The Curious Case of the Missing Limb on FDG PET Imaging.

ABSTRACT: A 58-year-old woman with poorly controlled diabetes, peripheral vascular disease, and end-stage renal disease requiring hemodialysis was referred for 18 F-FDG PET/CT to evaluate for source of sepsis. She had history of prior left forefoot and right second toe amputation, as well as left lower-limb dry gangrene for which she declined surgical management. We present a case of a nonamputated lower limb demonstrating regions of absolute photopenia, consistent with dry gangrene.

PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.

The PI3K/AKT/mTOR (PAM) signaling pathway is a highly conserved signal transduction network in eukaryotic cells that promotes cell survival, cell growth, and cell cycle progression. Growth factor signalling to transcription factors in the PAM axis is highly regulated by multiple cross-interactions with several other signaling pathways, and dysregulation of signal transduction can predispose to cancer development. The PAM axis is the most frequently activated signaling pathway in human cancer and is often implicated in resistance to anticancer therapies. Dysfunction of components of this pathway such as hyperactivity of PI3K, loss of function of PTEN, and gain-of-function of AKT, are notorious drivers of treatment resistance and disease progression in cancer. In this review we highlight the major dysregulations in the PAM signaling pathway in cancer, and discuss the results of PI3K, AKT and mTOR inhibitors as monotherapy and in co-administation with other antineoplastic agents in clinical trials as a strategy for overcoming treatment resistance. Finally, the major mechanisms of resistance to PAM signaling targeted therapies, including PAM signaling in immunology and immunotherapies are also discussed.

SIRIUS, Ultra-Scintillating Upconversion Breast Implant for Remote Orthotopic Photodynamic Therapy.

Present day strategies for delivery of wireless photodynamic therapy (PDT) to deep-seated targets are limited by the inadequacy of irradiance and insufficient therapeutic depth. Here we report the design and preclinical validation of a flexible wireless upconversion nanoparticle (UCNP) implant (SIRIUS) that is capable of large field, high intensity illumination for PDT of deep-seated tumors. The implant achieves this by incorporating submicrometer core-shell-shell NaYF4 UCNPs into its design, which significantly enhances upconversion efficiency and mitigates light loss from surface quenching. We demonstrate the efficacy of SIRIUS UCNP implant mediated PDT in preclinical breast cancer disease models. In our in vitro experiments, SIRIUS directed 5-Aminolevulinic Acid (5-ALA) based wireless PDT leads to significant reactive oxygen species (ROS) generation and tumor apoptosis in hormonal receptor+/HER2+ (MCF7) and triple-negative (MDA-MB-231) breast cancer cell lines. In our in vivo rodent model, SIRIUS-driven PDT is shown to be significant in regressing tumors when applied to orthotopically inoculated breast tumors. Following successful preclinical validation, we also describe a clinical prototype of UCNP breast implant with potential dual cosmetic and onco-therapeutic functions. SIRIUS is an upconversion breast implant for wireless PDT that fulfils all the design prerequisites necessary for seamless clinical translation.

COVID-19, Blood Lipid Changes, and Thrombosis.

Although there is increasing evidence that oxidative stress and inflammation induced by COVID-19 may contribute to increased risk and severity of thromboses, the underlying mechanism(s) remain to be understood. The purpose of this review is to highlight the role of blood lipids in association with thrombosis events observed in COVID-19 patients. Among different types of phospholipases A2 that target cell membrane phospholipids, there is increasing focus on the inflammatory secretory phospholipase A2 IIA (sPLA2-IIA), which is associated with the severity of COVID-19. Analysis indicates increased sPLA2-IIA levels together with eicosanoids in the sera of COVID patients. sPLA2 could metabolise phospholipids in platelets, erythrocytes, and endothelial cells to produce arachidonic acid (ARA) and lysophospholipids. Arachidonic acid in platelets is metabolised to prostaglandin H2 and thromboxane A2, known for their pro-coagulation and vasoconstrictive properties. Lysophospholipids, such as lysophosphatidylcholine, could be metabolised by autotaxin (ATX) and further converted to lysophosphatidic acid (LPA). Increased ATX has been found in the serum of patients with COVID-19, and LPA has recently been found to induce NETosis, a clotting mechanism triggered by the release of extracellular fibres from neutrophils and a key feature of the COVID-19 hypercoagulable state. PLA2 could also catalyse the formation of platelet activating factor (PAF) from membrane ether phospholipids. Many of the above lipid mediators are increased in the blood of patients with COVID-19. Together, findings from analyses of blood lipids in COVID-19 patients suggest an important role for metabolites of sPLA2-IIA in COVID-19-associated coagulopathy (CAC).

Biomimetic nanotherapeutics for targeted drug delivery to glioblastoma multiforme.

Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis and high mortality, with no curative treatment to date as limited trafficking across the blood-brain barrier (BBB) combined with tumor heterogeneity often leads to therapeutic failure. Although modern medicine poses a wide range of drugs that are otherwise efficacious in treating other tumors, they often do not achieve therapeutic concentrations in the brain, hence driving the need for more effective drug delivery strategies. Nanotechnology, an interdisciplinary field, has been gaining immense popularity in recent years for remarkable advancements such as nanoparticle (NP) drug carriers, which possess extraordinary versatility in modifying surface coatings to home in on target cells, including those beyond the BBB. In this review, we will be highlighting recent developments in biomimetic NPs in GBM therapy and how these allowed us to overcome the physiological and anatomical challenges that have long plagued GBM treatment.

The global impact of COVID-19 on abortion care.

Background: The COVID-19 pandemic placed unprecedented strain on healthcare globally, which exacerbated factors leading to unplanned pregnancies. Objectives: The primary objective was to analyze the effect of COVID-19 on abortion services globally. Secondary objectives were to discuss issues regarding access to safe abortion and provide recommendations on continued access during pandemics. Search strategy: A search for relevant articles was conducted by utilizing multiple databases (PubMed, Cochrane, etc.). Selection criteria: Studies on COVID-19 and abortion were included. Data collection & analysis: The legislation governing abortion services across the globe was examined, inclusive of modifications to service provision during the pandemic. Global data on abortion rates and analyses of selected articles were also included. Main results: 14 countries instituted legislative changes related to the pandemic, 11 relaxed abortion regulations, while three restricted abortion access. An increase in abortion rates was seen particularly where telemedicine was available. Where abortions were postponed, second-trimester abortions increased after services resumed. Conclusions: Legislation, risk of exposure to infection, and access to telemedicine affect access to abortion. The use of novel technologies, maintaining existing infrastructure and enhancing the roles of trained manpower for safe abortion access is recommended to avoid the marginalization of women's health and reproductive rights.

Unraveling female reproductive senescence to enhance healthy longevity.

In a society where women often want successful careers and equal opportunities to men, the early nature of ovarian aging often forces women to make difficult life choices between career and family development. Fertility in women begins to decline after the age of 37 years and it is rare for pregnancies to occur after 45. This reproductive decline in women is inevitable and culminates in menopause, which is a major driver of age-related diseases. In a world where biomedical advances are leading to modifiable biological outcomes, it is time to focus on mitigating female reproductive senescence to maintain fertility and preserve age-related hormonal functions, with the goal of providing increased life choices and enhancing healthspan. To date, reproductive longevity research remains an understudied field. More needs to be done to unravel the biology of the ovarian follicles, which are the functional units of reproductive lifespan and are comprised of cell types including the oocyte (female gamete) and a group of specialized supporting somatic cells. Biological attempts to maintain the quality and quantity of follicles in animal models through manipulating pathways involved in aging can potentially prolong female reproductive lifespan and healthspan. Here, we summarize the molecular events driving ovarian aging and menopause and the interventional strategies to offset these events. Developing solutions to female reproductive senescence will open doors to discover ways to enhance true healthy longevity for both men and women.

Effects of mobile health interventions on health-related outcomes in older adults with type 2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic metabolic condition that is associated with multiple comorbidities. Apart from pharmacological approaches, patient self-management remains the gold standard of care for diabetes. Improving patients' self-management among the elderly with mobile health (mHealth) interventions is critical, especially in times of the COVID-19 pandemic. However, the extent of mHealth efficacy in managing T2DM in the older population remains unknown. Hence, the present review examined the effectiveness of mHealth interventions on cardiometabolic outcomes in older adults with T2DM. METHODS: A systematic search from the inception till May 31, 2021, in the MEDLINE, Embase, and PubMed databases was conducted, and 16 randomized controlled trials were included in the analysis. RESULTS: The results showed significant benefits on glycosylated hemoglobin (HbA1c) (mean difference -0.24%; 95% confidence interval [CI]: -0.44, -0.05; p = 0.01), postprandial blood glucose (-2.91 mmol/L; 95% CI: -4.78, -1.03; p = 0.002), and triglycerides (-0.09 mmol/L; 95% CI: -0.17, -0.02; p = 0.010), but not on low-density lipoprotein cholesterol (-0.06 mmol/L; 95% CI: -0.14, 0.02; p = 0.170), high-density lipoprotein cholesterol (0.05 mmol/L; 95% CI: -0.03, 0.13; p = 0.220), and blood pressure (systolic blood pressure -0.82 mm Hg; 95% CI: -4.65, 3.00; p = 0.670; diastolic blood pressure -1.71 mmHg; 95% CI: -3.71, 0.29; p = 0.090). CONCLUSIONS: Among older adults with T2DM, mHealth interventions were associated with improved cardiometabolic outcomes versus usual care. Its efficacy can be improved in the future as the current stage of mHealth development is at its infancy. Addressing barriers such as technological frustrations may help strategize approaches to further increase the uptake and efficacy of mHealth interventions among older adults with T2DM.

Application of Optogenetics for Muscle Cells and Stem Cells.

This chapter describes the current progress of basic research, and potential therapeutic applications primarily focused on the optical manipulation of muscle cells and neural stem cells using microbial rhodopsin as a light-sensitive molecule. Since the contractions of skeletal, cardiac, and smooth muscle cells are mainly regulated through their membrane potential, several studies have been demonstrated to up- or downregulate the muscle contraction directly or indirectly using optogenetic actuators or silencers with defined stimulation patterns and intensities. Light-dependent oscillation of membrane potential also facilitates the maturation of myocytes with the development of T tubules and sarcomere structures, tandem arrays of minimum contractile units consists of contractile proteins and cytoskeletal proteins. Optogenetics has been applied to various stem cells and multipotent/pluripotent cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to generate light-sensitive neurons and to facilitate neuroscience. The chronic optical stimulation of the channelrhodopsin-expressing neural stem cells facilitates their neural differentiation. There are potential therapeutic applications of optogenetics in cardiac pacemaking, muscle regeneration/maintenance, locomotion recovery for the treatment of muscle paralysis due to motor neuron diseases such as amyotrophic lateral sclerosis (ALS). Optogenetics would also facilitate maturation, network integration of grafted neurons, and improve the microenvironment around them when applied to stem cells.

A Flexi-PEGDA Upconversion Implant for Wireless Brain Photodynamic Therapy.

Near-infrared (NIR) activatable upconversion nanoparticles (UCNPs) enable wireless-based phototherapies by converting deep-tissue-penetrating NIR to visible light. UCNPs are therefore ideal as wireless transducers for photodynamic therapy (PDT) of deep-sited tumors. However, the retention of unsequestered UCNPs in tissue with minimal options for removal limits their clinical translation. To address this shortcoming, biocompatible UCNPs implants are developed to deliver upconversion photonic properties in a flexible, optical guide design. To enhance its translatability, the UCNPs implant is constructed with an FDA-approved poly(ethylene glycol) diacrylate (PEGDA) core clad with fluorinated ethylene propylene (FEP). The emission spectrum of the UCNPs implant can be tuned to overlap with the absorption spectra of the clinically relevant photosensitizer, 5-aminolevulinic acid (5-ALA). The UCNPs implant can wirelessly transmit upconverted visible light till 8 cm in length and in a bendable manner even when implanted underneath the skin or scalp. With this system, it is demonstrated that NIR-based chronic PDT is achievable in an untethered and noninvasive manner in a mouse xenograft glioblastoma multiforme (GBM) model. It is postulated that such encapsulated UCNPs implants represent a translational shift for wireless deep-tissue phototherapy by enabling sequestration of UCNPs without compromising wireless deep-tissue light delivery.

Driving Neurogenesis in Neural Stem Cells with High Sensitivity Optogenetics.

Optogenetic stimulation of neural stem cells (NSCs) enables their activity-dependent photo-modulation. This provides a spatio-temporal tool for studying activity-dependent neurogenesis and for regulating the differentiation of the transplanted NSCs. Currently, this is mainly driven by viral transfection of channelrhodopsin-2 (ChR2) gene, which requires high irradiance and complex in vivo/vitro stimulation systems. Additionally, despite the extensive application of optogenetics in neuroscience, the transcriptome-level changes induced by optogenetic stimulation of NSCs have not been elucidated yet. Here, we made transformed NSCs (SFO-NSCs) stably expressing one of the step-function opsin (SFO)-variants of chimeric channelrhodopsins, ChRFR(C167A), which is more sensitive to blue light than native ChR2, via a non-viral transfection system using piggyBac transposon. We set up a simple low-irradiance optical stimulation (OS)-incubation system that induced c-fos mRNA expression, which is activity-dependent, in differentiating SFO-NSCs. More neuron-like SFO-NCSs, which had more elongated axons, were differentiated with daily OS than control cells without OS. This was accompanied by positive/negative changes in the transcriptome involved in axonal remodeling, synaptic plasticity, and microenvironment modulation with the up-regulation of several genes involved in the Ca2+-related functions. Our approach could be applied for stem cell transplantation studies in tissue with two strengths: lower carcinogenicity and less irradiance needed for tissue penetration.

Expanding the Toolbox of Upconversion Nanoparticles for In Vivo Optogenetics and Neuromodulation.

Optogenetics is an optical technique that exploits visible light for selective neuromodulation with spatio-temporal precision. Despite enormous effort, the effective stimulation of targeted neurons, which are located in deeper structures of the nervous system, by visible light, remains a technical challenge. Compared to visible light, near-infrared illumination offers a higher depth of tissue penetration owing to a lower degree of light attenuation. Herein, an overview of advances in developing new modalities for neural circuitry modulation utilizing upconversion-nanoparticle-mediated optogenetics is presented. These developments have led to minimally invasive optical stimulation and inhibition of neurons with substantially improved selectivity, sensitivity, and spatial resolution. The focus is to provide a comprehensive review of the mechanistic basis for evaluating upconversion parameters, which will be useful in designing, executing, and reporting optogenetic experiments.

Fibro-Neuronal Guidance on Common, 3D-Printed Textured Substrates.

Ability to direct neuronal growth not only carries great potential for treating neural conditions-for example, bridging traumatically shattered connections-but would also be an exquisite tool for bionic applications that require a physical interface between neurons and electronics. A testing platform is needed to better understand axonal guidance in the context of a specific in vivo application. Versatility of 3D printing technology allows tailoring to researcher needs, both in vitro and in vivo. In this paper, we establish a fibro-neuronal co-culture inspired by our neural interface research and demonstrate axon alignment on a textured substrate fabricated with a common, versatile 3D-printing set-up.

Upconversion amplification through dielectric superlensing modulation.

Achieving efficient photon upconversion under low irradiance is not only a fundamental challenge but also central to numerous advanced applications spanning from photovoltaics to biophotonics. However, to date, almost all approaches for upconversion luminescence intensification require stringent controls over numerous factors such as composition and size of nanophosphors. Here, we report the utilization of dielectric microbeads to significantly enhance the photon upconversion processes in lanthanide-doped nanocrystals. By modulating the wavefront of both excitation and emission fields through dielectric superlensing effects, luminescence amplification up to 5 orders of magnitude can be achieved. This design delineates a general strategy to converge a low-power incident light beam into a photonic hotspot of high field intensity, while simultaneously enabling collimation of highly divergent emission for far-field accumulation. The dielectric superlensing-mediated strategy may provide a major step forward in facilitating photon upconversion processes toward practical applications in the fields of photobiology, energy conversion, and optogenetics.

All-inorganic perovskite nanocrystal scintillators.

The rising demand for radiation detection materials in many applications has led to extensive research on scintillators1-3. The ability of a scintillator to absorb high-energy (kiloelectronvolt-scale) X-ray photons and convert the absorbed energy into low-energy visible photons is critical for applications in radiation exposure monitoring, security inspection, X-ray astronomy and medical radiography4,5. However, conventional scintillators are generally synthesized by crystallization at a high temperature and their radioluminescence is difficult to tune across the visible spectrum. Here we describe experimental investigations of a series of all-inorganic perovskite nanocrystals comprising caesium and lead atoms and their response to X-ray irradiation. These nanocrystal scintillators exhibit strong X-ray absorption and intense radioluminescence at visible wavelengths. Unlike bulk inorganic scintillators, these perovskite nanomaterials are solution-processable at a relatively low temperature and can generate X-ray-induced emissions that are easily tunable across the visible spectrum by tailoring the anionic component of colloidal precursors during their synthesis. These features allow the fabrication of flexible and highly sensitive X-ray detectors with a detection limit of 13 nanograys per second, which is about 400 times lower than typical medical imaging doses. We show that these colour-tunable perovskite nanocrystal scintillators can provide a convenient visualization tool for X-ray radiography, as the associated image can be directly recorded by standard digital cameras. We also demonstrate their direct integration with commercial flat-panel imagers and their utility in examining electronic circuit boards under low-dose X-ray illumination.

Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics.

Optogenetics has revolutionized the experimental interrogation of neural circuits and holds promise for the treatment of neurological disorders. It is limited, however, because visible light cannot penetrate deep inside brain tissue. Upconversion nanoparticles (UCNPs) absorb tissue-penetrating near-infrared (NIR) light and emit wavelength-specific visible light. Here, we demonstrate that molecularly tailored UCNPs can serve as optogenetic actuators of transcranial NIR light to stimulate deep brain neurons. Transcranial NIR UCNP-mediated optogenetics evoked dopamine release from genetically tagged neurons in the ventral tegmental area, induced brain oscillations through activation of inhibitory neurons in the medial septum, silenced seizure by inhibition of hippocampal excitatory cells, and triggered memory recall. UCNP technology will enable less-invasive optical neuronal activity manipulation with the potential for remote therapy.

Neuroprotective assessment of prolonged local hypothermia post contusive spinal cord injury in rodent model.

BACKGROUND CONTEXT: Although general hypothermia is recognized as a clinically applicable neuroprotective intervention, acute moderate local hypothermia post contusive spinal cord injury (SCI) is being considered a more effective approach. Previously, we have investigated the feasibility and safety of inducing prolonged local hypothermia in the central nervous system of a rodent model. PURPOSE: Here, we aimed to verify the efficacy and neuroprotective effects of 5 and 8 hours of local moderate hypothermia (30±0.5°C) induced 2 hours after moderate thoracic contusive SCI in rats. STUDY DESIGN: Rats were induced with moderate SCI (12.5 mm) at its T8 section. Local hypothermia (30±0.5°C) was induced 2 hours after injury induction with an M-shaped copper tube with flow of cold water (12°C), from the T6 to the T10 region. Experiment groups were divided into 5-hour and 8-hour hypothermia treatment groups, respectively, whereas the normothermia control group underwent no hypothermia treatment. METHODS: The neuroprotective effects were assessed through objective weekly somatosensory evoked potential (SSEP) and motor behavior (basso, beattie and bresnahan Basso, Beattie and Bresnahan (BBB) scoring) monitoring. Histology on spinal cord was performed until at the end of day 56. All authors declared no conflict of interest. This work was supported by the Singapore Institute for Neurotechnology Seed Fund (R-175-000-121-733), National University of Singapore, Ministry of Education, Tier 1 (R-172-000-414-112.). RESULTS: Our results show significant SSEP amplitudes recovery in local hypothermia groups starting from day 14 post-injury onward for the 8-hour treatment group, which persisted up to days 28 and 42, whereas the 5-hour group showed significant improvement only at day 42. The functional improvement plateaued after day 42 as compared with control group of SCI with normothermia. This was supported by both 5-hour and 8-hour improvement in locomotion as measured by BBB scores. Local hypothermia also observed insignificant changes in its SSEP latency, as compared with the control. In addition, 5- and 8-hour hypothermia rats' spinal cord showed higher percentage of parenchyma preservation. CONCLUSIONS: Early local moderate hypothermia can be induced for extended periods of time post SCI in the rodent model. Such intervention improves functional electrophysiological outcome and motor behavior recovery for a long time, lasting until 8 weeks.

Accuracy of magnetic resonance imaging in diagnosing lateral ankle ligament injuries: A comparative study with surgical findings and timings of scans.

OBJECTIVE: This study aimed to evaluate the accuracy of magnetic resonance imaging (MRI) in diagnosing lateral ankle ligament injuries and the effect of differences in time duration from injury to MRI. METHODS: Data were collected prospectively from 82 patients who underwent MRI and lateral ligament reconstruction, and were divided into either acute (≤3 months) or chronic (>3 months) group based on injury interval. Findings were classified as normal, partial, or complete tears of the anterior talofibular ligament (ATFL) and the calcaneofibular ligament (CFL). MRI results were compared with intraoperative findings and their accuracies were assessed using descriptive statistics. RESULTS: The accuracy of MRI for partial and complete tears of the ATFL was 74% and 79%, respectively, with sensitivity and specificity of 64% and 86% for partial tears, and 78% and 80% for complete tears, respectively. The accuracy of MRI was 66% and 88% for partial and complete tears of the CFL with a sensitivity and specificity of 41% and 87% for partial tears, and 61% and 95% for complete tears, respectively. A decrease in the MRI accuracy was observed in the chronic group. CONCLUSION: MRI is accurate in diagnosing ATFL injuries. It is specific but not sensitive for CFL tears. The accuracy is higher in the acute setting of 3 months or less from time of injury to MRI.