Macrofilaricidal Activity after Doxycycline Only Treatment of Onchocerca volvulus in an Area of Loa loa Co-Endemicity: A Randomized Controlled Trial

The control of onchocerciasis in Africa relies on the sustained delivery of ivermectin. In certain areas, annual treatments delivered with high population coverage for at least 15–17 years can break transmission. In other endemic settings this strategy alone is thought to be insufficient to eradicate the disease. One of the major limitations occurs in areas that are co-endemic with another filarial infection caused by Loa loa, due to the risk of a rare severe adverse event associated with the rapid killing of L. loa microfilariae in heavily parasitized individuals. There are also concerns over recent evidence of reduced efficacy of ivermectin and the possible development of resistance. An alternative approach is to target the Wolbachia bacterial endosymbionts of Onchocerca volvulus with the antibiotic, doxycycline. In an area of Cameroon co-endemic for onchocerciasis and loiasis we conducted a trial comparing doxycycline with or without ivermectin treatment to ivermectin treatment alone. A six-week course of doxycycline delivers macrofilaricidal and sterilizing activities, which is not dependent upon co-administration of ivermectin. Doxycycline is well tolerated in patients co-infected with moderate intensities of L. loa microfilariae. The trial indicates that anti-wolbachial therapy is a feasible alternative to ivermectin in communities co-endemic for onchocerciasis and loiasis

Removable partial dentures: The clinical need for innovation

Statement of problem: The number of partially dentate adults is increasing, and many patients will require replacement of missing teeth. Although current treatment options also include fixed partial dentures and implants, removable partial dentures (RPDs) can have advantages and are widely used in clinical practice. However, a significant need exists to advance materials and fabrication technologies because of the unwanted health consequences associated with current RPDs. Purpose: The purpose of this review was to assess the current state of and future need for prosthetics such as RPDs for patients with partial edentulism, highlight areas of weakness, and outline possible solutions to issues that affect patient satisfaction and the use of RPDs. Material and methods: The data on treatment for partial edentulism were reviewed and summarized with a focus on currently available and future RPD designs, materials, means of production, and impact on oral health. Data on patient satisfaction and compliance with RPD treatment were also reviewed to assess patient-centered care. Results: Design, materials, ease of repair, patient education, and follow-up for RPD treatment all had a significant impact on treatment success. Almost 40% of patients no longer use their RPD within 5 years because of factors such as sociodemographics, pain, and esthetics. Research on RPD-based treatment for partial edentulism for both disease-oriented and patient-centered outcomes is lacking. Conclusions: Future trials should evaluate new RPD materials and design technologies and include both long-term follow-up and health-related and patient-reported outcomes. Advances in materials and digital design/production along with patient education promise to further the application of RPDs and improve the quality of life for patients requiring RPDs

CyberKnife for hilar lung tumors: report of clinical response and toxicity

<p>Abstract</p> <p>Objective</p> <p>To report clinical efficacy and toxicity of fractionated CyberKnife radiosurgery for the treatment of hilar lung tumors.</p> <p>Methods</p> <p>Patients presenting with primary and metastatic hilar lung tumors, treated using the CyberKnife system with Synchrony fiducial tracking technology, were retrospectively reviewed. Hilar location was defined as abutting or invading a mainstem bronchus. Fiducial markers were implanted by conventional bronchoscopy within or adjacent to tumors to serve as targeting references. A prescribed dose of 30 to 40 Gy to the gross tumor volume (GTV) was delivered in 5 fractions. Clinical examination and PET/CT imaging were performed at 3 to 6-month follow-up intervals.</p> <p>Results</p> <p>Twenty patients were accrued over a 4 year period. Three had primary hilar lung tumors and 17 had hilar lung metastases. The median GTV was 73 cc (range 23-324 cc). The median dose to the GTV was 35 Gy (range, 30 - 40 Gy), delivered in 5 fractions over 5 to 8 days (median, 6 days). The resulting mean maximum point doses delivered to the esophagus and mainstem bronchus were 25 Gy (range, 11 - 39 Gy) and 42 Gy (range, 30 - 49 Gy), respectively. Of the 17 evaluable patients with 3 - 6 month follow-up, 4 patients had a partial response and 13 patients had stable disease. AAT t a median follow-up of 10 months, the 1-year Kaplan-Meier local control and overall survival estimates were 63% and 54%, respectively. Toxicities included one patient experiencing grade II radiation esophagitis and one patient experiencing grade III radiation pneumonitis. One patient with gross endobronchial tumor within the mainstem bronchus developed a bronchial fistula and died after receiving a maximum bronchus dose of 49 Gy.</p> <p>Conclusion</p> <p>CyberKnife radiosurgery is an effective palliative treatment option for hilar lung tumors, but local control is poor at one year. Maximum point doses to critical structures may be used as a guide for limiting toxicities. Preliminary results suggest that dose escalation alone is unlikely to enhance the therapeutic ratio of hilar lung tumors and novel approaches, such as further defining the patient population or employing the use of radiation sensitizers, should be investigated.</p

British signals intelligence and the 1916 Easter Rising in Ireland

Historians for decades have placed Room 40, the First World War British naval signals intelligence organization, at the centre of narratives about the British anticipation of and response to the Easter Rising in Ireland in 1916. A series of crucial decrypts of telegrams between the German embassy in Washington and Berlin, it has been believed, provided significant advance intelligence about the Rising before it took place. This article upends previous accounts by demonstrating that Room 40 possessed far less advance knowledge about the Rising than has been believed, with most of the supposedly key decrypts not being generated until months after the Rising had taken place

Geminivirus-Mediated Delivery of Florigen Promotes Determinate Growth in Aerial Organs and Uncouples Flowering from Photoperiod in Cotton

This article discusses geminivirus-mediated delivery of florigen. Florigen acts as a general growth hormone, advancing determinate growth. The findings extend our understanding of florigen as a general growth hormone and could benefit crop management techniques

Vagal Stimulation Modulates Inflammation through a Ghrelin Mediated Mechanism in Traumatic Brain Injury

Traumatic brain injury (TBI) releases a cascade of inflammatory cytokines. Vagal nerve stimulation (VNS) and ghrelin have known anti-inflammatory effects; furthermore, ghrelin release is stimulated by acetylcholine. We hypothesized VNS decreases post-TBI inflammation through a ghrelin-mediated mechanism. TBI was created in five groups of mice: sham, TBI, TBI/ghrelin, TBI/VNS, and TBI/VNS/ghrelin receptor antagonist (GRa). Serum and tissue ghrelin, and serum TNF-α were measured. Ghrelin increased following VNS 2 h post-TBI compared to sham or TBI. At 6 h, TBI and TBI/VNS/GRa had increased TNF-α compared to sham while TBI/VNS and TBI/ghrelin had TNF-α level comparable to sham. The highest ghrelin was measured in stomach where TBI decreased ghrelin in contrast to an increase by VNS. In conclusion, VNS increased serum ghrelin and decreased TNF-α following TBI. This was abrogated with GRa. Our data suggests that ghrelin plays an important role in the anti-inflammatory effects of VNS following TBI

Radical stereotactic radiosurgery with real-time tumor motion tracking in the treatment of small peripheral lung tumors

<p>Abstract</p> <p>Background</p> <p>Recent developments in radiotherapeutic technology have resulted in a new approach to treating patients with localized lung cancer. We report preliminary clinical outcomes using stereotactic radiosurgery with real-time tumor motion tracking to treat small peripheral lung tumors.</p> <p>Methods</p> <p>Eligible patients were treated over a 24-month period and followed for a minimum of 6 months. Fiducials (3–5) were placed in or near tumors under CT-guidance. Non-isocentric treatment plans with 5-mm margins were generated. Patients received 45–60 Gy in 3 equal fractions delivered in less than 2 weeks. CT imaging and routine pulmonary function tests were completed at 3, 6, 12, 18, 24 and 30 months.</p> <p>Results</p> <p>Twenty-four consecutive patients were treated, 15 with stage I lung cancer and 9 with single lung metastases. Pneumothorax was a complication of fiducial placement in 7 patients, requiring tube thoracostomy in 4. All patients completed radiation treatment with minimal discomfort, few acute side effects and no procedure-related mortalities. Following treatment transient chest wall discomfort, typically lasting several weeks, developed in 7 of 11 patients with lesions within 5 mm of the pleura. Grade III pneumonitis was seen in 2 patients, one with prior conventional thoracic irradiation and the other treated with concurrent Gefitinib. A small statistically significant decline in the mean % predicted DLCO was observed at 6 and 12 months. All tumors responded to treatment at 3 months and local failure was seen in only 2 single metastases. There have been no regional lymph node recurrences. At a median follow-up of 12 months, the crude survival rate is 83%, with 3 deaths due to co-morbidities and 1 secondary to metastatic disease.</p> <p>Conclusion</p> <p>Radical stereotactic radiosurgery with real-time tumor motion tracking is a promising well-tolerated treatment option for small peripheral lung tumors.</p

Crystal Structures of Malonyl-Coenzyme A Decarboxylase Provide Insights into Its Catalytic Mechanism and Disease-Causing Mutations

Malonyl-coenzyme A decarboxylase (MCD) is found from bacteria to humans, has important roles in regulating fatty acid metabolism and food intake, and is an attractive target for drug discovery. We report here four crystal structures of MCD from human, Rhodopseudomonas palustris, Agrobacterium vitis, and Cupriavidus metallidurans at up to 2.3 Å resolution. The MCD monomer contains an N-terminal helical domain involved in oligomerization and a C-terminal catalytic domain. The four structures exhibit substantial differences in the organization of the helical domains and, consequently, the oligomeric states and intersubunit interfaces. Unexpectedly, the MCD catalytic domain is structurally homologous to those of the GCN5-related N-acetyltransferase superfamily, especially the curacin A polyketide synthase catalytic module, with a conserved His-Ser/Thr dyad important for catalysis. Our structures, along with mutagenesis and kinetic studies, provide a molecular basis for understanding pathogenic mutations and catalysis, as well as a template for structure-based drug design

State Policy Responses to COVID-19 in Nursing Homes

Context: COVID-19 has a high case fatality rate in high-risk populations and can cause severe morbidity and high healthcare resource use. Nursing home residents are a high-risk population; they live in congregate settings, often with shared rooms, and require hands-on care. Objectives: To assess state responses to the coronavirus pandemic related to nursing homes in the first half of 2020. Methods: An in-depth examination of 12 states’ responses to the COVID-19 pandemic in nursing homes through June 2020, using publicly reported information such as government decrees, health department guidance, and news reports. Findings: No state emerged as a model of care. All states faced difficulty with limited availability of testing and Personal Protective Equipment (PPE). State-level efforts to increase pay and benefits as a strategy to enable infected staff to quickly physically separate from residents were minimal, and other separation strategies depended on the ability to obtain test results rapidly and on state rules regarding accepting discharged COVID-19 patients into nursing homes. Visitor restrictions to reduce risk were ubiquitous, though based on a slim evidence-base. Limitations: The information used was limited to that which was publicly available. Implications: Overall, the results suggest that the states that handle the ongoing pandemic in nursing homes best will be those that find ways to make sure nursing homes have the resources to follow best practices for testing, PPE, separation, and staffing. Evidence is needed on visitor restrictions and transmission, as states and their citizens would benefit from finding safe ways to relax visitor restrictions