Intravenous Immunoglobulin-Induced Aseptic Meningitis in a Dermatomyositis Patient.

Aseptic meningitis is a rare but serious complication of treatment with intravenous immunoglobulin (IVIG) and often mimics meningitis of infectious etiology which poses a challenge for timely diagnosis. Although there are published recommendations on the management of IVIG-induced complications, there are no clear guidelines on the continuation of IVIG use after resolution of aseptic meningitis. We present a case of IVIG-induced aseptic meningitis in a patient with a history of refractory dermatomyositis who had been treated with immunosuppressive therapy and IVIG infusions for over a year. The patient developed intense head and neck pain with associated photophobia 24 hours after the most recent IVIG infusion. The patient was managed with supportive care consisting of intravenous fluids and analgesics. The patient's aseptic meningitis resolved without neurological complications. Ultimately, the patient was restarted on IVIG due to the recurrence of weakness from dermatomyositis. The patient tolerated re-initiation of IVIG without recurrence of IVIG-induced complications. This case highlights the importance of considering IVIG-induced aseptic meningitis as a differential diagnosis in evaluating patients with non-infectious meningitis even after regular IVIG infusions. This case also demonstrates that it is safe to reinitiate IVIG after the resolution of IVIG-induced aseptic meningitis.

ALSUntangled #75: Portable neuromodulation stimulator therapy.

Spurred by patient interest, ALSUntangled herein examines the potential of the Portable Neuromodulation Stimulator (PoNS™) in treating amyotrophic lateral sclerosis (ALS). The PoNS™ device, FDA-approved for the treatment of gait deficits in adult patients with multiple sclerosis, utilizes translingual neurostimulation to stimulate trigeminal and facial nerves via the tongue, aiming to induce neuroplastic changes. While there are early, promising data for PoNS treatment to improve gait and balance in multiple sclerosis, stroke, and traumatic brain injury, no pre-clinical or clinical studies have been performed in ALS. Although reasonably safe, high costs and prescription requirements will limit PoNS accessibility. At this time, due to the lack of ALS-relevant data, we cannot endorse the use of PoNS as an ALS treatment.

Treatment with nanosomal paclitaxel lipid suspension versus conventional paclitaxel in metastatic breast cancer patients - a multicenter, randomized, comparative, phase II/III clinical study.

Background: A novel nanosomal paclitaxel lipid suspension (NPLS), free from Cremophor EL (CrEL) and ethanol, was developed to address the solvent-related toxicities associated with conventional paclitaxel formulation. Objective: To evaluate the efficacy and safety of NPLS versus CrEL-based paclitaxel (conventional paclitaxel) in patients with metastatic breast cancer (MBC). Design: A prospective, open-label, randomized, multiple-dose, parallel, phase II/III study. Methods: Adult (18-65 years) female patients with MBC who had previously failed at least one line of chemotherapy were randomized (2:2:1) to NPLS 175 mg/m2 every 3 weeks (Q3W, n = 48, arm A), NPLS 80 mg/m2 every week (QW, n = 45, arm B) without premedication or conventional paclitaxel (Taxol®, manufactured by Bristol-Myers Squibb, Princeton, NJ, USA) 175 mg/m2 Q3W (n = 27, arm C) with premedication. In the extension study, an additional 54 patients were randomized (2:1) to arm A (n = 37) or arm C (n = 17). Results: Pooled data from the primary study and its extension phase included 174 patients. The primary endpoint was the overall response rate (ORR). As per intent-to-treat analysis, ORR was significantly better in the NPLS QW arm as compared to conventional paclitaxel [44.4% (20/45) versus 22.7% (10/44), (p = 0.04)]. An improvement in ORR with NPLS Q3W versus conventional paclitaxel arm [29.4% (25/85) versus 22.7% (10/44)] (p = 0.53) was observed. Disease control rates observed were improved with NPLS Q3W versus conventional paclitaxel Q3W (77.7% versus 72.7%, p = 0.66) and with NPLS QW versus conventional paclitaxel Q3W (84.4% versus 72.7%, p = 0.20), although not significant. A lower incidence of grade III/IV peripheral sensory neuropathy, vomiting, and dyspnea was reported with NPLS Q3W versus conventional paclitaxel Q3W arms. Conclusion: NPLS demonstrated an improved tumor response rate and a favorable safety profile versus conventional paclitaxel. NPLS 80 mg/m2 QW demonstrated a significantly better response versus conventional paclitaxel 175 mg/m2 Q3W. Trial registration: Clinical Trial Registry-India (CTRI), CTRI/2010/091/001344 Registered on: 18 October 2010 (https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MjEzNQ==&Enc=&userName=CTRI/2010/091/001344), CTRI/2015/07/006062 Registered on: 31 July 2015 (https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MTE2Mjc=&Enc=&userName=CTRI/2015/07/006062).

Role of nanosomal paclitaxel lipid suspension (NPLS) in the treatment of patients with metastatic breast cancer (MBC) Why was the study done? Paclitaxel is a commonly used drug for the treatment of breast cancer. Conventional formulation of paclitaxel is known to cause side effects like injection site reactions. A newer formulation named NPLS was developed to overcome the limitations of the conventional paclitaxel. The current study was done to compare the safety and effectiveness of NPLS and conventional paclitaxel in patients with advanced breast cancer. What did the researchers do? The research team conducted a large study in multiple hospitals across India, involving women with advanced breast cancer who had experienced treatment failure with previous chemotherapy. A total of 174 patients were randomly assigned to receive either of the three treatment schedules: (1) NPLS every 3 weeks, (2) NPLS every week, (3) conventional paclitaxel every 3 weeks. What did the researchers find? The results showed that NPLS, in a weekly schedule, led to better tumor response rates compared to conventional paclitaxel given every 3 weeks. Additionally, NPLS demonstrated a favorable safety profile, as compared to conventional paclitaxel. What do the findings mean? These findings suggest that NPLS could be a promising alternative for women with advanced breast cancer. NPLS improved the response to treatment, with a better safety profile compared to conventional paclitaxel.

Subclinical atherosclerosis in multiple sclerosis.

Background: People with multiple sclerosis (MS) have an increased risk of ischemic heart disease as compared to people without MS after accounting for traditional vascular risk factors. Objective: We assessed whether subclinical atherosclerosis, an inflammatory disease of arteries, occurs in persons with MS who do not have traditional vascular risk factors, and whether the Framingham Score (FRS) predicted carotid intima media thickness (CIMT) similarly in people with and without MS. Methods: We recruited participants with and without MS who did not have vascular disease. Participants completed questionnaires, physical assessments, underwent an ultrasound (CIMT), and provided samples for HbA1c and lipid measurements. We defined subclinical atherosclerosis as an average CIMT ≥75th percentile, and tested the association between MS/not-MS, FRS, and atherosclerosis using logistic regression. Results: We recruited 106 participants with MS 101 without MS. The average (SD) CIMT did not differ between the MS (0.60 [0.11]) and non-MS (0.61 [0.12]) cohorts (p = 0.69), nor did the proportion with atherosclerosis (MS: 11.3% vs. non-MS 13.4%, p = 0.58). On regression analysis a 1-point increase in the FRS was associated with 11% increased odds of having atherosclerosis (95%CI: 1.04, 1.19) but MS was not. Conclusion: MS was not associated with subclinical atherosclerosis.

A pharmacological toolkit for human microglia identifies Topoisomerase I inhibitors as immunomodulators for Alzheimer's disease.

While efforts to identify microglial subtypes have recently accelerated, the relation of transcriptomically defined states to function has been largely limited to in silico annotations. Here, we characterize a set of pharmacological compounds that have been proposed to polarize human microglia towards two distinct states - one enriched for AD and MS genes and another characterized by increased expression of antigen presentation genes. Using different model systems including HMC3 cells, iPSC-derived microglia and cerebral organoids, we characterize the effect of these compounds in mimicking human microglial subtypes in vitro. We show that the Topoisomerase I inhibitor Camptothecin induces a CD74high/MHChigh microglial subtype which is specialized in amyloid beta phagocytosis. Camptothecin suppressed amyloid toxicity and restored microglia back to their homeostatic state in a zebrafish amyloid model. Our work provides avenues to recapitulate human microglial subtypes in vitro, enabling functional characterization and providing a foundation for modulating human microglia in vivo.

Role of Lateral Extra-articular Tenodesis in Restraining Internal Tibial Rotation: In Vitro Biomechanical Assessment of Lateral Tissue Engagement.

BACKGROUND: The way in which force increases in the anterolateral tissues and the lateral extra-articular tenodesis (LET) tissue to resist internal rotation (IR) of the tibia after anterior cruciate ligament (ACL) reconstruction in isolation and after LET augmentation, respectively, is not well understood. PURPOSE: (1) To compare in a cadaveric model how force increases (ie, engages) in the anterolateral tissues with IR of the tibia after isolated ACL reconstruction and in the LET tissue after augmentation of the ACL reconstruction with LET and (2) to determine whether IR of the tibia is related to engagement of the LET tissue. STUDY DESIGN: Controlled laboratory study. METHODS: IR moments were applied to 9 human cadaveric knees at 0°, 30°, 60°, and 90° of flexion using a robotic manipulator. Each knee was tested in 2 states: (1) after isolated ACL reconstruction with intact anterolateral tissues and (2) after LET was performed using a modified Lemaire technique with the LET tissue fixed at 60° of flexion under 44 N of tension. Resultant forces carried by the anterolateral tissues and the LET tissue were determined via superposition. The way force increased in these tissues was characterized via parameters of tissue engagement, namely in situ slack, in situ stiffness, and tissue force at peak applied IR moment, and then compared (α < .05). IR was related to parameters of engagement of the LET tissue via simple linear regression (α < .05). RESULTS: The LET tissue exhibited less in situ slack than the anterolateral tissues at 30°, 60°, and 90° of flexion (P≤ .04) and greater in situ stiffness at 30° and 90° of flexion (P≤ .043). The LET tissue carried greater force at the peak applied IR moment at 0° and 30° of flexion (P≤ .01). IR was related to the in situ slack of the LET tissue (R2≥ 0.88; P≤ .0003). CONCLUSION: LET increased restraint to IR of the tibia compared with the anterolateral tissue, particularly at 30°, 60°, and 90° of flexion. IR of the tibia was positively associated with in situ slack of the LET tissue. CLINICAL RELEVANCE: Fixing the LET at 60° of flexion still provided IR restraint in the more functionally relevant flexion angle of 30°. Surgeons should pay close attention to the angle of internal and/or external tibial rotation when fixing the LET tissue intraoperatively because this surgical parameter is related to in situ slack of the LET tissue and, therefore, the amount of IR of the tibia.

Early anticoagulation in patients with stroke and atrial fibrillation is associated with fewer ischaemic lesions at 1 month: the ATTUNE study.

BACKGROUND: The optimal time to commence anticoagulation in patients with atrial fibrillation (AF) after ischaemic stroke or transient ischaemic attack (TIA) is unclear, with guidelines differing in recommendations. A limitation of previous studies is the focus on clinically overt stroke, rather than radiologically obvious diffusion-weighted imaging ischaemic lesions. We aimed to quantify silent ischaemic lesions and haemorrhages on MRI at 1 month in patients commenced on early (<4 days) vs late (≥4 days) anticoagulation. We hypothesised that there would be fewer ischaemic lesions and more haemorrhages in the early anticoagulant group at 1-month MRI. METHODS: A prospective multicentre, observational cohort study was performed at 11 Australian stroke centres. Clinical and MRI data were collected at baseline and follow-up, with blinded imaging assessment performed by two authors. Timing of commencement of anticoagulation was at the discretion of the treating stroke physician. RESULTS: We recruited 276 patients of whom 208 met the eligibility criteria. The average age was 74.2 years (SD±10.63), and 79 (38%) patients were female. Median National Institute of Health Stroke Scale score was 5 (IQR 1-12). Median baseline ischaemic lesion volume was 5 mL (IQR 2-17). There were a greater number of new ischaemic lesions on follow-up MRI in patients commenced on anticoagulation ≥4 days after index event (17% vs 8%, p=0.04), but no difference in haemorrhage rates (22% vs 32%, p=0.10). Baseline ischaemic lesion volume of ≤5 mL was less likely to have a new haemorrhage at 1 month (p=0.02). There was no difference in haemorrhage rates in patients with an initial ischaemic lesion volume of >5 mL, regardless of anticoagulation timing. CONCLUSION: Commencing anticoagulation <4 days after stroke or TIA is associated with fewer ischaemic lesions at 1 month in AF patients. There is no increased rate of haemorrhage with early anticoagulation. These results suggest that early anticoagulation after mild-to-moderate acute ischaemic stroke associated with AF might be safe, but randomised controlled studies are needed to inform clinical practice.

Effect of Polypectomy Simulation-Based Mastery Learning on Skill Retention Among Practicing Endoscopists.

PURPOSE: Practicing endoscopists frequently perform and teach screening colonoscopies and polypectomies, but there is no standardized method to train and assess physicians who perform polypectomy procedures. The authors created a polypectomy simulation-based mastery learning (SBML) curriculum and hypothesized that completion of the curriculum would lead to immediate improvement in polypectomy skills and skill retention at 6 and 12 months after training. METHOD: The authors performed a pretest-posttest cohort study with endoscopists who completed SBML and were randomized to follow-up at 6 or 12 months from May 2021 to August 2022. Participants underwent SBML training, including a pretest, a video lecture, deliberate practice, and a posttest. All learners were required to meet or exceed a minimum passing standard on a 17-item skills checklist before completing training and were randomized to follow-up at 6 or 12 months. The authors compared simulated polypectomy skills performance on the checklist from pretest to posttest and posttest to 6- or 12-month follow-up test. RESULTS: Twenty-four of 30 eligible participants (80.0%) completed the SBML intervention, and 20 of 24 (83.3%) completed follow-up testing. The minimum passing standard was set at 93% of checklist items correct. The pretest passing rate was 4 of 24 participants (16.7%) compared with 24 of 24 participants (100%) at posttest ( P < .001). There were no significant differences in passing rates from posttest to combined 6- and 12-month posttest in which 18 of 20 participants (90.0%) passed. CONCLUSIONS: Before training and despite years of clinical experience, practicing endoscopists demonstrated poor performance of polypectomy skills. SBML was an effective method for practicing endoscopists to acquire and maintain polypectomy skills during a 6- to 12-month period.

Differences in resting state functional connectivity relative to multiple sclerosis and impaired information processing speed.

Background: Fifty-one percent of individuals with multiple sclerosis (MS) develop cognitive impairment (CI) in information processing speed (IPS). Although IPS scores are associated with health and well-being, neural changes that underlie IPS impairments in MS are not understood. Resting state fMRI can provide insight into brain function changes underlying impairment in persons with MS. Objectives: We aimed to assess functional connectivity (FC) differences in (i) persons with MS compared to healthy controls (HC), (ii) persons with both MS and CI (MS-CI) compared to HC, (iii) persons with MS that are cognitively preserved (MS-CP) compared to HC, (iv) MS-CI compared to MS-CP, and (v) in relation to cognition within the MS group. Methods: We included 107 participants with MS (age 49.5 ± 12.9, 82% women), and 94 controls (age 37.9 ± 15.4, 66% women). Each participant was administered the Symbol Digit Modalities Test (SDMT) and underwent a resting state fMRI scan. The MS-CI group was created by applying a z-score cut-off of ≤-1.5 to locally normalized SDMT scores. The MS-CP group was created by applying a z-score of ≥0. Control groups (HCMS-CI and HCMS-CP) were based on the nearest age-matched HC participants. A whole-brain ROI-to-ROI analysis was performed followed by specific contrasts and a regression analysis. Results: Individuals with MS showed FC differences compared to HC that involved the cerebellum, visual and language-associated brain regions, and the thalamus, hippocampus, and basal ganglia. The MS-CI showed FC differences compared to HCMS-CI that involved the cerebellum, visual and language-associated areas, thalamus, and caudate. SDMT scores were correlated with FC between the cerebellum and lateral occipital cortex in MS. No differences were observed between the MS-CP and HCMS-CP or MS-CI and MS-CP groups. Conclusion: Our findings emphasize FC changes of cerebellar, visual, and language-associated areas in persons with MS. These differences were apparent for (i) all MS participants compared to HC, (ii) MS-CI subgroup and their matched controls, and (iii) the association between FC and SDMT scores within the MS group. Our findings strongly suggest that future work that examines the associations between FC and IPS impairments in MS should focus on the involvement of these regions.

Optimized Red-Absorbing Dyes for Imaging and Sensing.

Rhodamine dyes are excellent scaffolds for developing a broad range of fluorescent probes. A key property of rhodamines is their equilibrium between a colorless lactone and fluorescent zwitterion. Tuning the lactone-zwitterion equilibrium constant (KL-Z) can optimize dye properties for specific biological applications. Here, we use known and novel organic chemistry to prepare a comprehensive collection of rhodamine dyes to elucidate the structure-activity relationships that govern KL-Z. We discovered that the auxochrome substituent strongly affects the lactone-zwitterion equilibrium, providing a roadmap for the rational design of improved rhodamine dyes. Electron-donating auxochromes, such as julolidine, work in tandem with fluorinated pendant phenyl rings to yield bright, red-shifted fluorophores for live-cell single-particle tracking (SPT) and multicolor imaging. The N-aryl auxochrome combined with fluorination yields red-shifted Förster resonance energy transfer (FRET) quencher dyes useful for creating a new semisynthetic indicator to sense cAMP using fluorescence lifetime imaging microscopy (FLIM). Together, this work expands the synthetic methods available for rhodamine synthesis, generates new reagents for advanced fluorescence imaging experiments, and describes structure-activity relationships that will guide the design of future probes.

Altered voxel-based and surface-based morphometry in inflammatory bowel disease.

Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is characterized by inflammation of the gastrointestinal tract and is a disorder of the brain-gut axis. Neuroimaging studies of brain function and structure have helped better understand the relationships between the brain, gut, and comorbidity in IBD. Studies of brain structure have primarily employed voxel-based morphometry to measure grey matter volume and surface-based morphometry to measure cortical thickness. Far fewer studies have employed other surface-based morphometry metrics such as gyrification, cortical complexity, and sulcal depth. In this study, brain structure differences between 72 adults with IBD and 90 healthy controls were assessed using all five metrics. Significant differences were found for cortical thickness with the IBD group showing extensive left-lateralized thinning, and for cortical complexity with the IBD group showing greater complexity in the left fusiform and right posterior cingulate. No significant differences were found in grey matter volume, gyrification, or sulcal depth. Within the IBD group, a post hoc analysis identified that disease duration is associated with cortical complexity of the right supramarginal gyrus, albeit with a more lenient threshold applied.

Vascular Disease Is Associated With Differences in Brain Structure and Lower Cognitive Functioning in Inflammatory Bowel Disease: A Cross-Sectional Study.

BACKGROUND: Vascular disease and cognitive impairment have been increasingly documented in inflammatory bowel disease (IBD), and both have been individually correlated with changes in brain structure. This study aimed to determine if both macro- and microstructural brain changes are prevalent in IBD and whether alterations in brain structure mediate the relationship between vascular disease and cognitive functioning. METHODS: Eighty-four IBD participants underwent multimodal magnetic resonance imaging. Volumetric and mean diffusivity measures of the thalamus, hippocampus, normal-appearing white matter, and white matter lesions were converted to age- and sex-adjusted z scores. Vascular comorbidity was assessed using a modified Framingham Risk Score and cognition was assessed using a battery of neuropsychological tests. Test scores were standardized using local regression-based norms. We generated summary statistics for the magnetic resonance imaging metrics and cognitive tests, and these were examined using canonical correlation analysis and linear regression modeling. RESULTS: Greater vascular comorbidity was negatively correlated with thalamic, normal-appearing white matter, and white matter lesion volumes. Higher Framingham Risk Score were also correlated with lower processing speed, learning and memory, and verbal fluency. Increased vascular comorbidity was predictive of poorer cognitive functioning, and this effect was almost entirely mediated (94.76%) by differences in brain structure. CONCLUSIONS: Vascular comorbidity is associated with deleterious effects on brain structure and lower cognitive functioning in IBD. These findings suggest that proper identification and treatment of vascular disease is essential to the overall management of IBD, and that certain brain areas may serve as critical targets for predicting the response to therapeutic interventions.

Vascular disease is associated with decreased cognitive performance in persons with inflammatory bowel disease, and this is mainly driven by changes in the brain, including both gray matter and white matter regions.

Update on Endovascular Therapy for Fibroids and Adenomyosis.

Uterine fibroids and adenomyosis are prevalent benign neoplasms that can lead to serious deleterious health effects including life-threatening anemia, prolonged menses, and pelvic pain; however, up to 40% of women remain undiagnosed. Traditional treatment options such as myomectomy or hysterectomy can effectively manage symptoms but may entail longer hospital stays and hinder future fertility. Endovascular treatment, such as uterine artery embolization (UAE), is a minimally invasive procedure that has emerged as a well-validated alternative to surgical options while preserving the uterus and offering shorter hospital stays. Careful patient selection and appropriate techniques are crucial to achieving optimal outcomes. There have been advancements in recent times that encompass pre- and postprocedural care aimed at enhancing results and alleviating discomfort prior to, during, and after UAE. Furthermore, success and reintervention rates may also depend on the size and location of the fibroids. This article reviews the current state of endovascular treatments of uterine fibroids and adenomyosis.

Automated Insulin Delivery with Remote Real-Time Continuous Glucose Monitoring for Hospitalized Patients with Diabetes: A Multicenter, Single-Arm, Feasibility Trial.

Introduction: Multiple daily injection insulin therapy frequently fails to meet hospital glycemic goals and is prone to hypoglycemia. Automated insulin delivery (AID) with remote glucose monitoring offers a solution to these shortcomings. Research Design and Methods: In a single-arm multicenter pilot trial, we tested the feasibility, safety, and effectiveness of the Omnipod 5 AID System with real-time continuous glucose monitoring (CGM) for up to 10 days in hospitalized patients with insulin-requiring diabetes on nonintensive care unit medical-surgical units. Primary endpoints included the proportion of time in automated mode and percent time-in-range (TIR 70-180 mg/dL) among participants with >48 h of CGM data. Safety endpoints included incidence of severe hypoglycemia and diabetes-related ketoacidosis (DKA). Additional glycemic endpoints, CGM accuracy, and patient satisfaction were also explored. Results: Twenty-two participants were enrolled; 18 used the system for a total of 96 days (mean 5.3 ± 3.1 days per patient), and 16 had sufficient CGM data required for analysis. Median percent time in automated mode was 95% (interquartile range 92%-98%) for the 18 system users, and the 16 participants with >48 h of CGM data achieved an overall TIR of 68% ± 16%, with 0.17% ± 0.3% time <70 mg/dL and 0.06% ± 0.2% time <54 mg/dL. Sensor mean glucose was 167 ± 21 mg/dL. There were no DKA or severe hypoglycemic events. All participants reported satisfaction with the system at study end. Conclusions: The use of AID with a disposable tubeless patch-pump along with remote real-time CGM is feasible in the hospital setting. These results warrant further investigation in randomized trials.

A modular chemigenetic calcium indicator enables in vivo functional imaging with near-infrared light.

Genetically encoded fluorescent calcium indicators have revolutionized neuroscience and other biological fields by allowing cellular-resolution recording of physiology during behavior. However, we currently lack bright, genetically targetable indicators in the near infrared that can be used in animals. Here, we describe WHaloCaMP, a modular chemigenetic calcium indicator built from bright dye-ligands and protein sensor domains that can be genetically targeted to specific cell populations. Fluorescence change in WHaloCaMP results from reversible quenching of the bound dye via a strategically placed tryptophan. WHaloCaMP is compatible with rhodamine dye-ligands that fluoresce from green to near-infrared, including several dye-ligands that efficiently label the central nervous system in animals. When bound to a near-infrared dye-ligand, WHaloCaMP1a is more than twice as bright as jGCaMP8s, and shows a 7× increase in fluorescence intensity and a 2.1 ns increase in fluorescence lifetime upon calcium binding. We use WHaloCaMP1a with near-infrared fluorescence emission to image Ca2+ responses in flies and mice, to perform three-color multiplexed functional imaging of hundreds of neurons and astrocytes in zebrafish larvae, and to quantitate calcium concentration using fluorescence lifetime imaging microscopy (FLIM).

Radial Tunnel Syndrome: Review and Best Evidence.

Radial tunnel syndrome (RTS) is caused by compression of the posterior interosseous nerve and consists of a constellation of symptoms that have previously been characterized as aspects of other disease processes, as opposed to a distinct diagnosis. First described in the mid-20th century as "radial pronator syndrome," knowledge regarding the anatomy and presentation of RTS has advanced markedly over the past several decades. However, there remains notable controversy and ongoing research regarding diagnostic imaging, nonsurgical treatment options, and indications for surgical intervention. In this review, we will discuss the anatomic considerations of RTS, relevant physical examination findings, potential diagnostic modalities, and outcomes of several treatment options.

Cartilage Restoration for Isolated Patellar Chondral Defects: An Updated Systematic Review.

Background: Patellar chondral lesions can be particularly challenging to manage in younger and more active populations. Purpose: To synthesize, organize, and summarize the results and complication rates of various patellar cartilage restoration techniques. Study Design: Systematic review; Level of evidence, 4. Methods: We performed this systematic review according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the Medline, Embase, Scopus, and Cochrane databases. Studies were included that reported on surgical treatment of patellar chondral defects with ≥5 patients and 12 months of follow-up data. Relevant demographic data from the included studies were extracted, and patient-reported outcome scores, visual analog scale for pain results, return-to-sport rate, complications, and concomitant procedures were documented. Results: There were 24 studies that met the inclusion criteria, with a total of 575 patients (male, n = 239; female, n = 336). In total, 6 surgical techniques were utilized. In 9 studies, the surgical procedure of choice was osteochondral autograft transplantation (OAT); 8 studies evaluated autologous chondrocyte implantation (ACI); 3 evaluated advanced microfracture/autologous matrix-induced chondrogenesis; 1 evaluated osteochondral allograft transplantation (OCA); 1 evaluated particulate juvenile articulated cartilage; and 2 evaluated a synthetic osteochondral graft. No uniform functional outcome score or assessment was utilized across studies. OAT was predominantly used for smaller chondral lesions (<2 cm2) and demonstrated minimal complication rates and satisfactory outcome scores. Advanced microfracture techniques showed promise, with improvement in outcome scores and zero complications. Matrix-induced ACI consistently exhibited higher mean improvement in the measured outcome scores and resulted in fewer complications when compared with previous generations of ACI. Conclusion: OAT and ACI were the most studied procedures for isolated patellar chondral defects. Advanced microfracture techniques showed promise, but indications (ie, size) and variability in techniques need to be elucidated in higher-level studies. Further prospective studies comparing OCA and matrix-induced ACI for larger patellar defects are necessary to determine the superior technique.

Free Tissue Transfer in Sickle Cell Disease: A Case Report and Systematic Review.

Hemoglobinopathies such as sickle cell disease (SCD) are traditionally considered a relative contraindication to free tissue transfer, due to concerns that erythrocyte sickling will increase the risk of microvascular thrombosis and flap failure. This article describes a case report with the successful use of free tissue transfer in a patient with SCD and provides a systematic literature review on free tissue transfer in SCD. A retrospective chart review was performed of a patient with SCD who underwent free tissue transfer at the authors' institution. A systematic literature review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed using the keywords "free tissue transfer," "free flap," or "microsurgery" and "sickle cell" on PubMed, Ovid/Medline, and Scopus. A 29-year-old male with delayed presentation of an electrical burn to the face and scalp underwent wound closure with a free anterolateral thigh flap. Key management principles included red blood cell transfusion to keep hemoglobin S under 30% and hemoglobin greater than 10 g/dL, maintenance of hydration, normothermia, adequate analgesia, and postoperative anticoagulation. Systematic literature review identified 7 articles describing 13 cases of free tissue transfer in 10 patients with SCD, with combined complete free flap success in 10 of the 13 flaps. Free tissue transfer can be successfully performed in patients with SCD. However, evidence on the optimal management of this unique patient population in the perioperative period after free tissue transfer is limited to case reports in the literature.

Glutamate indicators with improved activation kinetics and localization for imaging synaptic transmission.

The fluorescent glutamate indicator iGluSnFR enables imaging of neurotransmission with genetic and molecular specificity. However, existing iGluSnFR variants exhibit low in vivo signal-to-noise ratios, saturating activation kinetics and exclusion from postsynaptic densities. Using a multiassay screen in bacteria, soluble protein and cultured neurons, we generated variants with improved signal-to-noise ratios and kinetics. We developed surface display constructs that improve iGluSnFR's nanoscopic localization to postsynapses. The resulting indicator iGluSnFR3 exhibits rapid nonsaturating activation kinetics and reports synaptic glutamate release with decreased saturation and increased specificity versus extrasynaptic signals in cultured neurons. Simultaneous imaging and electrophysiology at individual boutons in mouse visual cortex showed that iGluSnFR3 transients report single action potentials with high specificity. In vibrissal sensory cortex layer 4, we used iGluSnFR3 to characterize distinct patterns of touch-evoked feedforward input from thalamocortical boutons and both feedforward and recurrent input onto L4 cortical neuron dendritic spines.

Lupus pathogenesis and autoimmunity are exacerbated by high fat diet-induced obesity in MRL/lpr mice.

OBJECTIVE: SLE is an autoimmune disease characterised by persistent inflammation and autoantibody production. Genetic predisposition and environmental factors such as a high-fat diet (HFD) may contribute to lupus development. However, the immune cell profile and gender difference in response to HFD in lupus have not been reported. Here we investigated the impact of HFD on lupus pathogenesis and autoimmunity using lupus-prone mice. METHODS: Thirty male and 30 female MRL/lymphoproliferation (lpr) mice were fed with regular diet (RD) or HFD. Body weights were recorded weekly. SLE progression was monitored by skin lesion, urine protein, titres of antidouble-strand DNA (dsDNA) and ANA. At week 14, kidney and skin tissue sections were stained with H&E and periodic acid-Schiff to detect histological kidney index and skin score. Splenocytes were identified by immunofluorescence staining and flow cytometry. RESULTS: HFD significantly increased body weight and lipid levels compared with RD (p<0.01). Skin lesions were observed in 55.6% of the HFD group compared with 11.1% of the RD group, with greater histopathological skin scores in the female HFD group (p<0.01). Although both male and female mice had higher serum IgG in the HFD group than in the RD group, only the male HFD group showed an increased trend in anti-dsDNA Ab and ANA titres. Kidney pathological changes in the HFD group were more severe in male mice than in female mice (p<0.05), detected by proteinuria, kidney index and glomerular cell proliferation. Significant increases of germinal centre B cells and T follicular helper cells were observed in the spleens of HFD mice (p<0.05). CONCLUSION: HFD induced an accelerated and exacerbated lupus development and autoimmunity in MRL/lpr mice. Our results parallel many known clinical lupus phenotypes and sexual dimorphism in which male patients are likelier to have a severe disease (nephritis) than female lupus patients who may have a broader range of lupus symptoms.