Real-Time Magnetic Resonance Imaging During Convective Gene Therapy Perfusion of the Brain.

This article discusses use of intraoperative MRI in convective gene therapy perfusion.

The Precedent set by Unprecedented Rainfall: Lessons to be Learnt From Disastrous Flooding in Pakistan.

Pakistan has suffered heavy losses due to the torrential monsoon rains of 2022. With obliterated infrastructure and rising disease burden, the nation is still reeling from the dismal aftermath. It is critical to understand that such catastrophes are not a 1-time calamity but are likely to become more frequent with growing severity of the climate crisis. These losses point to a more systemic problem that is a lack of preparedness, and without sustainable long-term measures in place, the nation remains just as vulnerable to the next 'unpredictable' weather contingency. Prior planning and effective allocation of resources can help develop a proactive response to future disasters of this magnitude.

Real-time ultrasound guidance in the endoscopic endonasal resection of a retro-odontoid pannus: Technical note and case illustration.

Background and Objectives: Odontoidectomy is a surgical procedure indicated in the setting of various pathologies, with the main goal of decompressing the ventral brain stem and spinal cord as a result of irreducible compression at the craniovertebral junction. The endoscopic endonasal approach has been increasingly used as an alternative to the transoral approach as it provides a straightforward, panoramic, and direct approach to the odontoid process. In addition, intraoperative ultrasound (US) guidance is a technique that can optimize safety and surgical outcomes in this context. It is used as an adjunct to neuronavigation and provides intraoperative confirmation of decompression of craniovertebral junction structures in real time. The authors aim to present the use and safe application of real-time intraoperative US guidance during endonasal endoscopic resection of a retro-odontoid pannus. Methods: A retrospective chart review of a single case was performed and presented herein as a case report and narrated operative video. Results: A minimally invasive US transducer was used intraoperatively to guide the resection of a retro-odontoid pannus and confirm spinal cord decompression in real time. Postoperative examination of the patient revealed immediate neurological improvement. Conclusions: Intraoperative ultrasonography is a well described and useful modality in neurosurgery. However, the use of intraoperative US guidance during endonasal endoscopic approaches to the craniovertebral junction has not been previously described. As demonstrated in this technical note, the authors show that this imaging modality can be added to the ever-evolving armamentarium of neurosurgeons to safely guide the decompression of neural structures within the craniocervical junction with good surgical outcomes.

Long-term safety of MRI-guided administration of AAV2-GDNF and gadoteridol in the putamen of individuals with Parkinson's disease.

Direct putaminal infusion of adeno-associated virus vector (serotype 2) (AAV2) containing the human glial cell line-derived neurotrophic factor (GDNF) transgene was studied in a phase I clinical trial of participants with advanced Parkinson's disease (PD). Convection-enhanced delivery of AAV2-GDNF with a surrogate imaging tracer (gadoteridol) was used to track infusate distribution during real-time intraoperative magnetic resonance imaging (iMRI). Pre-, intra-, and serial postoperative (up to 5 years after infusion) MRI were analyzed in 13 participants with PD treated with bilateral putaminal co-infusions (52 infusions in total) of AAV2-GDNF and gadoteridol (infusion volume, 450 mL per putamen). Real-time iMRI confirmed infusion cannula placement, anatomic quantification of volumetric perfusion within the putamen, and direct visualization of off-target leakage or cannula reflux (which permitted corresponding infusion rate/cannula adjustments). Serial post-treatment MRI assessment (n = 13) demonstrated no evidence of cerebral parenchyma toxicity in the corresponding regions of AAV2-GDNF and gadoteridol co-infusion or surrounding regions over long-term follow-up. Direct confirmation of key intraoperative safety and efficacy parameters underscores the safety and tissue targeting value of real-time imaging with co-infused gadoteridol and putative therapeutic agents (i.e., AAV2-GDNF). This delivery-imaging platform enhances safety, permits delivery personalization, improves therapeutic distribution, and facilitates assessment of efficacy and dosing effect.

Sex differences in thrombosis as it affects acute ischemic stroke.

Ischemic stroke is a devastating health problem, affecting approximately 800,000 patients in the US every year, making it the leading cause of combined death and disability in the country. Stroke has historically been thought of as predominantly impacting men, however it is becoming increasingly clear that stroke affects women to a greater degree than men. Indeed, women have worse outcomes compared to men following ischemic stroke. Recent clinical advances have shown great promise in acute stroke therapy, with the use of mechanical endovascular thrombectomy (with and without recombinant tissue plasminogen activator; rtPA) greatly improving outcomes. This observation makes it clear that removal of clots and reperfusion, either mechanically or pharmacologically, is critical for improving outcomes of patients following acute ischemic stroke. Despite these promising advances, long-term neurological sequelae persist in the post-stroke population. This review focuses on mechanisms of thrombosis (clot formation) as it pertains to stroke and important sex differences in thrombosis and responses to treatment. Finally, we describe recent data related to new therapeutic approaches to thrombolysis, with a particular focus on von Willebrand Factor (vWF).

Filaggrin mutations in relation to skin barrier and atopic dermatitis in early infancy.

BACKGROUND: Loss-of-function mutations in the skin barrier gene filaggrin (FLG) increase the risk of atopic dermatitis (AD), but their role in skin barrier function, dry skin and eczema in infancy is unclear. OBJECTIVES: To determine the role of FLG mutations in impaired skin barrier function, dry skin, eczema and AD at 3 months of age and throughout infancy. METHODS: FLG mutations were analysed in 1836 infants in the Scandinavian population-based PreventADALL study. Transepidermal water loss (TEWL), dry skin, eczema and AD were assessed at 3, 6 and 12 months of age. RESULTS: FLG mutations were observed in 166 (9%) infants. At 3 months, carrying FLG mutations was not associated with impaired skin barrier function (TEWL > 11·3 g m-2  h-1 ) or dry skin, but was associated with eczema [odds ratio (OR) 2·89, 95% confidence interval (CI) 1·95-4·28; P < 0·001]. At 6 months, mutation carriers had significantly higher TEWL than nonmutation carriers [mean 9·68 (95% CI 8·69-10·68) vs. 8·24 (95% CI 7·97-8·15), P < 0·01], and at 3 and 6 months mutation carriers had an increased risk of dry skin on the trunk (OR 1·87, 95% CI 1·25-2·80; P = 0·002 and OR 2·44, 95% CI 1·51-3·95; P < 0·001) or extensor limb surfaces (OR 1·52, 95% CI 1·04-2·22; P = 0·028 and OR 1·74, 95% CI 1·17-2·57; P = 0·005). FLG mutations were associated with eczema and AD in infancy. CONCLUSIONS: FLG mutations were not associated with impaired skin barrier function or dry skin in general at 3 months of age, but increased the risk for eczema, and for dry skin on the trunk and extensor limb surfaces at 3 and 6 months.

Negative pressure wound therapy in spinal fusion patients.

Post-operative wound complications are some of the most common acute complications following spine surgery. These surgical site infections (SSI) contribute to increased healthcare related costs. Negative pressure wound therapy (NPWT) has long been used for treatment of soft tissue injury or defects. NPWT may reduce the incident of SSI following spinal fusion procedures; however, its potential applications need further clarification. Thus, we conducted a retrospective analysis of two cohorts to compare NPWT to traditional sterile dressings following spinal fusions in regards to post-operative outcomes. Following institutional review board approval, 42 patients who had a NPWT were matched by type of surgery to 42 patients who had traditional dressings. A retrospective chart-review was completed. Outcome measures, particularly SSI and need for reoperation, were analyzed using one-way ANOVA for both univariate and multivariate analysis. When controlled for sex and body-mass index, the use of a NPWT was independently correlated with decreased SSI (P = .035). Superficial dehiscence, seroma, need for additional outpatient care, and need for operative revision were all found to occur at higher rates in the traditional dressing cohort. Closed incisional negative pressure wound therapy provides a cost-effective method of decreasing surgical site infection for posterior elective spine surgeries.

Outbreak investigation of Candida auris at a tertiary care hospital in Karachi, Pakistan.

BACKGROUND: From September 2014, a tertiary care hospital in Karachi, Pakistan, started diagnosing 3-5 cases/month of a yeast locally identified as Saccharomyces spp. resistant to fluconazole. US Centers for Disease Control and Prevention identified the isolates as Candida auris. The Pakistan Field Epidemiology and Laboratory Training Program (FELTP) and the hospital investigated the outbreak from April 2015 to January 2016. OBJECTIVE: The aim of the outbreak investigation was to determine the risk factors and to inform measures to limit the spread of the organism in the hospital. METHODS: Medical records, nursing schedules and infection control practices were reviewed. Sixty-two age- and sex-matched hospital controls from the same wards were identified. RESULTS: Thirty cases (17 males) were identified (mean age = 51.6 years, age range = 2-91 years), case fatality was 53%. Multivariate logistic regression showed that a history of surgery within 90 days of diagnosis, admission to the emergency department and history of chronic kidney disease were significantly associated with C. auris infection. DISCUSSION: This is the report of the outbreak investigation that triggered a global exploration of C. auris as a newly identified multidrug-resistant nosocomial organism, spreading within the hospital, especially among patients with invasive procedures. Unfortunately, we could not identify any specific source of the outbreak nor stop the transmission of the organism.

Direct convective delivery of adeno-associated virus gene therapy for treatment of neurological disorders.

Molecular biological insights have led to a fundamental understanding of the underlying genomic mechanisms of nervous system disease. These findings have resulted in the identification of therapeutic genes that can be packaged in viral capsids for the treatment of a variety of neurological conditions, including neurodegenerative, metabolic, and enzyme deficiency disorders. Recent data have demonstrated that gene-carrying viral vectors (most often adeno-associated viruses) can be effectively distributed by convection-enhanced delivery (CED) in a safe, reliable, targeted, and homogeneous manner across the blood-brain barrier. Critically, these vectors can be monitored using real-time MRI of a co-infused surrogate tracer to accurately predict vector distribution and transgene expression at the perfused site. The unique properties of CED of adeno-associated virus vectors allow for cell-specific transgene manipulation of the infused anatomical site and/or widespread interconnected sites via antero- and/or retrograde transport. The authors review the convective properties of viral vectors, associated technology, and clinical applications.

Defining symptoms of malaria in India in an era of asymptomatic infections.

BACKGROUND: Malaria is a major public health problem in India. Data from surveys totaling 3031 participants at three sites revealed a high proportion of asymptomatic infections, complicating diagnosis. The aim of this study was to identify differences in complaints and symptoms between sites, and factors associated with asymptomatic Plasmodium infections. METHODS: Published data from community-based cross-sectional studies conducted between 2012 and 2015 in Nadiad (Gujarat), Chennai (Tamil Nadu), and Rourkela (Odisha) as part of the Center for the Study of Complex Malaria in India were analysed. Complaints and symptoms were systematically recorded, and Plasmodium infections confirmed using microscopy, rapid diagnostic tests (RDTs), and polymerase chain reaction (PCR). Multivariate analyses were conducted to determine the association between general symptoms and age, season, or gender, and factors associated with asymptomatic Plasmodium infections were assessed. RESULTS: Complaints of any illness were lowest in Chennai (17.7%), 30.6% in Rourkela and 42.7% in Nadiad. Complaints were more often reported for children; gender differences were noted in Rourkela only. In Nadiad, 7.0% of 796 participants were positive for malaria by PCR (32% Plasmodium falciparum); 78.6% had a history of fever or documented fever, 14.3% had other symptoms, and 7.1% were "truly asymptomatic". For Chennai this was 29.2%, 4.2% and 66.7% respectively, with a malaria prevalence of 2.6% by PCR of 928 participants (29% P. falciparum). In Rourkela, with 7.7% of 1307 participants positive for malaria by PCR (82% P. falciparum), the percentages were 35.6%, 24.8% and 39.6%, respectively. In Rourkela, asymptomatic infections were associated with young age and male gender (microscopy or RDT), and with rainy season (PCR). In the same site, participants with Plasmodium vivax were more likely to be asymptomatic (11/18 or 61.1%) than persons with P. falciparum mono-infections (27/78 or 34.6%); gametocytes for P. falciparum were evenly distributed between symptomatic and asymptomatic infections (2/53 vs. 2/49, respectively). The addition of the symptoms "headache", "aches" and "chills" to fever improved the case-definition of symptomatic malaria. CONCLUSION: There were considerable differences in complaints at the three sites in India. Malaria and asymptomatic infections differ by region, indicating that malaria elimination will require localized approaches.

Corrigendum: Novel Genomic and Evolutionary Perspective of Cyanobacterial tRNAs.

[This corrects the article DOI: 10.3389/fgene.2017.00200.].

C1-2 facet disarticulation for correction of iatrogenic cervical kyphosis following occipital-cervical fusion.

The patient is a 69-year-old woman with a history of atlantoaxial instability and cervical pain who underwent an occipital-cervical fusion at an outside hospital. Five days following the procedure she required a PEG tube due to progressive dysphagia. Compared with preoperative imaging, x-ray shows cervical spine hyperextension with a significant decrease in the occipital-C2 angle. A swallow test confirmed aspiration and pharyngeal phase functional impairment. Two-stage surgery consisted of hardware removal, drilling the fused right C1-2 facet, reinstrumentation, and halo placement. The swallowing test confirmed there is no aspiration. We proceeded with rod placement. The patient recovered completely. The video can be found here: https://youtu.be/YzdJrOm46Y4.

Exploring reasons for overuse of contralateral prophylactic mastectomy in Canada.

Background: Contralateral prophylactic mastectomy (cpm) in women with known unilateral breast cancer (bca) has been increasing despite the lack of supportive evidence. The purpose of the present study was to identify the determinants of cpm in women with unilateral bca. Methods: This qualitative descriptive study used semi-structured interviews informed by the Theoretical Domains Framework. We interviewed 74 key informants (surgical oncologists, plastic surgeons, medical oncologists, radiation oncologists, nurses, women with bca) across Canada. Interviews were analyzed using thematic analysis and an analysis for shared and discipline-specific beliefs. Results: In total, 58 factors influencing the use of cpm were identified: 26 factors shared by various health care professional groups, 15 discipline-specific factors (identified by a single health care professional group), and 17 factors shared by women with unilateral bca. Health care professionals identified more factors discouraging the use of cpm (n = 26) than encouraging its use (n = 15); women with bca identified more factors encouraging use of cpm (n = 12) than discouraging its use (n = 5). The factor most commonly identified by health care professionals that encouraged cpm was lack of awareness of existing evidence or guidelines for the appropriate use of cpm (n = 44, 75%). For women with bca, the factor most likely influencing their decision for cpm was wanting a better esthetic outcome (n = 14, 93%). Conclusions: Multiple factors discouraging and encouraging the use of cpm in unilateral bca were identified. Those factors identify potential individual, team, organization, and system targets for behaviour change interventions to reduce cpm.

Intraosseous Orbital Cavernous Hemangioma with Frontal Extension and Dural Involvement.

Primary intraosseous cavernous hemangiomas are rare skull lesions that are not typically known to involve the orbital bones or the dura. We describe a rare case of a fronto-orbital bone cavernous hemangioma with extension into the dura. A 68-year-old female presented with a one-year history of diplopia with discomfort around her left orbit. Magnetic resonance images demonstrated a mass in the left frontal skull extending into the orbital rim. The patient underwent a craniotomy for tumor resection. Dural invasion was found intraoperatively. Gross total resection and reconstruction were achieved. On the postoperative follow-up, the patient was asymptomatic.  Primary calvarial intraosseous cavernous hemangiomas are most commonly located in the frontal and parietal bones. These lesions typically involve only the outer table of the skull. In lesions involving the orbit and dura, excision with cranioplasty can provide symptomatic relief with good cosmetic outcomes.

Acute presentation of spinal gouty arthritis: A case report and review of literature.

BACKGROUND: Gout is an inflammatory arthritis that results from faulty purine metabolism, affecting approximately 4% of adults in the US, and predominately affects people in the fourth decade of life. Further, spinal gout is rarely the first presentation of gout, especially in younger individuals. CASE DESCRIPTION: A 26-year-old male came to the emergency room with acute lower extremity numbness and weakness. The MR demonstrated an enhancing epidural lesion at T6-T8 in the mid-thoracic spine. He subsequently underwent a decompressive laminectomy and fusion at levels T6-T9, resulting in full recovery 1 year later. The pathology demonstrated needle-like monosodium urate crystals consistent with the diagnosis of spinal gouty arthritis. CONCLUSION: Gout rarely initially presents in a young adult in the spine. Here, we reviewed the case of spinal gout in a 26-year-old male who successfully underwent spinal surgery.

Hypertriglyceridemic Pancreatitis: Is Insulin Monotherapy A Feasible Therapeutic Option?

Hypertriglyceridemic pancreatitis (HTGP) is an uncommon but well-established clinical entity. Although the initial clinical features are similar to pancreatitis due to other etiologies, the severity of the disease and the risk of complications are higher in these patients. Prompt diagnosis and appropriate treatment are crucial in patients with hypertriglyceridemia-induced pancreatitis to avoid life-threatening complications. The initial conservative treatment is applied followed by additional specific therapies tailored to decrease serum triglyceride levels. This includes plasmapheresis, insulin, heparin infusion, and hemofiltration. After the acute episode, lifestyle modifications along with hypolipidemic medications should be initiated to prevent further events. Currently, there is paucity of the medical literature directly comparing different treatment modalities. This article illustrates the use of insulin therapy for HTGP as a feasible therapeutic choice. Randomized controlled trials are warranted to outline a generalized and efficient treatment for this serious disorder.

Wolbachia-induced transcription factor GATA4 suppresses ovary-specific genes blastoderm-specific protein 25D and imaginal disc growth factor.

The endosymbiotic bacterium Wolbachia infects a wide array of insect hosts and has been implicated in a range of biological modifications as a consequence of its infection. Previously, it was shown that the transcription factor GATA4 was significantly induced in Wolbachia wMelPop-CLA strain infected Aedes aegypti whole mosquitoes and cells. Here, we provide evidence that this induction also occurs in mosquito ovaries where the ovary-specific genes blastoderm-specific protein 25D (Bsg25D) and imaginal disc growth factor (Disc) are suppressed by Wolbachia. We further demonstrate that transcriptional depletion of GATA4 results in upregulation of both genes and conversely its overexpression leads to downregulation of the genes, suggesting that Wolbachia-induced GATA4 plays a suppressive regulatory role with regards to Bsg25D and Disc expression in mosquito ovaries. When the Disc gene was silenced in mosquitoes, we did not observe any difference in the number of mature ovarian follicles developed between treatment groups. However, we did find a significant delay in the hatching of eggs that had been laid by Disc knockdown mosquitoes.

Cardiovascular Health in St. Louis Bosnian-Americans.

In Bosnia and Herzegovina, cardiovascular disease accounts for nearly 50% of deaths. Cardiovascular health of resettled Bosnian-Americans has not been well-characterized. Our study aimed to quantify cardiovascular risk in Bosnian-Americans in St. Louis, the largest non-European center of resettlement. Seven community screenings focused on Bosnian-Americans were held. Cardiovascular risk was calculated to stratify individuals into low (<10%), moderate (10-20%), and high (>20%) risk. Those with self-reported coronary heart disease (CHD) or risk equivalent were considered high-risk. Two-hundred fifty Bosnian-Americans were screened; 51% (n = 128) consented to the IRB-approved study. Twenty-one percent were smokers, 33% obese, and 33% had hypertension. Excluding risk equivalent individuals, 5.7% of subjects were high-risk, increasing to 26.6% when including high-risk equivalents. Lipid abnormalities include elevated triglycerides (29.0%) and low HDL (50.0%). Compared to general American population studies, Bosnian-Americans have greater ten-year hard CHD risk. A community-based approach identified potential culturally-based lifestyle interventions including diet, exercise, and smoking.