The feasibility, acceptability and appropriateness of screening for frailty in Australians aged 75 years and over attending Australian general practice.

Background Globally, frailty is associated with a high prevalence of avoidable hospital admissions and emergency department visits, with substantial associated healthcare and personal costs. International guidelines recommend incorporation of frailty identification and care planning into routine primary care workflow to support patients who may be identified as pre-frail/frail. Our study aimed to: (1) determine the feasibility, acceptability, appropriateness and determinants of implementing a validated FRAIL Scale screening Tool into general practices in two disparate Australian regions (Sydney North and Brisbane South); and (2) map the resources and referral options required to support frailty management and potential reversal. Methods Using the FRAIL Scale Tool, practices screened eligible patients (aged ≥75years) for risk of frailty and referred to associated management options. The percentage of patients identified as frail/pre-frail, and management options and referrals made by practice staff for those identified as frail/pre-frail were recorded. Semi-structured qualitative interviews were conducted with practice staff to understand the feasibility, acceptability, appropriateness and determinants of implementing the Tool. Results The Tool was implemented by 19 general practices in two Primary Health Networks and 1071 consenting patients were assessed. Overall, 80% of patients (n =860) met the criterion for frailty: 33% of patients (n =352) were frail, and 47% were pre-frail (n =508). They were predominantly then referred for exercise prescription, medication reviews and geriatric assessment. The Tool was acceptable to staff and patients and compatible with practice workflows. Conclusions This study demonstrates that frailty is identified frequently in Australians aged ≥75years who visit their general practice. It's identification, linked with management support to reverse or reduce frailty risk, can be readily incorporated into the Medicare-funded annual 75+ Health Assessment.

Systematic Review and Meta-analysis of Laparoscopic Versus Open Radical Nephrectomy for Paediatric Renal Tumors With Focus on Wilms' Tumor.

OBJECTIVE: To summarize and evaluate the outcomes of laparoscopic radical nephrectomy (LRN) and compare its safety and efficacy with open radical nephrectomy (ORN) in pediatric renal tumors (RT) and Wilms' tumors (WT). BACKGROUND: ORN is the gold standard treatment for pediatric RT, consisting predominantly of WT. LRN is gaining popularity but remains controversial in pediatric surgical oncology. METHODS: A systematic search was performed for all eligible studies on LRN and comparative studies between LRN and ORN in pediatric RT and WT. Meta-analysis, subgroup analysis, and sensitivity analysis were conducted. The main endpoints were cancer-related outcomes and surgical morbidity. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. RESULTS: No levels I to II studies were identified. LRN was feasible in nearly 1 in 5 pediatric RT and WT after neoadjuvant chemotherapy, with pooled mid-term oncological outcomes (<7% local recurrence, >90% event-free survival) comparable with those of ORN. There was no strong evidence of an increased risk of intraoperative tumor spillage, but lymph node harvest was inadequate in LRN. Large tumors crossing the ipsilateral spinal border were associated with a trend for intraoperative complications and positive margins. Pooled complications rate and hospital stay duration were similar between LRN and ORN. Long-term (>3 years) outcomes are unknown. CONCLUSIONS: Available level III evidence indicates that LRN is a safe alternative to ORN for carefully selected cases, with similar spillage rates and mid-term oncological outcomes. However, there was no advantage in surgical morbidity and lymph node harvest was inadequate with LRN. Tumor-matched-group studies with long-term follow-up are required. LEVEL OF EVIDENCE: Level III.

The use of temozolomide in paediatric metastatic phaeochromocytoma/paraganglioma: A case report and literature review.

There is increasing evidence to support the use of temozolomide therapy for the treatment of metastatic phaeochromocytoma/paraganglioma (PPGL) in adults, particularly in patients with SDHx mutations. In children however, very little data is available. In this report, we present the case of a 12-year-old female with a SDHB-related metastatic paraganglioma treated with surgery followed by temozolomide therapy. The patient presented with symptoms of palpitations, sweating, flushing and hypertension and was diagnosed with a paraganglioma. The primary mass was surgically resected six weeks later after appropriate alpha- and beta-blockade. During the surgery extensive nodal disease was identified that had been masked by the larger paraganglioma. Histological review confirmed a diagnosis of a metastatic SDHB-deficient paraganglioma with nodal involvement. Post-operatively, these nodal lesions demonstrated tracer uptake on 18F-FDG PET-CT. Due to poor tumour tracer uptake on 68Ga-DOTATATE and 123I-MIBG functional imaging studies radionuclide therapy was not undertaken as a potential therapeutic option for this patient. Due to the low tumour burden and lack of clinical symptoms, the multi-disciplinary team opted for close surveillance for the first year, during which time the patient continued to thrive and progress through puberty. 13 months after surgery, evidence of radiological and biochemical progression prompted the decision to start systemic monotherapy using temozolomide. The patient has now completed ten cycles of therapy with limited adverse effects and has benefited from a partial radiological and biochemical response.

Gonadotrophin-independent Precocious Puberty Secondary to an Estrogen Secreting Adrenal Tumor.

BACKGROUND: Adrenal masses are rare in children and most commonly present with clinical features of virilization in the absence of activation of the pituitary axis-gonadotrophin-independent precocious puberty. OBSERVATIONS: We report an unusual case of a 7-year-old girl who presented with clinical signs suggestive of exposure to both androgens and estrogens. Imaging revealed a left-sided adrenal mass with no evidence of metastasis. She underwent successful laparoscopic unilateral adrenalectomy. Histology confirmed an adrenal adenoma. CONCLUSION: We conclude that adrenocortical tumors should be considered in children presenting with gonadotrophin-independent precocious puberty and raised estrogens.

Whole genome sequencing in the diagnosis of primary ciliary dyskinesia.

BACKGROUND: It is estimated that 1-13% of cases of bronchiectasis in adults globally are attributable to primary ciliary dyskinesia (PCD) but many adult patients with bronchiectasis have not been investigated for PCD. PCD is a disorder caused by mutations in genes required for motile cilium structure or function, resulting in impaired mucociliary clearance. Symptoms appear in infancy but diagnosis is often late or missed, often due to the lack of a "gold standard" diagnostic tool and non-specific symptoms. Mutations in > 50 genes account for around 70% of cases, with additional genes, and non-coding, synonymous, missense changes or structural variants (SVs) in known genes presumed to account for the missing heritability. METHODS: UK patients with no identified genetic confirmation for the cause of their PCD or bronchiectasis were eligible for whole genome sequencing (WGS) in the Genomics England Ltd 100,000 Genomes Project. 21 PCD probands and 52 non-cystic fibrosis (CF) bronchiectasis probands were recruited in Wessex Genome Medicine Centre (GMC). We carried out analysis of single nucleotide variants (SNVs) and SVs in all families recruited in Wessex GMC. RESULTS: 16/21 probands in the PCD cohort received confirmed (n = 9), probable (n = 4) or possible (n = 3) diagnosis from WGS, although 13/16 of these could have been picked up by current standard of care gene panel testing. In the other cases, SVs were identified which were missed by panel testing. We identified variants in novel PCD candidate genes (IFT140 and PLK4) in 2 probands in the PCD cohort. 3/52 probands in the non-CF bronchiectasis cohort received a confirmed (n = 2) or possible (n = 1) diagnosis of PCD. We identified variants in novel PCD candidate genes (CFAP53 and CEP164) in 2 further probands in the non-CF bronchiectasis cohort. CONCLUSIONS: Genetic testing is an important component of diagnosing PCD, especially in cases of atypical disease history. WGS is effective in cases where prior gene panel testing has found no variants or only heterozygous variants. In these cases it may detect SVs and is a powerful tool for novel gene discovery.

Properties of Non-Aminoglycoside Compounds Used to Stimulate Translational Readthrough of PTC Mutations in Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is a rare disease with autosomal recessive inheritance, caused mostly by bi-allelic gene mutations that impair motile cilia structure and function. Currently, there are no causal treatments for PCD. In many disease models, translational readthrough of premature termination codons (PTC-readthrough) induced by aminoglycosides has been proposed as an effective way of restoring functional protein expression and reducing disease symptoms. However, variable outcomes of pre-clinical trials and toxicity associated with long-term use of aminoglycosides prompt the search for other compounds that might overcome these problems. Because a high proportion of PCD-causing variants are nonsense mutations, readthrough therapies are an attractive option. We tested a group of chemical compounds with known PTC-readthrough potential (ataluren, azithromycin, tylosin, amlexanox, and the experimental compound TC007), collectively referred to as non-aminoglycosides (NAGs). We investigated their PTC-readthrough efficiency in six PTC mutations found in Polish PCD patients, in the context of cell and cilia health, and in comparison to the previously tested aminoglycosides. The NAGs did not compromise the viability of the primary nasal respiratory epithelial cells, and the ciliary beat frequency was retained, similar to what was observed for gentamicin. In HEK293 cells transfected with six PTC-containing inserts, the tested compounds stimulated PTC-readthrough but with lower efficiency than aminoglycosides. The study allowed us to select compounds with minimal negative impact on cell viability and function but still the potential to induce PTC-readthrough.

A novel ACE2 isoform is expressed in human respiratory epithelia and is upregulated in response to interferons and RNA respiratory virus infection.

Angiotensin-converting enzyme 2 (ACE2) is the main entry point in airway epithelial cells for SARS-CoV-2. ACE2 binding to the SARS-CoV-2 protein spike triggers viral fusion with the cell plasma membrane, resulting in viral RNA genome delivery into the host. Despite ACE2's critical role in SARS-CoV-2 infection, full understanding of ACE2 expression, including in response to viral infection, remains unclear. ACE2 was thought to encode five transcripts and one protein of 805 amino acids. In the present study, we identify a novel short isoform of ACE2 expressed in the airway epithelium, the main site of SARS-CoV-2 infection. Short ACE2 is substantially upregulated in response to interferon stimulation and rhinovirus infection, but not SARS-CoV-2 infection. This short isoform lacks SARS-CoV-2 spike high-affinity binding sites and, altogether, our data are consistent with a model where short ACE2 is unlikely to directly contribute to host susceptibility to SARS-CoV-2 infection.

Unexpected tunnelled central venous access demise: a single institutional study from the UK.

PURPOSE: To explore the factors involved in the demise of tunnelled central vascular access devices (CVADs) in children and describe patterns of failure. METHODS: A retrospective study including children under 16 years of age undergoing CVAD insertion in a tertiary centre between October 2014 and December 2019. The Kaplan-Meier estimator was used to study CVAD survival and piecewise exponential curves to approximate hazard rates. Related factors were analysed using multivariable regression. RESULTS: Totally, 684 CVADs were inserted in 499 children. Devices were in situ for 213,821 days (median 244.5). Of those, 261 CVADs (38.2%) failed prematurely; 176 (67%) required replacement. Tunnelled external lines (TELs) failed more frequently than totally implantable devices (p < 0.005).TEL displacement occurred in two high-risk phases, falling to baseline after 90 days. Low age at device insertion and open placement were strongly associated with an increased failure rate. Previous CVAD failure did not increase subsequent failure rate. Premature failure increased procedural cost by £153,949 per year. CONCLUSIONS: TIDs should be placed in preference to TELs where appropriate. TELs are at highest risk of displacement for 90 days and must be well secured for this duration. Meticulous line care offers significant potential cost savings by reducing line replacements. LEVEL OF EVIDENCE: Level III.

Super-Resolution Microscopy and FIB-SEM Imaging Reveal Parental Centriole-Derived, Hybrid Cilium in Mammalian Multiciliated Cells.

Motile cilia are cellular beating machines that play a critical role in mucociliary clearance, cerebrospinal fluid movement, and fertility. In the airways, hundreds of motile cilia present on the surface of a multiciliated epithelia cell beat coordinately to protect the epithelium from bacteria, viruses, and harmful particulates. During multiciliated cell differentiation, motile cilia are templated from basal bodies, each extending a basal foot-an appendage linking motile cilia together to ensure coordinated beating. Here, we demonstrate that among the many motile cilia of a multiciliated cell, a hybrid cilium with structural features of both primary and motile cilia is harbored. The hybrid cilium is conserved in mammalian multiciliated cells, originates from parental centrioles, and its cellular position is biased and dependent on ciliary beating. Furthermore, we show that the hybrid cilium emerges independently of other motile cilia and functions in regulating basal body alignment.

Stated preferences for relapsed or refractory mantle cell lymphoma treatments in Sweden and Germany.

Background: We aimed to elicit treatment preferences in relapsed/refractory mantle cell lymphoma (r/r MCL). Materials & methods: A discrete-choice experiment comprising six attributes ('overall survival', 'progression-free survival', 'fatigue', 'nausea', 'risk of serious infections' and 'treatment administration') was administered to r/r MCL patients, physicians and the general population (GP) in Sweden and Germany. Results: 18 patients, 68 physicians and 191 GP members participated. 'Overall survival' was the most important attribute, followed by 'risk of serious infection' and 'progression-free survival' among physicians and the GP. In contrast, 'treatment administration' was the second most important attribute to patients, followed by 'risk of serious infection.' Conclusion: Preferences for characteristics differentiating treatments of r/r MCL varies between patients, physicians and members of the GP.

Recurrent ovarian immature teratoma in a 12-year-old girl: Implications for management.

Immature teratomas (IT) are rare and recurrences uncommon. A 12-year-old female with grade 3 (high-grade) ovarian IT underwent surgical resection but experienced early recurrences; the first was treated with surgery but the second was metastatic and managed with chemotherapy, resulting in growing-teratoma-syndrome and need for further surgery. She now remains well in uneventful clinical follow-up. We believe chemotherapy could be reserved for very carefully selected recurrent IT cases, which may alter the natural history of disease.

Fatigue, treatment satisfaction and health-related quality of life among patients receiving novel drugs suppressing androgen signalling for the treatment of metastatic castrate-resistant prostate cancer.

Clinical studies have demonstrated the benefits of abiraterone acetate + prednisone (AAP) and enzalutamide (ENZ) in significantly improving survival among metastatic castration-resistant prostate cancer (mCRPC) patients. However, evidence regarding patient's real-world experience, particularly with respect to fatigue, treatment satisfaction and health-related quality of life (HRQoL) is limited. Interviews were initially conducted with patients (n = 38) and carers (n = 12) to elicit qualitative data regarding their experiences. Findings informed the design of a quantitative, multinational online survey of mCRPC patients (n = 152) receiving AAP or ENZ. Participants completed validated questionnaires assessing fatigue (Brief Fatigue Inventory), treatment satisfaction (Cancer Therapy Satisfaction Questionnaire) and HRQoL (EuroQol-5-Dimensions). Results indicated that patients were generally satisfied with these therapies, more specifically with reductions in prostate-specific antigen levels and extended survival. Fatigue was commonly linked to poor HRQoL and responses indicated that significantly fewer patients in the AAP group reported feeling usually tired or fatigued in the last week compared to the ENZ group (33% vs. 55%, p = 0.006 respectively). Findings highlight the benefit of AAP and ENZ in promoting the "quality" of extended survival. That fatigue was lower among patients receiving AAP may be important for informing treatment decisions. Further research is needed to gain deeper insights.

Primary ciliary dyskinesia ciliated airway cells show increased susceptibility to Haemophilus influenzae biofilm formation.

Non-typeable Haemophilus influenzae (NTHi) is the most common pathogen in primary ciliary dyskinesia (PCD) patients. We hypothesised that abnormal ciliary motility and low airway nitric oxide (NO) levels on airway epithelial cells from PCD patients might be permissive for NTHi colonisation and biofilm development.We used a primary epithelial cell co-culture model to investigate NTHi infection. Primary airway epithelial cells from PCD and non-PCD patients were differentiated to ciliation using an air-liquid interface culture and then co-cultured with NTHi.NTHi adherence was greater on PCD epithelial cells compared to non-PCD cells (p<0.05) and the distribution of NTHi on PCD epithelium showed more aggregated NTHi in biofilms (p<0.001). Apart from defective ciliary motility, PCD cells did not significantly differ from non-PCD epithelial cells in the degree of ciliation and epithelial integrity or in cytokine, LL-37 and NO production. Treatment of PCD epithelia using exogenous NO and antibiotic significantly reduced NTHi viability in biofilms compared with antibiotic treatment alone.Impaired ciliary function was the primary defect in PCD airway epithelium underlying susceptibility to NTHi biofilm development compared with non-PCD epithelium. Although NO responses were similar, use of targeted NO with antibiotics enhanced killing of NTHi in biofilms, suggesting a novel therapeutic approach.

Successfully implementing a diabetic retinopathy screening service in general practice: What does the evidence tell us?

BACKGROUND: We previously showed that general-practice based screening for diabetic retinopathy significantly improves recording of screening outcomes and follow-up for Australians with type 2 diabetes. In 2016, two Medicare Benefits Schedule item numbers were launched to support screening in general practice. However, there is little evidence-based information to guide practices in successfully implementing screening models for diabetic retinopathy. The objective of this study was to develop an evidence-based framework to guide successful general-practice based screening for diabetic retinopathy. METHODS: Thematic analysis was used to identify and classify recurrent themes from qualitative and observational data gathered from general practices and staff undertaking successful screening for diabetic retinopathy. RESULTS: Seven themes (a combination of enablers and potential risks) were identified as key components of successful screening for diabetic retinopathy in general practice.

MicroRNA-328 is involved in wound repair process in human bronchial epithelial cells.

Our aim was to investigate the role of microRNA on epithelial wound repair by global microRNA silencing. We have also analysed the influence of five miRNAs (miR-328, miR-342, miR-411, miR-609, miR-888, previously identified) on wound repair in 16HBE14o-bronchial epithelial cell line. Cells were transfected with siRNAs against human DROSHA and DICER1 or miRNA mimics or inhibitors. Wounding assays were performed and the cells were observed using time-lapse microscopy. The area of damage was calculated at chosen time points, followed by data analysis. Cells with silenced global miRNA expression showed a significantly slower repair rate compared to the control cells (p=0.001). For miR-328, we observed significantly delayed repair in cells transfected with the inhibitor compared to control (p=0.02). Global microRNA silencing significantly decreased the repair rate of airway epithelial cells in vitro, indicating an important role of miRNA in the regulation of wound repair and that miR-328, possibly involved in actin pathway, may be a potent modifier of this process.

Diagnosis of primary ciliary dyskinesia: potential options for resource-limited countries.

Primary ciliary dyskinesia is a genetic disease of ciliary function leading to chronic upper and lower respiratory tract symptoms. The diagnosis is frequently overlooked because the symptoms are nonspecific and the knowledge about the disease in the primary care setting is poor. Additionally, none of the available tests is accurate enough to be used in isolation. These tests are expensive, and need sophisticated equipment and expertise to analyse and interpret results; diagnosis is therefore only available at highly specialised centres. The diagnosis is particularly challenging in countries with limited resources due to the lack of such costly equipment and expertise.In this review, we discuss the importance of early and accurate diagnosis especially for countries where the disease is clinically prevalent but diagnostic tests are lacking. We review the diagnostic tests available in specialised centres (nasal nitric oxide, high-speed video microscopy, transmission electron microscopy, immunofluorescence and genetics). We then consider modifications that might be considered in less well-resourced countries whilst maintaining acceptable accuracy.

Discovery of imidazopyridazines as potent Pim-1/2 kinase inhibitors.

High levels of Pim expression have been implicated in several hematopoietic and solid tumor cancers, suggesting that inhibition of Pim signaling could provide patients with therapeutic benefit. Herein, we describe our progress towards this goal using a screening hit (rac-1) as a starting point. Modification of the indazole ring resulted in the discovery of a series of imidazopyridazine-based Pim inhibitors exemplified by compound 22m, which was found to be a subnanomolar inhibitor of the Pim-1 and Pim-2 isoforms (IC50 values of 0.024nM and 0.095nM, respectively) and to potently inhibit the phosphorylation of BAD in a cell line that expresses high levels of all Pim isoforms, KMS-12-BM (IC50=28nM). Profiling of Pim-1 and Pim-2 expression levels in a panel of multiple myeloma cell lines and correlation of these data with the potency of compound 22m in a proliferation assay suggests that Pim-2 inhibition would be advantageous for this indication.

Primary Air-Liquid Interface Culture of Nasal Epithelium for Nasal Drug Delivery.

Nasal drug administration is a promising alternative to oral and parenteral administration for both local and systemic delivery of drugs. The benefits include its noninvasive nature, rapid absorption, and circumvention of first pass metabolism. Hence, the use of an in vitro model using human primary nasal epithelial cells could be key to understanding important functions and parameters of the respiratory epithelium. This model will enable investigators to address important and original research questions using a biologically relevant in vitro platform that mimics the in vivo nasal epithelial physiology. The purpose of this study was to establish, systematically characterize, and validate the use of a primary human nasal epithelium model cultured at the air-liquid interface for the study of inflammatory responses and drug transport and to simultaneously quantify drug effects on ciliary activity.

Diabetic Retinopathy Screening and Monitoring of Early Stage Disease in Australian General Practice: Tackling Preventable Blindness within a Chronic Care Model.

INTRODUCTION: Diabetic retinopathy (DR) is the leading cause of preventable blindness in Australia. Up to 50% of people with proliferative DR who do not receive timely treatment will become legally blind within five years. Innovative and accessible screening, involving a variety of primary care providers, will become increasingly important if patients with diabetes are to receive optimal eye care. METHOD: An open controlled trial design was used. Five intervention practices in urban, regional, and rural Australia partnered with ophthalmologists via telehealth undertook DR screening and monitoring of type 2 diabetes patients and were compared with control practices undertaking usual care 2011-2014. RESULTS: Recorded screening rates were 100% across intervention practices, compared with 22-53% in control practices. 31/577 (5%) of patients in the control practices were diagnosed with mild-moderate DR, of whom 9 (29%) had appropriate follow-up recorded. This was compared with 39/447 (9%) of patients in the intervention group, of whom 37 (95%) had appropriate follow-up recorded. DISCUSSION AND CONCLUSION: General practice-based DR screening via Annual Cycle of Care arrangements is effective across differing practice locations. It offers improved recording of screening outcomes for Australians with type 2 diabetes and better follow-up of those with screen abnormalities.

Patient, physician, and general population preferences for treatment characteristics in relapsed or refractory chronic lymphocytic leukemia: A conjoint analysis.

Due to the disease heterogeneity, treatments for chronic lymphocytic leukemia (CLL) have differed with respect to efficacy and toxicity. Limited options have also been available regarding modalities of administration. Our study objective was to estimate preferences for treatment characteristics (or "attributes") in relapsed/refractory (r/r) CLL. Patients, physicians (hematologists/oncologists), and members from the general population from Germany and Sweden completed a conjoint analysis comprising six CLL treatment attributes: (i) overall survival (OS), (ii) progression-free survival (PFS), (iii) fatigue, (iv) nausea, (v) risk of serious infections, and (vi) treatment administration (each described in three levels). We estimated the relative importance of each attribute by fitting a hierarchical Bayesian model. A total of 190 German and 121 Swedish individuals participated. In the pooled sample, OS was the most important attribute (36%), followed by risk of serious infection (21%), treatment administration (13%), fatigue (12%), PFS (11%), and nausea (7%). Treatment administration was more important to patients (all p<0.004), OS was more important to physicians (all p<0.001), and risk of serious infections was more important to the general population than to physicians (p<0.001). Our results could be helpful to align therapeutic decision-making in r/r CLL with patient preferences to improve care satisfaction and treatment compliance.