Cellular migration into a subretinal honeycomb-shaped prosthesis for high-resolution prosthetic vision.

In patients blinded by geographic atrophy, a subretinal photovoltaic implant with 100 µm pixels provided visual acuity closely matching the pixel pitch. However, such flat bipolar pixels cannot be scaled below 75 µm, limiting the attainable visual acuity. This limitation can be overcome by shaping the electric field with 3-dimensional (3-D) electrodes. In particular, elevating the return electrode on top of the honeycomb-shaped vertical walls surrounding each pixel extends the electric field vertically and decouples its penetration into tissue from the pixel width. This approach relies on migration of the retinal cells into the honeycomb wells. Here, we demonstrate that majority of the inner retinal neurons migrate into the 25 µm deep wells, leaving the third-order neurons, such as amacrine and ganglion cells, outside. This enables selective stimulation of the second-order neurons inside the wells, thus preserving the intraretinal signal processing in prosthetic vision. Comparable glial response to that with flat implants suggests that migration and separation of the retinal cells by the walls does not cause additional stress. Furthermore, retinal migration into the honeycombs does not negatively affect its electrical excitability, while grating acuity matches the pixel pitch down to 40 µm and reaches the 27 µm limit of natural resolution in rats with 20 µm pixels. These findings pave the way for 3-D subretinal prostheses with pixel sizes of cellular dimensions.

Electrical synapse structure requires distinct isoforms of a postsynaptic scaffold.

Electrical synapses are neuronal gap junction (GJ) channels associated with a macromolecular complex called the electrical synapse density (ESD), which regulates development and dynamically modifies electrical transmission. However, the proteomic makeup and molecular mechanisms utilized by the ESD that direct electrical synapse formation are not well understood. Using the Mauthner cell of zebrafish as a model, we previously found that the intracellular scaffolding protein ZO1b is a member of the ESD, localizing postsynaptically, where it is required for GJ channel localization, electrical communication, neural network function, and behavior. Here, we show that the complexity of the ESD is further diversified by the genomic structure of the ZO1b gene locus. The ZO1b gene is alternatively initiated at three transcriptional start sites resulting in isoforms with unique N-termini that we call ZO1b-Alpha, -Beta, and -Gamma. We demonstrate that ZO1b-Beta and ZO1b-Gamma are broadly expressed throughout the nervous system and localize to electrical synapses. By contrast, ZO1b-Alpha is expressed mainly non-neuronally and is not found at synapses. We generate mutants in all individual isoforms, as well as double mutant combinations in cis on individual chromosomes, and find that ZO1b-Beta is necessary and sufficient for robust GJ channel localization. ZO1b-Gamma, despite its localization to the synapse, plays an auxiliary role in channel localization. This study expands the notion of molecular complexity at the ESD, revealing that an individual genomic locus can contribute distinct isoforms to the macromolecular complex at electrical synapses. Further, independent scaffold isoforms have differential contributions to developmental assembly of the interneuronal GJ channels. We propose that ESD molecular complexity arises both from the diversity of unique genes and from distinct isoforms encoded by single genes. Overall, ESD proteomic diversity is expected to have critical impacts on the development, structure, function, and plasticity of electrical transmission.

Feasibility and Acceptability of Home-Delivered Medically Tailored Meals for Treatment of Diabetes in Pregnancy.

BACKGROUND: Diabetes complicates ≤7% of pregnancies in the United States. Although medical nutrition therapy is the mainstay of diabetes treatment, many barriers exist to the successful implementation of dietary modifications. Home-delivered medically tailored meals (MTMs) are promising to overcome such barriers. OBJECTIVE: The objective of this study was to evaluate the feasibility and acceptability of home-delivered MTM in pregnant patients with diabetes. METHODS: We performed a prospective cohort study of home-delivered MTM for pregnant patients with diabetes using a mixed-methods approach. Participants <35 wk of gestation at the time of enrollment received weekly home delivery of diabetes-specific meals. Qualitative semistructured interviews were conducted to gain insight into participants' experience. Diabetes self-efficacy was assessed pre- and postintervention using the Diabetes Self-Efficacy Scale and 2-Item Diabetes Distress Screening Scale. The difference in mean scores was compared using t-tests with P value of <0.05 considered significant. Feasibility and acceptability were evaluated through participants' attitude toward MTM in qualitative interviews and indirectly evaluated through diabetes self-efficacy surveys. RESULTS: Twenty pregnant people with diabetes who received home-delivered MTM during pregnancy were interviewed postpartum. Participants found this program convenient for various reasons, including reduced time for grocery shopping and preparing meals. Participants were satisfied with meals, citing a positive impact on diabetes management, accessibility of healthy foods, reduced stress with meal planning, and greater perceived control of blood glucose. Most participants shared meals with their families or received specific meals for their dependents, which was positively received. Reduced financial and mental stress was also widely reported. Diabetes self-efficacy was significantly improved postintervention with MTM. CONCLUSION: Home-delivered MTM is feasible and acceptable in pregnant patients with diabetes and may improve diabetes self-efficacy. Individual experiences offered insight into various barriers overcome by using this service. Home-delivered MTM may help ensure an accessible, healthy diet for pregnant patients with diabetes.

Persistent hepatitis B virus and HIV coinfections in dually humanized mice engrafted with human liver and immune system.

Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), remains a major medical problem. HBV has a high propensity for progressing to chronicity and can result in severe liver disease, including fibrosis, cirrhosis, and hepatocellular carcinoma. CHB patients frequently present with viral coinfection, including human immunodeficiency virus type (HIV) and hepatitis delta virus. About 10% of chronic HIV carriers are also persistently infected with HBV, which can result in more exacerbated liver disease. Mechanistic studies of HBV-induced immune responses and pathogenesis, which could be significantly influenced by HIV infection, have been hampered by the scarcity of immunocompetent animal models. Here, we demonstrate that humanized mice dually engrafted with components of a human immune system and a human liver supported HBV infection, which was partially controlled by human immune cells, as evidenced by lower levels of serum viremia and HBV replication intermediates in the liver. HBV infection resulted in priming and expansion of human HLA-restricted CD8+ T cells, which acquired an activated phenotype. Notably, our dually humanized mice support persistent coinfections with HBV and HIV, which opens opportunities for analyzing immune dysregulation during HBV and HIV coinfection, and preclinical testing of novel immunotherapeutics.

Peptide-Functionalized Carbon Nanotube Chemiresistors: The Effect of Nanotube Density on Gas Sensing.

Biorecognition element (BRE)-based carbon nanotube (CNT) chemiresistors have tremendous potential to serve as highly sensitive, selective, and power-efficient volatile organic compound (VOC) sensors. While many research groups have studied BRE-functionalized CNTs in material science and device development, little attention has been paid to optimizing CNT density to improve chemiresistor performance. To probe the effect of CNT density on VOC detection, we present the chemiresistor-based sensing results from two peptide-based CNT devices counting more than 60 different individual measurements. We find that a lower CNT density shows a significantly higher noise level and device-to-device variation while exhibiting mildly better sensitivity. Further investigation with SEM images suggests that moderately high CNT density with a stable connection of the nanotube network is desirable to achieve the best signal-to-noise ratio. Our results show an essential design guideline for tuning the nanotube density to provide sensitive and stable chemiresistors.

'Sufficient Pain relief ' as a Practical Benchmark in Cancer Pain Management: A Prospective Study of Serial Pain Scores, Patient-rated Pain Relief and Perceived Sufficiency of Analgesics.

Objectives: Serial pain scores are used to guide pain management but there can be variability in what constitutes 'adequate' pain relief for an individual patient. We aimed to evaluate how patient-rated sufficiency of pain relief corresponded to pain scores, pain relief scores, and the felt need for increasing analgesics. Material and Methods: Baseline and follow-up scores on the 11-point numerical rating scale (11-NRS) and verbal rating scale were obtained for116 patients with cancer pain. Patients used the pain relief sufficiency rating (PRSR) to rate pain relief as 'no reduction,' 'some reduction, but not enough,' 'sufficient reduction,' and 'very good reduction.' They also rated analgesics as 'sufficient' or 'insufficient.' Receiver-operating characteristic (ROC) curve analysis was used to compare PRSR responses with follow-up pain scores, patient rated percentage pain relief, and the perceived need for an increase in analgesics. Results: The 11-NRS had an area under the ROC curve of 94.2% against the PRSR. A pain score of three provided the best cutoff to identify adequate pain relief (88.2% sensitivity and 85.7% specificity). Follow-up verbal pain scores corresponded to PRSR categories (severe pain: no reduction; moderate pain: some reduction; mild pain: sufficient reduction and no pain: very good reduction). The PRSR identified 97.3% of patients who wanted analgesics increased and 85% of those who said pain medications were sufficient. Conclusion: The PRSR is a brief, simple and intuitive measure to elicit patient perceptions on the sufficiency of pain relief. Our findings suggest that it might be a useful tool in pain and symptom management.

Partnering on the Social Determinants of Health With the Community Health Improvement Matrix.

The research goal was to describe local health department community health improvement plans and hospital implementation strategies, assessing the extent to which they address the social determinants of health. In 2014, we used a grounded theory approach to conceptualize the extent of social determinant efforts in a purposive sample of improvement plans and implementation strategies (N = 12) taken from the community health assessment database pilot project (N = 502). We developed the Community Health Improvement Matrix (CHIM), categorizing public health activities according to target and prevention levels. In 2016, we surveyed NACCHO's Performance Improvement Workgroup (N = 9) using CHIM categories. In 2017, we tested the interrater reliability of the CHIM through an analysis of stories in 30 states (N = 101). We shared the CHIM in conferences, trainings, and focused conversations. The CHIM provides a framework for local public health partners to work together to address social determinants.

Pretherapy neutrophil to lymphocyte ratio and platelet to lymphocyte ratio do not predict survival in resectable pancreatic cancer.

BACKGROUND: Pretherapy serum neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) have both been identified as prognostic in pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to identify the prognostic implication of pretherapy NLR and PLR in patients with resectable PDAC. METHODS: Data were collected retrospectively on patients operated at our institution between 2004 and 2014. A Cox proportional hazards model was used to investigate the relationship between clinical and pathological parameters, NLR and PLR to overall survival (OS). Survival data were analyzed using the Kaplan-Meier method. RESULTS: 217 patients were analyzed with a median overall survival (OS) of 17.5 months. Factors identified as being predictive of OS by univariate analysis included age, receipt of adjuvant therapy, margin positivity, pathologic angiolymphatic invasion, T-stage, and N-stage (P < 0.05). Factors identified as being independently predictive of OS by multivariate analysis included age and angiolymphatic invasion (P < 0.05). NLR and PLR were not predictive of OS. Survival analysis demonstrated no difference in OS in patients who had high or low NLR or PLR. DISCUSSION: Pretherapy NLR and PLR do not predict survival in patients who underwent pancreatectomy for PDAC at our institution.

The extent of root resorption and tooth movement following the application of ascending and descending magnetic forces: a prospective split mouth, microcomputed-tomography study.

OBJECTIVE: Various factors have been examined in the literature in an attempt to reduce the incidence and severity of root resorption. The purpose of the present investigation is to test the null hypothesis that there is no difference in relation to force level using gradually increasing (ascending) and decreasing (descending) orthodontic force generated by magnets on the severity of Orthodontically Induced Inflammatory Iatrogenic Root Resorption (OIIRR) and amount of tooth movement. METHODS: Twenty maxillary first premolars from 10 patients were subjected to ascending (25-225 g, magnets in attraction) and descending (225 to 25 g, magnets in repulsion) buccal forces using a split mouth design over an 8-week period. Polyvinyl siloxane impressions were taken at week 0, 4, and 8 to record the tooth movement. After 8 weeks, the teeth were extracted, scanned, with micro-CT in 16.9 µm resolution, and the root resorption craters were localized circumferentially and quantified at each level of the root. RESULTS: The total volume of OIIRR with ascending force was 1.20 mm3, and with descending force was 1.25 mm3, and there was no statistically significant difference between them. OIIRR on the palatal surface (0.012 mm3) was significantly less than on the buccal surface (0.057 mm3) and than on the mesial surface (0.035 mm3). There is no statistically significant difference in the degree of OIIRR between different level of the root (cervical, middle, and apical) at different surfaces. Moreover, the amount of tooth movement, at 0-, 4-, and 8-week interval, secondary to an ascending and descending force application was not statistically significant. CONCLUSIONS: There is no short-term (8 weeks) statistically significant difference between orthodontic ascending and descending forces, from 25 to 225 g and from 225 to 25 g, respectively, in term of severity and location of OIIRR as well as the amount of tooth movement. The buccal surface of the root showed highest degree of OIIRR compared to other root's surfaces.

Epithelial membrane protein-2 (EMP2) activates Src protein and is a novel therapeutic target for glioblastoma.

Despite recent advances in molecular classification, surgery, radiotherapy, and targeted therapies, the clinical outcome of patients with malignant brain tumors remains extremely poor. In this study, we have identified the tetraspan protein epithelial membrane protein-2 (EMP2) as a potential target for glioblastoma (GBM) killing. EMP2 had low or undetectable expression in normal brain but was highly expressed in GBM as 95% of patients showed some expression of the protein. In GBM cells, EMP2 enhanced tumor growth in vivo in part by up-regulating αvß3 integrin surface expression, activating focal adhesion kinase and Src kinases, and promoting cell migration and invasion. Consistent with these findings, EMP2 expression significantly correlated with activated Src kinase in patient samples and promoted tumor cell invasion using intracranial mouse models. As a proof of principle to determine whether EMP2 could serve as a target for therapy, cells were treated using specific anti-EMP2 antibody reagents. These reagents were effective in killing GBM cells in vitro and in reducing tumor load in subcutaneous mouse models. These results support the role of EMP2 in the pathogenesis of GBM and suggest that anti-EMP2 treatment may be a novel therapeutic treatment.

Modified Sequential Organ Failure Assessment score for predicting mortality in emergency department patients with sepsis.

OBJECTIVE: Several scoring systems have been proposed for EDs to identify patients at increased risk of mortality from sepsis. The modified Sequential Organ Failure Assessment (mSOFA) score, proposed in 2019, demonstrated a high negative predictive value. We aimed to validate mSOFA and compare its accuracy for predicting 30-day mortality to the simple bedside score, quick SOFA (qSOFA). METHODS: Over 1 month in 2018, consecutive patients with suspected sepsis were prospectively identified. A retrospective chart review was conducted to calculate both the mSOFA and qSOFA scores for these patients. The primary outcome was 30-day mortality. RESULTS: There were 252 patients with suspected sepsis identified over the study period. Thirty-day mortality was 13/39 (33.3%) for those with a positive mSOFA and 15/211 (7.1%) for those with a negative mSOFA score. Sensitivity was 46.4% (95% confidence interval [CI] 27.5-66.1%), specificity 88.3% (95% CI 83.3-92.2%), positive likelihood ratio 3.96 (95% CI 2.32-6.78), negative likelihood ratio 0.61 (95% CI 0.43-0.86). The area under the curve (AUC) was 0.74 (95% CI 0.64-0.85). qSOFA sensitivity was 39.3% (95% CI 21.5-59.4%), specificity 91.9% (95% CI 87.5-95.1%), positive likelihood ratio 4.85 (95% CI 2.56-9.18) and negative likelihood ratio 0.66 (95% CI 0.49-0.89). The AUC for qSOFA was 0.81 (95% CI 0.73-0.88). The difference in the AUC was -0.07 (95% CI -0.18 to 0.05), P = 0.25. CONCLUSIONS: In the present study, neither mSOFA nor qSOFA was adequately sensitive for predicting 30-day mortality, although both scores were highly specific and their overall accuracy was similar. The added complexity of the mSOFA without a significant increase in discriminative ability makes it unlikely to replace qSOFA in the ED setting.

Strabismus and Pediatric Psychiatric Illness: A Literature Review.

PURPOSE: This literature review aims to investigate the potential association between strabismus and mental illness among children. MATERIALS: The search was conducted in the PubMed and Google Scholar databases using a wide range of search terms related to strabismus, mental disorders, psychiatric illness, childhood, and adolescence. RESULTS: Eleven published studies were included in this review. The findings from this review suggest an association between strabismus and mental illness. Negative attitudes and social bias against children with strabismus were also noted. CONCLUSIONS: These findings should alert healthcare providers to counsel children and their caregivers regarding the risk for mood disorders in children with strabismus and to consider mental health screening and referral as needed.

DPPIV+ fibro-adipogenic progenitors form the niche of adult skeletal muscle self-renewing resident macrophages.

Adult tissue-resident macrophages (RMs) are either maintained by blood monocytes or through self-renewal. While the presence of a nurturing niche is likely crucial to support the survival and function of self-renewing RMs, evidence regarding its nature is limited. Here, we identify fibro-adipogenic progenitors (FAPs) as the main source of colony-stimulating factor 1 (CSF1) in resting skeletal muscle. Using parabiosis in combination with FAP-deficient transgenic mice (PdgfrαCreERT2 × DTA) or mice lacking FAP-derived CSF1 (PdgfrαCreERT2 × Csf1flox/null), we show that local CSF1 from FAPs is required for the survival of both TIM4- monocyte-derived and TIM4+ self-renewing RMs in adult skeletal muscle. The spatial distribution and number of TIM4+ RMs coincide with those of dipeptidyl peptidase IV (DPPIV)+ FAPs, suggesting their role as CSF1-producing niche cells for self-renewing RMs. This finding identifies opportunities to precisely manipulate the function of self-renewing RMs in situ to further unravel their role in health and disease.

YB1 modulates the DNA damage response in medulloblastoma.

Y-box binding protein 1 (YBX1 or YB1) is a therapeutically relevant oncoprotein capable of RNA and DNA binding and mediating protein-protein interactions that drive proliferation, stemness, and resistance to platinum-based therapies. Given our previously published findings, the potential for YB1-driven cisplatin resistance in medulloblastoma (MB), and the limited studies exploring YB1-DNA repair protein interactions, we chose to investigate the role of YB1 in mediating radiation resistance in MB. MB, the most common pediatric malignant brain tumor, is treated with surgical resection, cranio-spinal radiation, and platinum-based chemotherapy, and could potentially benefit from YB1 inhibition. The role of YB1 in the response of MB to ionizing radiation (IR) has not yet been studied but remains relevant for determining potential anti-tumor synergy of YB1 inhibition with standard radiation therapy. We have previously shown that YB1 drives proliferation of cerebellar granular neural precursor cells (CGNPs) and murine Sonic Hedgehog (SHH) group MB cells. While others have demonstrated a link between YB1 and homologous recombination protein binding, functional and therapeutic implications remain unclear, particularly following IR-induced damage. Here we show that depleting YB1 in both SHH and Group 3 MB results not only in reduced proliferation but also synergizes with radiation due to differential response dynamics. YB1 silencing through shRNA followed by IR drives a predominantly NHEJ-dependent repair mechanism, leading to faster γH2AX resolution, premature cell cycle re-entry, checkpoint bypass, reduced proliferation, and increased senescence. These findings show that depleting YB1 in combination with radiation sensitizes SHH and Group 3 MB cells to radiation.

Parental perceived immigration threat and children's mental health, self-regulation and executive functioning in pre-Kindergarten.

Many children in immigrant households endure unique stressors shaped by national, state, and local immigration policies and enforcement activity in the United States. Qualitative studies find that during times of heightened immigration enforcement, children as young as 3 years of age show signs of behavioral distress related to national anti-immigrant sentiment and the possibility of losing a parent. Using multiple sources of data from 168 racially and ethnically diverse families of children in pre-Kindergarten, the present study examined variability in perceived levels of immigration enforcement threat by parental immigrant status and ethnicity. This study examined associations between immigration enforcement threat and child mental health, self-regulation, and executive functioning and whether parent immigrant status or child gender moderates these associations. We found substantial variability in perceived immigration threat, with immigrant parents and Latinx parents reporting significantly greater levels of immigration threat compared to nonimmigrant parents and non-Latinx parents. Immigration enforcement threat was associated with greater child separation anxiety and overanxious behaviors, and lower self-regulation among boys and girls and among children of immigrant and U.S.-born parents. In contrast to our hypothesis, immigration enforcement threat was associated with higher self-regulation according to independent assessor ratings. Educators and healthcare providers working with young children from immigrant and Latinx households should be aware of the disproportionate stress experienced by immigrant and Latinx families due to a xenophobic sociopolitical climate marked by heightened immigration enforcement threat and racist, anti-immigrant rhetoric. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Electronic photoreceptors enable prosthetic visual acuity matching the natural resolution in rats.

Localized stimulation of the inner retinal neurons for high-acuity prosthetic vision requires small pixels and minimal crosstalk from the neighboring electrodes. Local return electrodes within each pixel limit the crosstalk, but they over-constrain the electric field, thus precluding the efficient stimulation with subretinal pixels smaller than 55 µm. Here we demonstrate a high-resolution prosthetic vision based on a novel design of a photovoltaic array, where field confinement is achieved dynamically, leveraging the adjustable conductivity of the diodes under forward bias to turn the designated pixels into transient returns. We validated the computational modeling of the field confinement in such an optically-controlled circuit by in-vitro and in-vivo measurements. Most importantly, using this strategy, we demonstrated that the grating acuity with 40 µm pixels matches the pixel pitch, while with 20 µm pixels, it reaches the 28 µm limit of the natural visual resolution in rats. This method enables customized field shaping based on individual retinal thickness and distance from the implant, paving the way to higher acuity of prosthetic vision in atrophic macular degeneration.

Neither protective nor harmonized: the crossborder regulation of medical devices in the EU.

To what extent does inadequate market regulation contribute to poor health outcomes? A series of prominent scandals involving harmful medical devices has made improving the regulation of these devices an urgent problem for the European Union (EU). This is, however, a specific example of a general phenomenon. The EU remains first and foremost a large and integrated market within which the EU institutions have considerable regulatory authority. Even if there is little EU commitment to a health or social policy agenda, its use of that regulatory authority shapes health care cost and quality and should be understood as health policy. We use data from EU-level and national policy documents to analyse the EU's current regulatory framework for medical devices and assess its likely future efficacy. Despite revising the medical devices directive to require more stringent pre-authorization requirements for high-risk medical devices and improvements in post-market surveillance, the key underlying problems of market fragmentation and patient safety persist. Without strong and consistent support for the implementation of the new directive, the likely result is the status quo, with significant consequences for health in Europe.

Seizure and delirium secondary to carboplatin and pantoprazole therapy-induced hypomagnesemia in a cancer patient.

Active surveillance and treatment of hypomagnesemia along with strict avoidance of concurrent offending agents is essential to prevent its grave clinical consequences among patients on carboplatin therapy.

FOXO1 expression in chondrocytes modulates cartilage production and removal in fracture healing.

Fracture healing is a multistage process characterized by inflammation, cartilage formation, bone deposition, and remodeling. Chondrocytes are important in producing cartilage that forms the initial anlagen for the hard callus needed to stabilize the fracture site. We examined the role of FOXO1 by selective ablation of FOXO1 in chondrocytes mediated by Col2α1 driven Cre recombinase. Experimental mice with lineage-specific FOXO1 deletion (Col2α1Cre+FOXO1L/L) and negative control littermates (Col2α1Cre-FOXO1L/L) were used for in vivo, closed fracture studies. Unexpectedly, we found that in the early phases of fracture healing, FOXO1 deletion significantly increased the amount of cartilage formed, whereas, in later periods, FOXO1 deletion led to a greater loss of cartilage. FOXO1 was functionally important as its deletion in chondrocytes led to diminished bone formation on day 22. Mechanistically, the early effects of FOXO1 deletion were linked to increased proliferation of chondrocytes through enhanced expression of cell cycle genes that promote proliferation and reduced expression of those that inhibit it and increased expression of cartilage matrix genes. At later time points experimental mice with FOXO1 deletion had greater loss of cartilage, enhanced formation of osteoclasts, increased IL-6 and reduced numbers of M2 macrophages. These results identify FOXO1 as a transcription factor that regulates chondrocyte behavior by limiting the early expansion of cartilage and preventing rapid cartilage loss at later phases.