Corneal pannus, Herbert's pits and conjunctival inflammation in older children in Papua New Guinea.

PURPOSE: The prevalence of trachomatous inflammation-follicular (TF) in Papua New Guinea (PNG) suggests antibiotic mass drug administration (MDA) is needed to eliminate trachoma as a public health problem but the burden of trichiasis is low. As a result, WHO issued bespoke recommendations for the region. If ≥ 20% of 10-14-year-olds have both any conjunctival scarring (C1 or C2 or C3) and corneal pannus and/or Herbert's pits, MDA should be continued. Equally, if ≥ 5% of that group have both moderate/severe conjunctival scarring (C2 or C3) and corneal pannus and/or Herbert's pits, MDA should be continued. METHODS: We identified 14 villages where > 20% of 1-9-year-olds had TF during baseline mapping undertaken 4 years and 1 month previously. Every child aged 10-14 years in those villages was eligible to be examined for clinical signs of corneal pannus, Herbert's pits and conjunctival scarring. A grading system that built on existing WHO grading systems was used. RESULTS: Of 1,293 resident children, 1,181 (91%) were examined. Of 1,178 with complete examination data, only one (0.08%) individual had concurrent scarring and limbal signs. CONCLUSIONS: The WHO-predefined criteria for continuation of MDA were not met. Ongoing behavioural and environmental improvement aspects of the SAFE strategy may contribute to integrated NTD control. Surveillance methods should be strengthened to enable PNG health authorities to identify future changes in disease prevalence.

Electron-Withdrawing meso-Substituents Turn On Magneto-Optical Activity in Porphyrins.

A series of square planar metalloporphyrins (M(TPP), TPP is 5,10,15,20-tetraphenylporphyrin and M(TPFPP), TPFPP is 5,10,15,20-tetrapentafluorophenylporphyrin; M is Zn2+, Ni2+, Pd2+, or Pt2+) with distinct meso-substituents were prepared, and their magneto-optical activity (MOA) was characterized by magnetic circular dichroism (MCD) and magneto-optical rotary dispersion spectroscopy (MORD; also known as Faraday rotation spectroscopy). MOA is crucial in the development of next-generation magneto-optical devices and quantum computing. The data show that the presence of meso-pentafluorophenyl substituents results in significant increase in MOA in comparison to the homologous phenyl group. Differences in the MOA of these metalloporphyrins are rationalized using the Gouterman four-orbital model and pave the way for rational design of improved and tailorable magneto-optical materials.

Characterizing Program Delivery for an Effective Multicomponent Sepsis Recovery Intervention.

Rationale: A recent randomized controlled trial revealed that a multicomponent sepsis transition and recovery (STAR) program delivered through specialized nurse navigators was effective in reducing a composite of 30-day readmission and mortality. Better understanding of patterns of care provided by the STAR program is needed to promote implementation and dissemination of this effective program.Objectives: This study characterizes individual care activities and distinct "packages" of care delivered by the STAR program.Methods: We performed a secondary analysis of data from the intervention arm of the IMPACTS (Improving Morbidity during Post-Acute Care Transitions for Sepsis) randomized controlled trial, conducted at three urban hospitals in the southeastern United States from January 2019 to March 2020. We used a structured data collection process to identify STAR nurse navigator care activities from electronic health record documentation. We then used latent class analysis to identify groups of patients receiving distinct combinations of intervention components. We evaluated differences in patient characteristics and outcomes between groups receiving distinct intervention packages.Results: The 317 sepsis survivors enrolled into the intervention arm of the IMPACTS trial received one or more of nine unique care activities delivered by STAR nurse navigators (care coordination, health promotion counseling, emotional listening, symptom management, medication management, chronic disease management, addressing social determinants of health, care setting advice and guidance, and primary palliative care). Patients received a median of three individual care activities (interquartile range, 2-5). Latent class analysis revealed four distinct packages of care activities delivered to patients with different observable characteristics and different frequency of 30-day readmission and mortality.Conclusions: We identified nine care activities delivered by an effective STAR program and four distinct latent classes or packages of intervention delivery. These results can be leveraged to increase widespread implementation and provide targets to augment future program delivery.

Cardiac myxomas: causes, presentations, diagnosis, and management.

Cardiac myxomas (CM) are one of the most common benign tumors which are typical in adults with a yearly incidence of 0.5-1 case per million individuals. This review article includes discussions based on existing literature on the role of interleukin interactions in the pathophysiology of cardiac myxoma which can lead to embolic complications, aneurysms, and CNS involvement. The objective of this narrative review was to study the variable clinical presentations of cardiac myxoma, its detection and diagnosis involving multiple modalities like genetic and hematological testing, echocardiography, CT, and MRI, of which transoesophageal echocardiogram shows excellent precision with a 90% to 96% accuracy in diagnosing CM. Individuals with the Carney complex are prone to such neoplasia. Cardiac myxomas are challenging to diagnose due to the ambiguity of their differential with thrombi. Myxomas can also be diagnosed by tumor markers like interleukin-6 and endothelial growth factors. The management of CM includes surgical excision like median sternotomy and robotic minimally invasive surgery. The use of robotic surgery in CM increased from 1.8% in 2012 to 15.1% in 2018. Tumor recurrences are uncommon but can occur due to inadequate surgical resection.

Tapirira guianensis is Selectively Cytotoxic, Induces Apoptosis to the Glioblastoma and Decreases Tumor Growth and Angiogenesis in vivo.

Glioblastoma is the most frequent primary malignant brain tumor without effective treatment, which makes this work extremely relevant. The study of the bioactive compounds from medicinal plants plays an important role in the discovery of new drugs.This research investigated the constituents of Tapirira guianensis and its antitumor potential (in vitro and in vivo) in glioblastoma. The T. guianensis extracts were characterized by mass spectrometry. The ethyl acetate partition (01ID) and its fractions 01ID-F2 and 01ID-F4 from T. guianensis showed potential antitumor treatment evidenced by selective cytotoxicity for GAMG with IC50 14.1 µg/mL, 83.07 µg/mL, 59.27 µg/mL and U251 with IC50 25.92 µg/mL, 37.3 µg/mL and 18.84 µg/mL. Fractions 01ID-F2 and 01ID-F4 were 10 times more selective when compared to TMZ and 01ID for the two evaluated cell lines. T. guianensis also reduced matrix metalloproteinases 2 - 01ID-F2 (21.84%), 01ID-F4 (29.6%) and 9 - 01ID-F4 (73.42%), ID-F4 (53.84%) activities, and induced apoptosis mainly through the extrinsic pathway. Furthermore, all treatments significantly reduced tumor size (01ID p < 0,01, 01ID-F2 p < 0,01 and 01ID-F4 p < 0,0001) and caused blood vessels to shrink in vivo. The present findings highlight that T. guianensis exhibits considerable antitumor potential in preclinical studies of glioblastoma. This ability may be related to the phenolic compounds and sesquiterpene derivatives identified in the extracts. This study deserves further in vivo research, followed by clinical investigation.

Methicillin-Resistant Staphylococcus aureus Colonization in Intensive Care and Burn Units: A Narrative Review.

Methicillin-resistant Staphylococcus aureus (MRSA) is a common hospital-acquired pathogen and can cause a wide spectrum of infections. In recent years, MRSA has emerged as a significant public health concern, particularly in hospitals. Intensive care units (ICUs) and burn units are high-risk areas for hospital-acquired MRSA infections, which can lead to increased morbidity, mortality, and healthcare costs. MRSA exhibits resistance to multiple antibiotics and can cause serious infections, including but not limited to pneumonia, endocarditis, and cutaneous infections, particularly in patients with burn injuries. The prevention and effective management of MRSA infections in both burn patients and those in ICUs is crucial, with strategies like isolation, regular disinfection, and prophylactic intranasal mupirocin. Early diagnosis of MRSA infection and isolation of patients is vital to prevent the spread of MRSA. Implementation of prevention strategies faces many challenges, such as cost, and the most successful infection management practices are still debated. This review has highlighted the substantial concern of MRSA colonization in intensive care and burn units. MRSA poses a significant risk to vulnerable patients, influenced by factors such as compromised immunity and invasive procedures. The prevalence of MRSA colonization varies, influenced by regional factors and infection control practices. Combating MRSA requires a multifaceted approach, including stringent infection control measures and education for healthcare workers and patients. As we move forward, continued research and cooperation are essential to reduce the burden of MRSA in these critical care settings.

Congenital subglottic cyst: a rare cause for sudden airway compromise in a newborn.

A full-term infant developed stridor, respiratory distress and hypercarbia shortly after birth requiring urgent airway intervention. The patient underwent urgent intubation via rigid bronchoscopy. The diagnosis of congenital subglottic cyst was made. The cyst was decompressed and the patient was extubated the following day. On repeat laryngoscopy 1 month later, there was no residual disease and the patient remained symptom free. Congenital subglottic cysts are extremely rare and the diagnosis can be either missed or misdiagnosed with more common causes of stridor, such as laryngomalacia. Subglottic cysts may cause total airway obstruction and even death if they are large enough and not treated immediately.

Apolipoprotein E4 as a Novel Treatment Target for Alzheimer's Disease.

The importance of Alzheime's Disease (AD) research has never been greater from a worldwide perspective with the disease becoming increasingly prevalent with life expectancy on the rise. One emerging factor that has presented as a serious risk that still requires more research and understanding is the role and effects of Apolipoprotein E4 (ApoE4). When present, individuals are three times more likely to develop AD in their lifetime. This is due to ApoE4's ability to not only increase amyloid beta plaque aggregation ApoE4 also increases hyperphosphorylation of tau causing neurofibrillary tangles. These two factors are the well-known hallmarks for AD, which increase the importance for ApoE4 research as it affects both major aspects. Treatment for AD has always been an issue due to a variety of factors with only a few approved for use today. These approved treatments are only to ease and supress symptoms rather than treating the disease. Dementia symptoms such as memory loss, language problems, motor skills, irritability and paranoia are all symptoms that destroy patient's ability to function in their communities. Inhibiting ApoE4 and reducing its toxic effects is a promising theory that has the ability to extend AD patients' lifespan and prolong capable brain function limiting brain tissue degradation.

Predicting cardiac adverse events in patients receiving immune checkpoint inhibitors: a machine learning approach.

BACKGROUND: Treatment with immune checkpoint inhibitors (ICIs) has been associated with an increased rate of cardiac events. There are limited data on the risk factors that predict cardiac events in patients treated with ICIs. Therefore, we created a machine learning (ML) model to predict cardiac events in this at-risk population. METHODS: We leveraged the CancerLinQ database curated by the American Society of Clinical Oncology and applied an XGBoosted decision tree to predict cardiac events in patients taking programmed death receptor-1 (PD-1) or programmed death ligand-1 (PD-L1) therapy. All curated data from patients with non-small cell lung cancer, melanoma, and renal cell carcinoma, and who were prescribed PD-1/PD-L1 therapy between 2013 and 2019, were used for training, feature interpretation, and model performance evaluation. A total of 356 potential risk factors were included in the model, including elements of patient medical history, social history, vital signs, common laboratory tests, oncological history, medication history and PD-1/PD-L1-specific factors like PD-L1 tumor expression. RESULTS: Our study population consisted of 4960 patients treated with PD-1/PD-L1 therapy, of whom 418 had a cardiac event. The following were key predictors of cardiac events: increased age, corticosteroids, laboratory abnormalities and medications suggestive of a history of heart disease, the extremes of weight, a lower baseline or on-treatment percentage of lymphocytes, and a higher percentage of neutrophils. The final model predicted cardiac events with an area under the curve-receiver operating characteristic of 0.65 (95% CI 0.58 to 0.75). Using our model, we divided patients into low-risk and high-risk subgroups. At 100 days, the cumulative incidence of cardiac events was 3.3% in the low-risk group and 6.1% in the high-risk group (p<0.001). CONCLUSIONS: ML can be used to predict cardiac events in patients taking PD-1/PD-L1 therapy. Cardiac risk was driven by immunological factors (eg, percentage of lymphocytes), oncological factors (eg, low weight), and a cardiac history.

Mechanistic Modelling of Slow and Fast NHEJ DNA Repair Pathways Following Radiation for G0/G1 Normal Tissue Cells.

Mechanistic in silico models can provide insight into biological mechanisms and highlight uncertainties for experimental investigation. Radiation-induced double-strand breaks (DSBs) are known to be toxic lesions if not repaired correctly. Non-homologous end joining (NHEJ) is the major DSB-repair pathway available throughout the cell cycle and, recently, has been hypothesised to consist of a fast and slow component in G0/G1. The slow component has been shown to be resection-dependent, requiring the nuclease Artemis to function. However, the pathway is not yet fully understood. This study compares two hypothesised models, simulating the action of individual repair proteins on DSB ends in a step-by-step manner, enabling the modelling of both wild-type and protein-deficient cell systems. Performance is benchmarked against experimental data from 21 cell lines and 18 radiation qualities. A model where resection-dependent and independent pathways are entirely separated can only reproduce experimental repair kinetics with additional restraints on end motion and protein recruitment. However, a model where the pathways are entwined was found to effectively fit without needing additional mechanisms. It has been shown that DaMaRiS is a useful tool when analysing the connections between resection-dependent and independent NHEJ repair pathways and robustly matches with experimental results from several sources.

Closed reduction of glenohumeral dislocations with associated tuberosity fracture in the emergency department is safe.

AIM: A fracture of the tuberosity is associated with 16% of glenohumeral dislocations. Extension of the fracture into the humeral neck can occur during closed manipulation, leading some to suggest that all such injures should be managed under general anaesthesia in the operating theatre. The purpose of this study was to establish the safety of reduction of glenohumeral dislocations with tuberosity fractures in the emergency department (ED). PATIENTS AND METHODS: We reviewed 188 consecutive glenohumeral dislocations with associated tuberosity fractures identified from a prospective orthopaedic trauma database. Patient demographics, injury details, emergency department management and complications were recorded. The method of reduction, sedation, grade of clinician and outcome were documented. RESULTS: The mean age was 61 years (range 18-96 years) with 79 males and 109 females. The majority of injuries (146, 78%) occurred after a fall from standing height. Closed reduction under sedation in the ED was successful in 162 (86%) cases. Of the remainder, 22 (11%) failed closed reduction under sedation and subsequently went to theatre and 6 (3%) were deemed not suitable for ED manipulation. At presentation 35 (19%) patients had a nerve injury, of which 29 (90%) resolved spontaneously. Two iatrogenic fractures occurred during close manipulation, one in the ED and the other in the operating theatre. Therefore, the risk of iatrogenic propagation of the fracture into the proximal humerus neck was 0.5% if the reduction was performed in the ED, and 1% over-all. More than two attempted reductions predicted a failed ED reduction (P = 0.001). CONCLUSION: Closed reduction of glenohumeral dislocations with associated tuberosity fractures in the ED is safe, with a rate of iatrogenic fracture of 1%. These injuries should be managed by those with appropriate experience only after two adequate radiographic views. In cases where there is ambiguity over the integrity of the humeral neck, reduction should be delayed until multiplanar CT imaging has been obtained.

Trachoma, Anti-Pgp3 Serology, and Ocular Chlamydia trachomatis Infection in Papua New Guinea.

BACKGROUND: In Melanesia, the prevalence of trachomatous inflammation-follicular (TF) suggests that public health-level interventions against active trachoma are needed. However, the prevalence of trachomatous trichiasis is below the threshold for elimination as a public health problem and evidence of conjunctival infection with trachoma's causative organism (Chlamydia trachomatis [CT]) is rare. Here, we examine the prevalence of ocular infection with CT and previous exposure to CT in three evaluation units (EUs) of Papua New Guinea. METHODS: All individuals aged 1-9 years who were examined for clinical signs of trachoma in 3 Global Trachoma Mapping Project EUs were eligible to take part in this study (N = 3181). Conjunctival swabs were collected from 349 children with TF and tested by polymerase chain reaction to assess for ocular CT infection. Dried blood spots were collected from 2572 children and tested for anti-Pgp3 antibodies using a multiplex assay. RESULTS: The proportion of children with TF who had CT infection was low across all 3 EUs (overall 2%). Anti-Pgp3 seroprevalence was 5.2% overall and there was no association between anti-Pgp3 antibody level and presence of TF. In 2 EUs, age-specific seroprevalence did not increase significantly with increasing age in the 1- to 9-year-old population. In the third EU, there was a statistically significant change with age but the overall seroprevalence and peak age-specific seroprevalence was very low. CONCLUSIONS: Based on these results, together with similar findings from the Solomon Islands and Vanuatu, the use of TF to guide antibiotic mass drug administration decisions in Melanesia should be reviewed.

Percutaneous reduction and fixation of low energy Lisfranc injuries results in better outcome compared to open reduction and internal fixation: Results from a matched case-control study with minimum 12 months follow up.

BACKGROUND: Percutaneous fixation of Lisfranc injuries is potentially less invasive to traditional open techniques but evidence of any clinical benefit is lacking. The aim of this study is to compare the clinical outcomes of percutaneous reduction and internal fixation (PRIF) of low energy Lisfranc injuries with a matched, control group of patients treated with ORIF. METHODS: Over a seven-year period (2012-2019), 16 consecutive patients with a low energy Lisfranc injury (Myerson B2-type) were treated with PRIF. Patient demographics, injury mechanism and radiological outcomes were recorded within a prospectively maintained database at the institution. This study sample was matched for age, sex and mechanism of injury to a control group of 16 patients with similar low energy Lisfranc injuries (Myerson B2-type) treated with ORIF. Clinical outcome was compared using the American Orthopaedic Foot and Ankle Society (AOFAS) midfoot score and Manchester Oxford Foot Questionnaire (MOXFQ). RESULTS: At a mean follow up of 43 months (95% CI 35.6 - 50.4), both the AOFAS and MOXFQ scores were significantly higher in the PRIF group compared to the control ORIF group (AOFAS 89.1vs 76.4, p=0.03; MOXFQ 10.0 vs 27.6, p=0.03). There were no immediate postoperative complications in either group. There was no radiological evidence of midfoot osteoarthritis in the PRIF group, three patients in the ORIF group developed midfoot osteoarthritis (p=0.2). CONCLUSIONS: PRIF of low energy Lisfranc injures is a safe, minimally invasive technique and is associated with better mid-term clinical outcomes compared to ORIF.

DNA sequencing of anatomy lab cadavers to provide hands-on precision medicine introduction to medical students.

BACKGROUND: Medical treatment informed by Precision Medicine is becoming a standard practice for many diseases, and patients are curious about the consequences of genomic variants in their genome. However, most medical students' understanding of Precision Medicine derives from classroom lectures. This format does little to foster an understanding for the potential and limitations of Precision Medicine. To close this gap, we implemented a hands-on Precision Medicine training program utilizing exome sequencing to prepare a clinical genetic report of cadavers studied in the anatomy lab. The program reinforces Precision Medicine related learning objectives for the Genetics curriculum. METHODS: Pre-embalmed blood samples and embalmed tissue were obtained from cadavers (donors) used in the anatomy lab. DNA was isolated and sequenced and illustrative genetic reports provided to the students. The reports were used to facilitate discussion with students on the implications of pathogenic genomic variants and the potential correlation of these variants in each "donor" with any anatomical anomalies identified during cadaver dissection. RESULTS: In 75% of cases, analysis of whole exome sequencing data identified a variant associated with increased risk for a disease/abnormal condition noted in the donor's cause of death or in the students' anatomical findings. This provided students with real-world examples of the potential relationship between genomic variants and disease risk. Our students also noted that diseases associated with 92% of the pathogenic variants identified were not related to the anatomical findings, demonstrating the limitations of Precision Medicine. CONCLUSION: With this study, we have established protocols and classroom procedures incorporating hands-on Precision Medicine training in the medical student curriculum and a template for other medical educators interested in enhancing their Precision Medicine training program. The program engaged students in discovering variants that were associated with the pathophysiology of the cadaver they were studying, which led to more exposure and understanding of the potential risks and benefits of genomic medicine.

Abundance of ethnically biased microsatellites in human gene regions.

Microsatellites-a type of short tandem repeat (STR)-have been used for decades as putatively neutral markers to study the genetic structure of diverse human populations. However, recent studies have demonstrated that some microsatellites contribute to gene expression, cis heritability, and phenotype. As a corollary, some microsatellites may contribute to differential gene expression and RNA/protein structure stability in distinct human populations. To test this hypothesis, we investigate genotype frequencies, functional relevance, and adaptive potential of microsatellites in five super-populations (ethnicities) drawn from the 1000 Genomes Project. We discover 3,984 ethnically-biased microsatellite loci (EBML); for each EBML at least one ethnicity has genotype frequencies statistically different from the remaining four. South Asian, East Asian, European, and American EBML show significant overlap; on the contrary, the set of African EBML is mostly unique. We cross-reference the 3,984 EBML with 2,060 previously identified expression STRs (eSTRs); repeats known to affect gene expression (64 total) are over-represented. The most significant pathway enrichments are those associated with the matrisome: a broad collection of genes encoding the extracellular matrix and its associated proteins. At least 14 of the EBML have established links to human disease. Analysis of the 3,984 EBML with respect to known selective sweep regions in the genome shows that allelic variation in some of them is likely associated with adaptive evolution.

Rapid assessment of avoidable blindness in Papua New Guinea: a nationwide survey.

OBJECTIVE: To estimate the prevalence and main causes of blindness and vision impairment in people aged 50 years and older in Papua New Guinea (PNG). DESIGN: National cross-sectional population-based survey in National Capital District (NCD), Highlands, Coastal and Islands regions. METHODS: Adults aged 50 years and above were recruited from 100 randomly selected clusters. Each participant underwent monocular presenting and pinhole visual acuity (VA) assessment and lens examination. Those with pinhole VA<6/12 in either eye had a dilated fundus examination to determine the primary cause of reduced vision. Those with obvious lens opacity were interviewed on barriers to cataract surgery. RESULTS: A total of 4818 adults were examined. The age-adjusted and sex-adjusted prevalence of blindness (VA <3/60), severe vision impairment (SVI, VA <6/60 but ≥3/60), moderate vision impairment (MVI, VA <6/18 but ≥6/60) and early vision impairment (EVI, VA <6/12 but ≥6/18) was 5.6% (95% CI 4.9% to 6.3%), 2.9% (95% CI 2.5% to 3.4%), 10.9% (95% CI 9.9% to 11.9%) and 7.3% (95% CI 6.6% to 8.0%), respectively. The main cause of blindness, SVI and MVI was cataract, while uncorrected refractive error was the main cause of EVI. A significantly higher prevalence of blindness, SVI and MVI occurred in the Highlands compared with NCD. Across all regions, women had lower cataract surgical coverage and spectacle coverage than men. CONCLUSIONS: PNG has one of the highest reported prevalence of blindness globally. Cataract and uncorrected refractive error are the main causes, suggesting a need for increased accessible services with improved resources and advocacy for enhancing eye health literacy.

Rapid assessment of avoidable blindness and diabetic retinopathy in people aged 50 years and older in the National Capital District of Papua New Guinea.

BACKGROUND/AIMS: To conduct an assessment of avoidable blindness, diabetes mellitus and diabetic retinopathy (DR) in adults aged 50 years and older in the National Capital District (NCD) region of Papua New Guinea (PNG). METHODS: A cross-sectional population-based survey was performed for which 25 clusters of 50 people aged ≥50 years were randomly selected from the NCD region. The standardised rapid assessment of avoidable blindness (RAAB) with diabetic retinopathy (+DR) methodology was used. Blindness was defined as presenting visual acuity <3/60 in the better eye. Participants were classified as having diabetes if they were known to have diabetes or if their random blood glucose level was ≥200 mg/dL. Dilated fundus examination and Scottish DR grading were performed. RESULTS: In total, 1192 out of 1250 eligible participants (95.4%) were examined. Of these, 7.8% had known or newly diagnosed diabetes. Seventy-one per cent of participants with known diabetes had a blood glucose level ≥200 mg/dL, and 82.9% had never had an ophthalmological examination for DR. Prevalence of DR and/or maculopathy was 46.4%. The age-adjusted and sex-adjusted prevalence of diabetes was estimated at 8.1% (95% CI 5.7% to 10.4%) in the population aged 50 years or older in the NCD region of PNG. CONCLUSIONS: Prevalence of diabetes in adults aged 50 years and older was lower than reported elsewhere in the region, and lower than other RAAB+DR surveys. Despite this, the prevalence of DR is high compared with other RAAB+DR surveys and demonstrates the need for increased awareness and accessibility to eye services for people with diabetes.

The irreversible ERBB1/2/4 inhibitor neratinib interacts with the PARP1 inhibitor niraparib to kill ovarian cancer cells.

The irreversible ERBB1/2/4 inhibitor neratinib has been shown to rapidly down-regulate the expression of ERBB1/2/4 as well as the levels of c-MET, PDGFRα and mutant RAS proteins via autophagic degradation. Neratinib interacted in an additive to synergistic fashion with the approved PARP1 inhibitor niraparib to kill ovarian cancer cells. Neratinib and niraparib caused the ATM-dependent activation of AMPK which in turn was required to cause mTOR inactivation, ULK-1 activation and ATG13 phosphorylation. The drug combination initially increased autophagosome levels followed later by autolysosome levels. Preventing autophagosome formation by expressing activated mTOR or knocking down of Beclin1, or knock down of the autolysosome protein cathepsin B, reduced drug combination lethality. The drug combination caused an endoplasmic reticulum stress response as judged by enhanced eIF2α phosphorylation that was responsible for reducing MCL-1 and BCL-XL levels and increasing ATG5 and Beclin1 expression. Knock down of BIM, but not of BAX or BAK, reduced cell killing. Expression of activated MEK1 prevented the drug combination increasing BIM expression and reduced cell killing. Downstream of the mitochondrion, drug lethality was partially reduced by knock down of AIF, but expression of dominant negative caspase 9 was not protective. Our data demonstrate that neratinib and niraparib interact to kill ovarian cancer cells through convergent DNA damage and endoplasmic reticulum stress signaling. Cell killing required the induction of autophagy and was cathepsin B and AIF -dependent, and effector caspase independent.

Biomechanical Comparison of Intramedullary Fibular Nail Versus Plate and Screw Fixation.

BACKGROUND: Clinical evidence has shown that percutaneous ankle fracture fixation using an intramedullary fibular nail results in good outcomes at 1 year and reduces postoperative wound complications in patients with vulnerable soft tissues. Confirmatory biomechanical evidence of its strength when used to secure a supination external rotation (SER) IV (AO/OTA 44B-type) fracture, compared with traditional plates and screws, is currently lacking. METHODS: Twenty cadaveric lower limbs (10 cadavers) had a SER IV injury surgically created. One leg was randomly allocated to fixation with a fibular nail and the other a lag screw and neutralization plate. A mechanical testing apparatus subjected all lower limbs to an axially loaded supination external rotation force to failure. RESULTS: Superior ultimate torque to failure was demonstrated with a trend toward increased energy absorption in the nail group ( P = .28 and .07, respectively). No difference was demonstrated in angle at failure. All specimens in the plate group lost reduction at the bone-metal interface as a result of screw pullout. In contrast, all specimens in the nail group failed because of disruption of the lateral ligaments. CONCLUSIONS: This study demonstrated greater torque to failure and better maintenance of the fibular construct for the intramedullary fibular nail compared to standard plating. CLINICAL RELEVANCE: These results suggest that the previously documented clinical benefits of the fibular nail are complemented by biomechanical properties that compare favorably to standard techniques.