visible and near-infrared spectrum photonic integrated circuits are quickly becoming a key technology to address the scaling challenges in quantum information and biosensing. Thus far, integrated photonic platforms in this spectral range have lacked integrated photodetectors. Here, we report silicon nitride-on-silicon waveguide photodetectors that are monolithically integrated in a visible light photonic platform on silicon. Owing to a leaky-wave silicon nitride-on-silicon design, the devices achieved a high external quantum efficiency of >60% across a record wavelength span from λ ~ 400 nm to ~640 nm, an opto-electronic bandwidth up to 9 GHz, and an avalanche gain-bandwidth product up to 173 ± 30 GHz. As an example, a photodetector was integrated with a wavelength-tunable microring in a single chip for on-chip power monitoring.

Low-loss broadband bi-layer edge couplers for visible light.

Low-loss broadband fiber-to-chip coupling is currently challenging for visible-light photonic-integrated circuits (PICs) that need both high confinement waveguides for high-density integration and a minimum feature size above foundry lithographical limit. Here, we demonstrate bi-layer silicon nitride (SiN) edge couplers that have ≤ 4 dB/facet coupling loss with the Nufern S405-XP fiber over a broad optical wavelength range from 445 to 640 nm. The design uses a thin layer of SiN to expand the mode at the facet and adiabatically transfers the input light into a high-confinement single-mode waveguide (150-nm thick) for routing, while keeping the minimum nominal lithographic feature size at 150 nm. The achieved fiber-to-chip coupling loss is about 3 to 5 dB lower than that of single-layer designs with the same waveguide confinement and minimum feature size limitation.

Implantable photonic neural probes for light-sheet fluorescence brain imaging.

Significance: Light-sheet fluorescence microscopy (LSFM) is a powerful technique for high-speed volumetric functional imaging. However, in typical light-sheet microscopes, the illumination and collection optics impose significant constraints upon the imaging of non-transparent brain tissues. We demonstrate that these constraints can be surmounted using a new class of implantable photonic neural probes. Aim: Mass manufacturable, silicon-based light-sheet photonic neural probes can generate planar patterned illumination at arbitrary depths in brain tissues without any additional micro-optic components. Approach: We develop implantable photonic neural probes that generate light sheets in tissue. The probes were fabricated in a photonics foundry on 200-mm-diameter silicon wafers. The light sheets were characterized in fluorescein and in free space. The probe-enabled imaging approach was tested in fixed, in vitro, and in vivo mouse brain tissues. Imaging tests were also performed using fluorescent beads suspended in agarose. Results: The probes had 5 to 10 addressable sheets and average sheet thicknesses < 16 µ m for propagation distances up to 300 µ m in free space. Imaging areas were as large as ≈ 240 µ m × 490 µ m in brain tissue. Image contrast was enhanced relative to epifluorescence microscopy. Conclusions: The neural probes can lead to new variants of LSFM for deep brain imaging and experiments in freely moving animals.

Visible-light silicon nitride waveguide devices and implantable neurophotonic probes on thinned 200 mm silicon wafers.

We present passive, visible light silicon nitride waveguides fabricated on ≈ 100 µm thick 200 mm silicon wafers using deep ultraviolet lithography. The best-case propagation losses of single-mode waveguides were ≤ 2.8 dB/cm and ≤ 1.9 dB/cm over continuous wavelength ranges of 466-550 nm and 552-648 nm, respectively. In-plane waveguide crossings and multimode interference power splitters are also demonstrated. Using this platform, we realize a proof-of-concept implantable neurophotonic probe for optogenetic stimulation of rodent brains. The probe has grating coupler emitters defined on a 4 mm long, 92 µm thick shank and operates over a wide wavelength range of 430-645 nm covering the excitation spectra of multiple opsins and fluorophores used for brain stimulation and imaging.

Report of a bi-allelic truncating germline mutation in TP53.

The TP53 gene is fundamental to genomic integrity, cell cycle regulation, and apoptosis; it is the most commonly mutated gene in human cancer. Heterozygous germline mutations cause the autosomal dominant cancer predisposition syndrome, Li-Fraumeni Syndrome. Homozygous germline TP53 mutations in humans are rare. We report an infant from a consanguineous family who presented with synchronous malignancies. Remarkably, he carries a homozygous germline TP53 mutation (NM_000546.4:c.52delA), predicted to cause protein truncation. The family history is consistent with Li-Fraumeni syndrome.

Glioblastoma in a patient with tuberous sclerosis.

Tuberous sclerosis complex (TSC) is a multisystem, autosomal dominant disorder with a wide clinical spectrum. The most common brain tumor associated with TSC is the low grade subependymal giant cell astrocytoma. Reports of high grade primary brain tumors in patients with TSC are rare. TSC1/2 mutation has been identified in glioblastoma (GBM) even though it probably does not increase the overall risk for GBM in patients with TSC. We present a 58-year-old patient with known TSC, admitted for new neurological symptoms, diagnosed with a large heterogeneous tumor involving most of the corpus callosum. Stereotactic needle brain biopsy confirmed the diagnosis to be GBM. Five previously reported similar cases are reviewed, reflecting diversity in clinical and radiological findings and indicating that a high index of clinical suspicion must be maintained in patients with TSC.

Multi-layer silicon nitride-on-silicon polarization-independent grating couplers.

A polarization-independent grating coupler is proposed and demonstrated in a 3-layer silicon nitride-on-silicon photonic platform. Polarization independent coupling was made possible by the supermodes and added degrees of geometric freedom unique to the 3-layer photonic platform. The grating was designed via optimization algorithms, and the simulated peak coupling efficiency was -2.1 dB with a 1 dB polarization dependent loss (PDL) bandwidth of 69 nm. The fabricated grating couplers had a peak coupling efficiency of -4.8 dB with 1 dB PDL bandwidth of over 100 nm.

U-shaped PN junctions for efficient silicon Mach-Zehnder and microring modulators in the O-band: erratum.

We correct two minor errors in the manuscript. The effective diameter of the ring modulator should be 62.5 µm rather than 65 µm. The factor, g, in the FOM for comparing between the O- and C-band results should be 0.83 instead of 0.7.

Tri-layer silicon nitride-on-silicon photonic platform for ultra-low-loss crossings and interlayer transitions.

We present a three-layer silicon nitride on silicon platform for constructing very large photonic integrated circuits. Efficient interlayer transitions are enabled by the close spacing between adjacent layers, while ultra-low-loss crossings are enabled by the large spacing between the topmost and bottommost layers. We demonstrate interlayer taper transitions with losses < 0.15 dB for wavelengths spanning from 1480 nm to 1620 nm. Our overpass waveguide crossings exhibit insertion loss < 2.1 mdB and crosstalk below -56 dB in the wavelength range between 1480 nm and 1620 nm with losses as low as 0.28 mdB. Our platform architecture is suited to meet the demands of large-scale photonic circuits which contain hundreds of crossings.

U-shaped PN junctions for efficient silicon Mach-Zehnder and microring modulators in the O-band.

We demonstrate U-shaped silicon PN junctions for energy efficient Mach-Zehnder modulators and ring modulators in the O-band. This type of junction has an improved modulation efficiency compared to existing PN junction geometries, has low losses, and supports high-speed operation. The U-shaped junctions were fabricated in an 8" silicon photonics platform, and they were incorporated in travelling-wave Mach-Zehnder modulators and microring modulators. For the high-bandwidth Mach-Zehnder modulator, the DC VπL at -0.5 V bias was 4.6 V·mm. It exhibited a 3dB bandwidth of 13 GHz, and eye patterns at up to 24 Gb/s were observed. A VπL as low as ~2.6 V·mm at a -0.5 V bias was measured in another device. The ring modulator tuning efficiency was 40 pm·V-1 between 0 V and -0.5 V bias. It had a 3-dB bandwidth of 13.5 GHz and open eye patterns at up to 13 Gb/s were measured. This type of PN junctions can be easily fabricated without extra masks and can be incorporated into generic silicon photonics platforms.

Germanium-on-SOI waveguides for mid-infrared wavelengths.

We report on the development of Germanium-on-SOI waveguides for mid-infrared wavelengths. The strip waveguides have been formed in 0.85 and 2 µm thick Ge grown on SOI substrate with 220 nm thick Si overlayer. The propagation loss for various waveguide widths has been measured using the Fabry-Perot method with temperature tuning. The minimum loss of ~8 dB/cm has been achieved for 0.85 µm thick Ge core using 3.682 µm laser excitation. The transparency of these waveguides has been measured up to at least 3.82 µm.

Visualization of microbleeds with optical histology in mouse model of cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) is a neurovascular disease that is strongly associated with an increase in the number and size of spontaneous microbleeds. Conventional methods of magnetic resonance imaging for detection of microbleeds, and positron emission tomography with Pittsburgh Compound B imaging for amyloid deposits, can separately demonstrate the presence of microbleeds and CAA in affected brains in vivo; however, there still is a critical need for strong evidence that shows involvement of CAA in microbleed formation. Here, we show in a Tg2576 mouse model of Alzheimer's disease, that the combination of histochemical staining and an optical clearing method called optical histology, enables simultaneous, co-registered three-dimensional visualization of cerebral microvasculature, microbleeds, and amyloid deposits. Our data suggest that microbleeds are localized within the brain regions affected by vascular amyloid deposits. All observed microhemorrhages (n=39) were in close proximity (0 to 144 µm) with vessels affected by CAA. Our data suggest that the predominant type of CAA-related microbleed is associated with leaky or ruptured hemorrhagic microvasculature. The proposed methodological and instrumental approach will allow future study of the relationship between CAA and microbleeds during disease development and in response to treatment strategies.

Nonoperative management of craniovertebral junction and cutaneous tuberculosis.

BACKGROUND: Craniovertebral junction (CVJ) and cutaneous tuberculosis (TB) are both rare, each occurring in 0.3-1.0% of patients. To our knowledge, there are no existing cases reporting these manifestations of TB simultaneously. We report a case of TB involving the left CVJ as well as the skin, and discuss our management while providing a review of the literature. CASE DESCRIPTION: An adult patient was presented with progressive nocturnal neck pain associated with the development of several skin lesions. Investigations revealed multiple osseous lesions including the left CVJ. Biopsy of the CVJ lesion was unamenable due to proximity of the vertebral artery; therefore, the patient underwent biopsy of the other sites. Histological examination demonstrated features consistent with TB infection and the patient commenced 12 months of standard anti-TB therapy with cervical spine immobilization. At 2-month review, the patient was well with a near-complete resolution of neck pain and cutaneous lesions. Repeat imaging at 6 months follow-up demonstrated a stable C1 lesion with no evidence of instability. CONCLUSION: CVJ TB may be treated solely with anti-TB therapy and immobilization to good effect if there is no gross instability or neurological deficit. Similarly, cutaneous TB responds well to standard anti- TB therapy. Our experience suggests that co-existing tuberculous lesions in the CVJ and skin can be simultaneously managed with standard therapy without significant alterations to treatment regimes or prognosis.

Optical properties of mouse brain tissue after optical clearing with FocusClear™.

Fluorescence microscopy is commonly used to investigate disease progression in biological tissues. Biological tissues, however, are strongly scattering in the visible wavelengths, limiting the application of fluorescence microscopy to superficial (<200µm) regions. Optical clearing, which involves incubation of the tissue in a chemical bath, reduces the optical scattering in tissue, resulting in increased tissue transparency and optical imaging depth. The goal of this study was to determine the time- and wavelength-resolved dynamics of the optical scattering properties of rodent brain after optical clearing with FocusClear™. Light transmittance and reflectance of 1-mm mouse brain sections were measured using an integrating sphere before and after optical clearing and the inverse adding doubling algorithm used to determine tissue optical scattering. The degree of optical clearing was quantified by calculating the optical clearing potential (OCP), and the effects of differing OCP were demonstrated using the optical histology method, which combines tissue optical clearing with optical imaging to visualize the microvasculature. We observed increased tissue transparency with longer optical clearing time and an analogous increase in OCP. Furthermore, OCP did not vary substantially between 400 and 1000 nm for increasing optical clearing durations, suggesting that optical histology can improve ex vivo visualization of several fluorescent probes.

Targeting DNA methylation to the genome.

Proving direct relationships between DNA alterations and phenotypes is challenging. For epigenetics researchers, linking DNA methylation with human disease is no exception. But Patrick Lo looks at how two researchers are developing new methods to try to trace the road from DNA methylation to human biology.

A 10 year retrospective study of surgical outcomes of adult intracranial pilocytic astrocytoma.

Pilocytic astrocytomas (PA) are benign neoplasms commonly located in the cerebellum with a peak incidence in the first two decades of life. PA occurrence in adults is rare and very little information is available in the literature about tumour characteristics in this population. This study retrospectively identified 20 adults with PA. The characteristics of the tumour, treatment modalities and patient outcomes are discussed, as well as identifying factors that may be associated with worse prognosis. The mean age at diagnosis was 27 years. The majority of PA were located in the posterior fossa. Other tumour locations included the cerebral hemispheres, brainstem, tectal plate and optochiasmatic region (optic chiasm, hypothalamus and third ventricle). All patients in this study underwent surgery, two received adjuvant chemotherapy and one received adjuvant radiotherapy. Tumour recurrence occurred in six patients and two eventually died from the disease. When achieved, complete tumour resection was found to be curative. Tumour location affects extent of surgical resection; tumours in inaccessible locations were associated with higher rates of recurrence. Overall survival and progression free survival rates were 87% and 60% respectively. The degree of surgical resection and tumour location were found to affect prognosis. Unfavourable outcomes were observed in these adults with PA compared to those expected for a younger population, suggesting a possible association between age and outcome.

Pediatric dural arteriovenous malformations.

Pediatric dural arteriovenous malformations (dAVMs) are rare lesions that have a high mortality rate and require complex management. The authors report 3 cases of pediatric dAVMs that presented with macrocrania and extracranial venous distension. Dural sinus thrombosis developed in 2 of the cases prior to any intervention, which is an unusual occurrence for this particular disease. All 3 cases were treated using staged endovascular embolization with a favorable outcome in 1 case and a poor outcome in the other 2 cases. Complications developed in all cases and included dural sinus thrombosis, parenchymal hemorrhage, intracranial venous hypertension, and seizures. The strategies and challenges used in managing these patients will be presented and discussed, along with a review of the literature. While outcomes remain poor, the authors conclude that prompt treatment with endovascular embolization provides the best results for children with these lesions. A well-established venous collateral circulation draining directly to the internal jugular veins may further improve the rate of favorable outcome after embolization.