Federal Response to the Opioid Crisis.

PURPOSE OF REVIEW: In light of the current crisis in opioid involved overdose deaths, the federal Department of Health and Human Services operating divisions are working together to implement a data-driven, research-based strategy to reduce opioid misuse and its consequences. RECENT FINDINGS: The strategy has five elements: (1) strengthening public health data collection and reporting; (2) advancing the practice of pain management; (3) improving access to addiction prevention, treatment, and recovery support services; (4) increasing availability of overdose-reversing drugs; and (5) supporting cutting-edge research in treatment of pain, opioid use disorder, and associated conditions. The Department of Health and Human Services has developed a concerted, coordinated evidence-based effort across department divisions to reduce opioid misuse, prevalence of opioid use disorder, and reduce deaths due to opioid use.

Association of outcomes and anti-Xa levels in the treatment of pediatric venous thromboembolism.

BACKGROUND: There are few data in the pediatric population evaluating the relationship between measured anti-Xa levels during enoxaparin therapy and thrombotic outcomes. OBJECTIVE: To determine whether there is a difference in outcomes in children who receive enoxaparin with mean anti-Xa levels between 0.45 and 0.79 unit/ml (low therapeutic range) versus between 0.80 and 1.05 unit/ml (high therapeutic range) throughout their course of their treatment. METHODS: We retrospectively identified subjects with uncomplicated venous thromboembolism treated with enoxaparin. RESULTS: Of 69 patients with any response to therapy, 48 (70%) had mean anti-Xa levels in the low therapeutic range and 21 (30%) had mean anti-Xa levels in the high therapeutic range. Of 20 patients with no documented response to therapy, 13 (65%) had mean anti-Xa levels in the low therapeutic range and 7 (35%) had mean anti-Xa levels in the high therapeutic range. Forty-eight (79%) of the 61 patients with low-range mean anti-Xa level had any response to therapy. Twenty-one (75%) of the 28 patients with high-range mean anti-Xa level had any response to therapy. Chi-square test (P = 0.080) and logistic regression (OR = 1.23, P = 0.70) demonstrated no significant association between mean anti-Xa range (lower vs. upper) and therapy response. CONCLUSIONS: There was no statistically significant difference between low-range versus high-range mean anti-Xa levels and thrombus resolution. Empiric clinical practices of targeting anti-Xa levels in the higher therapeutic range to achieve better outcomes may not be warranted.

Selective ion exchange governed by the Irving-Williams series in K2Zn3[Fe(CN)6]2 nanoparticles: toward a designer prodrug for Wilson's disease.

The principle of the Irving-Williams series is applied to the design of a novel prodrug based on K2Zn3[Fe(CN)6]2 nanoparticles (ZnPB NPs) for Wilson's disease (WD), a rare but fatal genetic disorder characterized by the accumulation of excess copper in the liver and other vital organs. The predetermined ion-exchange reaction rather than chelation between ZnPB NPs and copper ions leads to high selectivity of such NPs for copper in the presence of the other endogenous metal ions. Furthermore, ZnPB NPs are highly water-dispersible and noncytotoxic and can be readily internalized by cells to target intracellular copper ions for selective copper detoxification, suggesting their potential application as a new-generation treatment for WD.

The emerging role of neuroimmune interactions in atopic dermatitis and itch.

Millions of people globally suffer from allergic diseases, and the cases have been rising in the past decades. One of the major manifestations of allergic diseases is itch, which is an unpleasant symptom that triggers the urge to scratch and greatly affects the quality of life. Thus, research on how sensation of itch is detected/transmitted from the contact of the allergen to the nervous system is crucial in mitigating itch. Recent studies have attempted to elucidate the mechanisms of itch in allergic diseases. Here, we aim to review the endogenous mediators released from immune/nonimmune skin cells (that are indirectly involved in the propagation of itch) and the sensory neurons that express receptors for these itch mediators that are associated with direct transmission of itch in cutaneous allergic diseases. As the mechanisms for allergic itch become clearer, new therapeutic approaches to relieve itch are likely to be developed. Recent clinical trials are testing numerous compounds that target the endogenous mediators and their receptors. These studies provide the possibility of more effective itch treatment for allergic diseases.

Primary orbital extraskeletal osteosarcoma.

The authors describe a case of orbital extraskeletal osteosarcoma. A 78-year-old man with a history of rheumatoid arthritis on long-term corticosteroids had a left medial canthal basal cell carcinoma excision followed by adjuvant radiotherapy. Twelve months later, he re-presented with a large rapidly-growing calcified mass involving his left medial canthus and orbit. An incisional biopsy demonstrated an infiltrate of atypical cells exhibiting mitotic activity with a rosette arrangement around partially calcified necrotic tissue. The patient underwent orbital exenteration and a partial maxillectomy. Histopathology demonstrated an extraskeletal osteosarcoma. It is extremely rare for this tumor to occur in the orbit. Immunosuppression and adjuvant radiotherapy were possible predisposing factors in the development of this tumor. Extraskeletal osteosarcoma (ESOS) is a malignant tumour that produces osteoid. It develops in soft tissue without continuity to bone or periosteum. It is rare and comprises fewer than 5% of all osteosarcomas. Extraskeletal osteosarcoma primarily affects patients above 50 years of age and has a poor prognosis. In this report, we describe the clinical, radiologic, and pathologic records of a rare case of primary ESOS of the orbit.

Cranial nerve involvement in varicella zoster virus after renal transplantation.

This case describes a 60-year-old immunosuppressed man after renal transplant who presented to the emergency department with 1 week of generalized weakness, a 20-lb unintentional weight loss, sore throat, dysarthria, dysphagia, cough, and shortness of breath. Additionally, he developed tinnitus, headaches, photophobia, and neck stiffness. He underwent an extensive workup including a lumbar puncture with meningitis and encephalitis panel, which was positive for varicella zoster virus. He never developed a dermatomal vesicular rash but had persistent dysphagia and aspiration and was eventually diagnosed with Vernet syndrome. This case highlights theories for the increase in varicella zoster virus encephalitis cases causing neurologic symptoms and proposes that this trend is likely to continue.

Varicella-zoster virus causing a ring-like cerebral lesion in AIDS.

We report a 50-year-old man with a possible stroke 3 months earlier, recurrent shingles outbreaks, and male-who-has-sex-with-men status who presented to the emergency department with worsening confusion, lower-extremity weakness, gait imbalance, and incontinence. Given his clinically immunocompromised state, the patient was started on intravenous acyclovir. A human immunodeficiency virus (HIV) test returned positive, magnetic resonance imaging of the brain showed a ring-enhancing lesion, and lumbar puncture was positive for varicella-zoster virus. Eventual brain biopsy of the ring-enhancing lesion confirmed vasculitis. This case highlights the broad differential of a ring-enhancing lesion and the importance of early HIV screening.

Single-cell RNA sequencing of equine mesenchymal stromal cells from primary donor-matched tissue sources reveals functional heterogeneity in immune modulation and cell motility.

BACKGROUND: The efficacy of mesenchymal stromal cell (MSC) therapy is thought to depend on the intrinsic heterogeneity of MSC cultures isolated from different tissue sources as well as individual MSCs isolated from the same tissue source, neither of which is well understood. To study this, we used MSC cultures isolated from horses. The horse is recognized as a physiologically relevant large animal model appropriate for translational MSC studies. Moreover, due to its large size the horse allows for the simultaneous collection of adequate samples from multiple tissues of the same animal, and thus, for the unique collection of donor matched MSC cultures from different sources. The latter is much more challenging in mice and humans due to body size and ethical constraints, respectively. METHODS: In the present study, we performed single-cell RNA sequencing (scRNA-seq) on primary equine MSCs that were collected from three donor-matched tissue sources; adipose tissue (AT), bone marrow (BM), and peripheral blood (PB). Based on transcriptional differences detected with scRNA-seq, we performed functional experiments to examine motility and immune regulatory function in distinct MSC populations. RESULTS: We observed both inter- and intra-source heterogeneity across the three sources of equine MSCs. Functional experiments demonstrated that transcriptional differences correspond with phenotypic variance in cellular motility and immune regulatory function. Specifically, we found that (i) differential expression of junctional adhesion molecule 2 (JAM2) between MSC cultures from the three donor-matched tissue sources translated into altered cell motility of BM-derived MSCs when RNA interference was used to knock down this gene, and (ii) differences in C-X-C motif chemokine ligand 6 (CXCL6) expression in clonal MSC lines derived from the same tissue source correlated with the chemoattractive capacity of PB-derived MSCs. CONCLUSIONS: Ultimately, these findings will enhance our understanding of MSC heterogeneity and will lead to improvements in the therapeutic potential of MSCs, accelerating the transition from bench to bedside.

Secreted sphingomyelins modulate low mammary cancer incidence observed in certain mammals.

Determining mechanisms that naturally protect species from developing cancer is critical in order to prevent and treat cancer. Here, we describe a novel cancer-suppressing mechanism, via the secretion of bioactive factors by mammary cells, that is present in domesticated mammals with a low mammary cancer incidence. Specifically, these bioactive factors induced triple-negative breast cancer cell (TNBC) death in vitro and reduced tumorigenicity in a xenograft TNBC mouse model in vivo. RNA deep sequencing showed significant downregulation of genes associated with breast cancer progression in secretome-cultured TNBC cells. Further in-depth multi-omics analysis identified sphingomyelins as key secreted factors, and their role was confirmed via inhibition of the sphingomyelin signaling pathway. We speculate that secreted sphingomyelins in the mammary gland of mammals with a naturally low incidence of mammary cancer mediate the elimination of cancer cells. This study contributes to the growing list of protective mechanisms identified in cancer-proof species.

Long-term microstructural changes following epikeratophakia: in vivo confocal microscopy study.

The unilateral epikeratophakic eye of a 20-year-old woman with a history of congenital cataracts was examined using laser scanning in vivo confocal microscopy 17 years after transplantation. In vivo confocal microscopy demonstrated a reduced keratocyte density in the grafted lenticule and the host stroma, with unusual elongated and tortuous hyperreflective branching structures in the anterior stroma of the host cornea. The sub-basal nerve plexus was present in the lenticule, although with a reduced nerve density. The appearance of the host endothelium was similar to that observed in Fuchs endothelial dystrophy. Dramatic microstructural changes were observed in almost all layers of the cornea 17 years after epikeratophakia. Although no longer performed as routine practice, in vivo confocal microscopy examination of epikeratophakia has provided fascinating insight into the potential corneal adaptations at a cellular level.

Citation analysis of the most influential authors and ophthalmology journals in the field of cataract and corneal refractive surgery 2000-2004.

PURPOSE: To identify the most published authors on the topics of 'cataract' and 'LASIK', the journals in which they publish, and the citation patterns of the most-cited articles by these authors over a 5-year publication period. METHODS: Science Citation Index Expanded (SCI) was used to identify the 30 most-published authors in 'cataract' and 'laser in situ keratomileusis' (LASIK) (2000-2004 inclusive). SCI was subsequently used to analyse the recorded articles for each author in terms of source journal, the most commonly cited articles and citation source. RESULTS: Of the 30 most-published authors in the fields of cataract and LASIK, the USA was the most well-represented source country, accounting for 33%; 20% were from Australia, and 17% from Austria. Germany and Japan each contributed 7%. Eighty per cent of the publications produced by these 30 authors (2000-2004) were in 10 journals, of which the Journal of Cataract and Refractive Surgery (JCRS) published more than one-third. Of the three most-cited articles for each author, the greatest number were published in JCRS (35.6%). The citation count of the articles had a weak correlation to the journal impact factor of the source journal; however, the self-citation rate of these articles did not. CONCLUSIONS: The USA and Australia together were the source of more than half of the most-published authors on cataract and LASIK and the majority of articles published by the 30 most prolific authors were published in only 10 journals. The impact factors of the publication journals preferred by these authors are influenced by the article citation counts, not vice versa.

Infectious endophthalmitis: clinical features, management and visual outcomes.

AIM: To identify the clinical features and outcomes of infectious endophthalmitis in New Zealand. METHODS: A retrospective review was performed on all patients presenting at Auckland Public Hospital with presumed infectious endophthalmitis between 1996 and 2004. RESULTS: One hundred and six patients were diagnosed with infectious endophthalmitis over the 9-year study period. More than half the infections occurred in the perioperative setting (58.5%), with the next most common group being patients with a history of ocular trauma (18.9%). Endogenous endophthalmitis accounted for 16.0% of the cases while a small percentage arose from other causes. The mean interval between the onset of symptoms and presentation was 4.2 +/- 7.9 days. There was no significant difference in outcomes between clinical settings (P = 0.616) or between gram-positive, gram-negative and fungal infections (P = 0.090). Evisceration/enucleation was more likely in Pacific peoples and those with poor presenting visual acuity. CONCLUSIONS: The most common clinical scenario for patients presenting with presumed infectious endophthalmitis in this series was in the perioperative setting. We did not find that the prognosis was influenced by the microbiological isolate or clinical setting. However, those patients presenting with poor acuities typically had the worst outcomes. Pacific ethnicity was also associated with increased rate of complications.

Identifying Additional Risk Factors for Thrombosis and Pregnancy Morbidities Among Antiphospholipid Antibodies Carriers.

The evaluation of thrombotic and pregnancy risks associated with antiphospholipid antibodies (aPL)in individual patients without antiphospholipid syndrome (APS) clinical manifestation is challenging. Our aim is to identify additional risk factors or potential candidate "second hits" for APS clinical events in a large cohort of ethnically diverse aPL-positive patients. We included 219 consecutive aPL-positive patients who attended clinic at our institution. All patients had at least 1 persistent high titer (≥99 percentiles) aPL. Independent risk factors for thrombosis and pregnancy morbidities among patients with positive aPL were evaluated. When assessing risk factors associated with pregnancy morbidities, only female controls of reproductive age (age ≤45) were used. Pearson χ2 analysis and multivariable logistic regression were used to evaluate correlation between different risk factors and clinical manifestations. Of the 219 aPL-positive patients, 120 (54.8%) patients had criteria APS clinical manifestations and 99 patients did not. A total of 46.1% were Caucasian, 26.4% of African descent, 16.9% Hispanic, 1.8% Asian, and 8.7% were unspecified. Among traditional risk factors and signs of endothelial injury, only hypertension demonstrated an independent association with arterial thrombosis (odds ratio [OR] = 3.826, 95% confidence interval [CI]: 1.597-9.167, P = .0026), and lupus anticoagulant (LA) demonstrated an independent association with venous thrombosis (OR = 3.308, 95% CI: 1.544-7.085, P = .0021). None of the evaluated risk factors demonstrated a significant association with pregnancy morbidity. Hypertension is a potential predictor of arterial thrombosis and the presence of LA is a potential predictor of venous thrombosis in aPL-positive patients.

Relationship between retinal nerve fiber layer and visual field sensitivity as measured by optical coherence tomography in chiasmal compression.

PURPOSE: To investigate the spatial relationship between retinal nerve fiber layer (RNFL) thickness measured with optical coherence tomography (OCT) and visual field sensitivity (VFS) measured by standard automated perimetry (SAP) in chiasmal compression. METHODS: Twenty-six patients with chiasmal compression were enrolled. RNFL thickness was measured with the StratusOCT and VFS with SAP (Humphrey Field Analyzer; both from Carl Zeiss Meditec, Dublin, CA). Relationships between RNFL thickness (in clock hours, hemifields, and sectors) and VFS (zones were divided into hemifields, quadrants, and sectors based on a validated visual field map) expressed in a decibel scale and 1/lambert (L) were evaluated by linear and nonlinear regression. Coefficients of determination (R(2)) were calculated by using a multivariate model. RESULTS: Average RNFL thickness correlated strongly with pattern standard deviation (PSD; R = 0.622) and mean deviation (MD; R = 0.413). The four strongest correlations were between the 8 o'clock OCT position (temporal disc), with the temporal hemifield (R = -0.813), the superotemporal quadrant (R = -0.847), the inferotemporal quadrant (R = -0.855), and the field sector representing the papillomacular bundle (R = -0.809). Coefficients of determination improved significantly in all sectors when time since surgery was included in the regression model-most notably, average thickness and 1/L (R(2) = 0.35-0.49), the decibels (R(2) = 0.31-0.47), and the temporal sector (R(2) = 0.44-0.57). CONCLUSIONS: This is the first study to compare the structure-function correlation of RNFL measured by OCT with SAP in patients with chiasmal compression. RNFL is topographically related globally and sectorally to decreased SAP, with the temporal sectors showing the strongest correlations. The correlation between RNFL and VFS strengthens as the time from surgical intervention increases.

Multifocal malignant optic glioma of adulthood presenting as acute anterior optic neuropathy.

We report a 63-year-old, previously healthy female patient with glioblastoma multiforme of the optic nerve and chiasm presenting as acute anterior optic neuropathy. She presented with a 3-week history of progressively increasing headaches, retrobulbar pain, rapidly progressive visual loss in the right eye and blurred vision in the left eye. Early clinical examination revealed right optic disc swelling and she was initially diagnosed with demyelinating optic neuritis. Her clinical course deteriorated with total visual loss in the right eye and progressive visual loss in the left eye despite treatment with intravenous (IV) methylprednisone and IV immunoglobulins. MRI revealed enhancement of the right optic nerve and optic chiasm, with multiple periventricular hyperintense foci. Six weeks later, the patient presented with left facial palsy and left hemiparesis. Follow-up MRI showed multiple enhancing lesions in addition to the previous lesions involving right lentiform and right thalamic nucleus, right cerebral peduncle, right temporal and parietal lobes. Although the optic nerve biopsy was inconclusive, the brain biopsy revealed glioblastoma multiforme. This report demonstrated that malignant glioma of adulthood may be multicentric and may mimic optic neuritis clinically, which might help explain the difficulties in diagnosis.