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.

Biallelic variants in CEP164 cause a motile ciliopathy-like syndrome.

Ciliopathies may be classed as primary or motile depending on the underlying ciliary defect and are usually considered distinct clinical entities. Primary ciliopathies are associated with multisystem syndromes typically affecting the brain, kidney, and eye, as well as other organ systems such as the liver, skeleton, auditory system, and metabolism. Motile ciliopathies are a heterogenous group of disorders with defects in specialised motile ciliated tissues found within the lung, brain, and reproductive system, and are associated with primary ciliary dyskinesia, bronchiectasis, infertility and rarely hydrocephalus. Primary and motile cilia share defined core ultra-structures with an overlapping proteome, and human disease phenotypes can reflect both primary and motile ciliopathies. CEP164 encodes a centrosomal distal appendage protein vital for primary ciliogenesis. Human CEP164 mutations are typically described in patients with nephronophthisis-related primary ciliopathies but have also been implicated in motile ciliary dysfunction. Here we describe a patient with an atypical motile ciliopathy phenotype and biallelic CEP164 variants. This work provides further evidence that CEP164 mutations can contribute to both primary and motile ciliopathy syndromes, supporting their functional and clinical overlap, and informs the investigation and management of CEP164 ciliopathy patients.

An eConsultant versus a hospital-based outpatient consultation for general (internal) medicine: a costing analysis.

BACKGROUND: The eConsultant model of care is an outpatient substitution approach which has been evaluated and implemented extensively internationally. It provides an asynchronous, digital, clinician-to-clinician advice service, giving primary care physicians remote access to specialist support for patient care within 3 business days. Results from initial trials of the eConsultant model in Australia support international evidence of reduced wait times and improved access to specialist input, avoidance of face-to-face hospital outpatient visits, and better integrated care. This study compared the cost of delivery of an eConsultant episode of care with that of a hospital-based outpatient appointment. METHODS: A cost-minimisation analysis, using a decision analytic model, was used to compare the two approaches. eConsultant costs were calculated from specialist reported data (minutes spent preparing the response; the number of patients referred subsequently for a hospital-based outpatient appointment) and administration staff data (time spent recording the occasion-of-service). Outpatient costs were calculated using finance data and information from outpatient clinic managers at the hospital-based outpatient clinic. The primary outcome was incremental cost saving per patient from a hospital system perspective. Uncertainty was explored using one-way sensitivity analyses and characterised with probabilistic sensitivity analysis using 10,000 Monte Carlo simulations. RESULTS: The traditional referral pathway cost estimate was $587.20/consult compared to $226.13/consult for an eConsultant episode: an efficiency saving of $361.07 per patient. The incremental difference between eConsultant and traditional care was most sensitive to the cost estimate of an outpatient attendance, the time for a specialist to complete an eConsult, and the probability of a patient requiring a face-to-face hospital-based attendance following an eConsult. However, at the upper bounds of each of these estimates, an eConsult remained the most cost-efficient model. In 96.5% of the Monte Carlo simulations eConsult was found to be more cost efficient than the traditional approach. CONCLUSIONS: The eConsultant model of care was associated with a 61.5% efficiency gain, allowing diversion of support to hospital-based outpatient appointments.

The Queensland Virtual Integrated Practice (VIP) partnership program pilot study: an Australian-first model of care to support rural general practice.

BACKGROUND: There is a critical lack of medical workforce internationally, and this is particularly notable in rural and remote Australia where strategies to address workforce shortages are urgently required. This pilot study aimed to implement and evaluate a Virtual Integrated Practice (VIP) Program in the Australian rural primary care setting. METHODS: The VIP model was developed using co-creation methodology and involves an urban GP joining a rural general practice team to provide ongoing care to patients remotely via secure telehealth. The pilot study was conducted in two western Queensland general practices, commencing in October 2021 with one rural practice and extending to an additional rural practice from November 2022. Evaluation included a retrospective review of service, billing and cost data, and an online survey for patients. Ethical approval was obtained from the University of Queensland Human Research Ethics Committee (Project number: 2021/HE002434). RESULTS: There were 1468 services provided through to December 2022, including general consults (n = 1197), therapeutic procedures (n = 68), mental health treatment plans (n = 68) and chronic disease management plans (n = 59). Patients were predominantly female (73.1%) and did not have their appointment at the practice (57.8%). Among 1282 occasions of service, less than 20% of consultations (n = 224) required support from staff (e.g., a nurse), and more than half were repeat patient encounters (53.0%). Survey respondents (n = 45) indicated that they were satisfied (9.3%) or highly satisfied (90.7%) with the care provided, and importantly, 95.5% of respondents reported that the service improved their access to the GP. More than 20% of respondents indicated that they would attend the Emergency Department if virtual care was not available. CONCLUSIONS: Data from this pilot study has informed translation to an additional 20 vulnerable rural general practices in three further rural regions in Queensland in 2023 and evaluation is ongoing. This pilot study demonstrates the feasibility and acceptability of an innovative, digitally supported community-focussed, healthcare initiative to arrest the decline in rural general practice workforce, improve patient care access and support rural practice viability.

Offsite primary care providers using telehealth to support a sustainable workforce in rural and remote general practice: A rapid review of the literature.

INTRODUCTION: Rural and remote general practices face increasing demands for care without the workforce required to meet patient needs. The coronavirus pandemic has created an opportunity to explore sustainable, telehealth-driven solutions to this chronic and complex problem. OBJECTIVE: This review examined interventions using offsite primary care providers to deliver ongoing patient care via telehealth to support rural and remote general practices. We aimed to understand the impact of such interventions on the Quadruple Aim (patient experience, provider experience, health care costs, and health outcomes). DESIGN: A rapid review of studies published from 2011 and grey literature published from 2016. FINDINGS: Six studies met the eligibility criteria. No eligible Australian studies were identified. Most studies investigated ongoing primary care services provided via telehealth by offsite pharmacists. Patients and rural primary care staff reported positive experiences with the interventions. One study demonstrated potential return on investment for rural practices. While one study reported clinically and statistically significant improvements in health outcomes over time, two studies did not observe statistically significant differences in health outcomes between intervention and control cohorts. DISCUSSION: The Quadruple Aim should be carefully considered when designing, implementing, and evaluating interventions that involve offsite primary care providers using telehealth to support a sustainable workforce in rural and remote general practice. CONCLUSION: Sustainable solutions to workforce shortages in rural and remote general practice are needed urgently. Using offsite primary care providers to deliver telehealth and support practices in these regions is one possible solution that warrants further investigation, particularly in Australia.

Towards an artificial human lung: modelling organ-like complexity to aid mechanistic understanding.

Respiratory diseases account for over 5 million deaths yearly and are a huge burden to healthcare systems worldwide. Murine models have been of paramount importance to decode human lung biology in vivo, but their genetic, anatomical, physiological and immunological differences with humans significantly hamper successful translation of research into clinical practice. Thus, to clearly understand human lung physiology, development, homeostasis and mechanistic dysregulation that may lead to disease, it is essential to develop models that accurately recreate the extraordinary complexity of the human pulmonary architecture and biology. Recent advances in micro-engineering technology and tissue engineering have allowed the development of more sophisticated models intending to bridge the gap between the native lung and its replicates in vitro Alongside advanced culture techniques, remarkable technological growth in downstream analyses has significantly increased the predictive power of human biology-based in vitro models by allowing capture and quantification of complex signals. Refined integrated multi-omics readouts could lead to an acceleration of the translational pipeline from in vitro experimental settings to drug development and clinical testing in the future. This review highlights the range and complexity of state-of-the-art lung models for different areas of the respiratory system, from nasal to large airways, small airways and alveoli, with consideration of various aspects of disease states and their potential applications, including pre-clinical drug testing. We explore how development of optimised physiologically relevant in vitro human lung models could accelerate the identification of novel therapeutics with increased potential to translate successfully from the bench to the patient's bedside.

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.

Implementing a general practitioner-to-general physician eConsult service (eConsultant) in Australia.

BACKGROUND: In response to lengthy wait times for specialist outpatient appointments, electronic consultation (eConsult) services have developed globally, providing asynchronous, secure and timely communication between general practitioner (GP) and specialist. This study aims to track adoption of a Queensland eConsultant service in two Australian Primary Health Networks (Western Queensland and Brisbane South) to understand key barriers and enablers to adoption and inform modification of the implementation strategy.  METHODS: Our theory-informed mixed-methods evaluation assessed implementation between July 2020 and March 2022. Adoption and implementation activities were prospectively recorded in bespoke tracking spreadsheets with implementation activities coded against the Expert Recommendations for Implementing Change (ERIC) strategies. Semi-structured interviews with GPs and stakeholders informed by the Consolidated Framework for Implementation Research (CFIR) were conducted to understand determinants of implementation.  RESULTS: Of the 40 practices invited to take part in the eConsultant service, 20 (50%) enrolled. Of the 97 GPs who consented, 38 sent at least one Request for Advice (RFA) to the eConsultant with a total of 112 RFA sent. Implementation was predominantly guided by eight strategies. Qualitative interviews were conducted with 11 GPs and 4 stakeholders (12 from rural/remote regions, 11 females and two sole practitioners). Interviewees felt the eConsultant service supported outpatient appointment avoidance and provided efficient, timely access to specialist support for GPs and their patients. Barriers identified to using eConsultant related to digital infrastructure, competing priorities, and keeping the service 'front of mind'. Key enablers identified were the relative advantage of eConsultant over other options, patient benefits and COVD-19 facilitating the use of digital technology. CONCLUSIONS: This evaluation highlighted service enablers as well as user priorities for broader implementation. A focus on a well-integrated digital system and availability of a variety of eConsultant specialties are seen as key strategies to embedding the eConsultant option in GP advice processes in Australia.

Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort.

BACKGROUND: Primary ciliary dyskinesia (PCD), a genetically heterogeneous condition enriched in some consanguineous populations, results from recessive mutations affecting cilia biogenesis and motility. Currently, diagnosis requires multiple expert tests. METHODS: The diagnostic utility of multigene panel next-generation sequencing (NGS) was evaluated in 161 unrelated families from multiple population ancestries. RESULTS: Most (82%) families had affected individuals with biallelic or hemizygous (75%) or single (7%) pathogenic causal alleles in known PCD genes. Loss-of-function alleles dominate (73% frameshift, stop-gain, splice site), most (58%) being homozygous, even in non-consanguineous families. Although 57% (88) of the total 155 diagnostic disease variants were novel, recurrent mutations and mutated genes were detected. These differed markedly between white European (52% of families carry DNAH5 or DNAH11 mutations), Arab (42% of families carry CCDC39 or CCDC40 mutations) and South Asian (single LRRC6 or CCDC103 mutations carried in 36% of families) patients, revealing a striking genetic stratification according to population of origin in PCD. Genetics facilitated successful diagnosis of 81% of families with normal or inconclusive ultrastructure and 67% missing prior ultrastructure results. CONCLUSIONS: This study shows the added value of high-throughput targeted NGS in expediting PCD diagnosis. Therefore, there is potential significant patient benefit in wider and/or earlier implementation of genetic screening.

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.

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.

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.

Clinical outcomes of an integrated primary-secondary model of care for individuals with complex type 2 diabetes: a non-inferiority randomised controlled trial.

AIMS/HYPOTHESIS: The aim of the study was to determine if a Beacon model of integrated care utilising general practitioners (GPs) with special interests could achieve similar clinical outcomes to a hospital-based specialist diabetes outpatient clinic. METHODS: This pragmatic non-inferiority multisite randomised controlled trial assigned individuals with complex type 2 diabetes to care delivered by a Beacon clinic or to usual care delivered by a hospital outpatient department, in a 3:1 ratio. Owing to the nature of the study, researchers were only blinded during the allocation process. Eligible participants were aged 18 or over, had been referred by their usual GP to the hospital central referral hub with type 2 diabetes and had been triaged to be seen within 30 or 90 days. The intervention consisted of diabetes management in primary care by GPs with a special interest who had been upskilled in complex diabetes under the supervision of an endocrinologist. The primary outcome was HbA1c at 12 months post-recruitment. The non-inferiority margin was 4.4 mmol/mol (0.4%). Both per-protocol and intention-to-treat analyses are reported. RESULTS: Between 27 November 2012 and 14 July 2015, 352 individuals were recruited and 305 comprised the intention-to-treat sample (71 in usual care group and 234 in the Beacon model group). The Beacon model was non-inferior to usual care for both the per-protocol (difference -0.38 mmol/mol [95% CI -4.72, 3.96]; -0.03% [95% CI -0.43, 0.36]) and the intention-to-treat (difference -1.28 mmol/mol [95% CI -5.96, 3.40]; -0.12% [95% CI -0.55, 0.31]) analyses. Non-inferiority was sustained in a sensitivity analysis at 12 months. There were no statistically or clinically significant differences in the secondary outcomes of BP, lipids or quality of life as measured by the 12 item short-form health survey (SF-12v2) and the diabetes-related quality of life (DQoL-Brief) survey. Safety indicators did not differ between groups. Participant satisfaction on the eight-item client satisfaction questionnaire (CSQ-8) was good in both groups, but scores were significantly higher in the Beacon model group than the usual care group (mean [SD] 28.4 [4.9] vs 25.6 [4.9], respectively, p < 0.001). CONCLUSIONS/INTERPRETATION: In individuals with type 2 diabetes, a model of integrated care delivered in the community by GPs with a special interest can safely achieve clinical outcomes that are not inferior to those achieved with gold-standard hospital-based specialist outpatient clinics. Individuals receiving care in the community had greater satisfaction. Further studies will determine the cost of delivering this model of care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12612000380897 FUNDING: The study was funded by the Australian National Health and Medical Research Council (GNT1001157).

Risk factors for situs defects and congenital heart disease in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is associated with abnormal organ positioning (situs) and congenital heart disease (CHD). This study investigated genotype-phenotype associations in PCD to facilitate risk predictions for cardiac and laterality defects. This retrospective cohort study of 389 UK patients with PCD found 51% had abnormal situs and 25% had CHD and/or laterality defects other than situs inversus totalis. Patients with biallelic mutations in a subset of nine PCD genes had normal situs. Patients with consanguineous parents had higher odds of situs abnormalities than patients with non-consanguineous parents. Patients with abnormal situs had higher odds of CHD and/or laterality defects.

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.

High prevalence of CCDC103 p.His154Pro mutation causing primary ciliary dyskinesia disrupts protein oligomerisation and is associated with normal diagnostic investigations.

RATIONALE: Primary ciliary dyskinesia is a genetically heterogeneous inherited condition characterised by progressive lung disease arising from abnormal cilia function. Approximately half of patients have situs inversus. The estimated prevalence of primary ciliary dyskinesia in the UK South Asian population is 1:2265. Early, accurate diagnosis is key to implementing appropriate management but clinical diagnostic tests can be equivocal. OBJECTIVES: To determine the importance of genetic screening for primary ciliary dyskinesia in a UK South Asian population with a typical clinical phenotype, where standard testing is inconclusive. METHODS: Next-generation sequencing was used to screen 86 South Asian patients who had a clinical history consistent with primary ciliary dyskinesia. The effect of a CCDC103 p.His154Pro missense variant compared with other dynein arm-associated gene mutations on diagnostic/phenotypic variability was tested. CCDC103 p.His154Pro variant pathogenicity was assessed by oligomerisation assay. RESULTS: Sixteen of 86 (19%) patients carried a homozygous CCDC103 p.His154Pro mutation which was found to disrupt protein oligomerisation. Variable diagnostic test results were obtained including normal nasal nitric oxide levels, normal ciliary beat pattern and frequency and a spectrum of partial and normal dynein arm retention. Fifteen (94%) patients or their sibling(s) had situs inversus suggesting CCDC103 p.His154Pro patients without situs inversus are missed. CONCLUSIONS: The CCDC103 p.His154Pro mutation is more prevalent than previously thought in the South Asian community and causes primary ciliary dyskinesia that can be difficult to diagnose using pathology-based clinical tests. Genetic testing is critical when there is a strong clinical phenotype with inconclusive standard diagnostic tests.

Questionnaires that measure the quality of relationships between patients and primary care providers: a systematic review.

BACKGROUND: International guidance on models of care stress the importance of good quality, continuous patient-provider relationships to support high quality and efficient care and hospital avoidance. However, assessing the quality of patient-provider relationships is challenging due to its experiential nature. The aim of this study was to undertake a systematic review to identify questionnaires previously developed or used to assess the quality of continuous relationships between patients and their provider in primary care. METHODS: MEDLINE, PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and SCOPUS databases were searched for English language studies published between 2009 and 2017. Key terms used identified studies conducted in the primary care setting examining relationships between patients and providers. Studies that focused on the conceptualisation, development, testing or review of a questionnaire, or studies that used a questionnaire for assessing the quality of continuous relationships between patients and providers were eligible. Studies that did not assess quality via a questionnaire, only assessed single aspects of relationships, only assessed single encounters, assessed transitions between settings or assessed relationships using an index were excluded. Information on validity testing of each relevant questionnaire identified from articles was reviewed to inform recommendations for future research and evaluation. RESULTS: Twenty-seven studies met the eligibility criteria, including 14 unique questionnaires. The questionnaires were diverse in length, scope, focus and level of validity testing. Five questionnaires were considered not feasible for future use due to size and lack of development work. Three questionnaires were considered strongest candidates for use in future work based on being relevant to the topic and primary care setting, freely available in English and not needing additional pilot work prior to use. These three questionnaires were the Care Continuity Across Levels of Care Scale, the Nijmegan Continuity Questionnaire and the Patient-Doctor Depth of Relationship Tool. CONCLUSIONS: This study provides an overview of 14 unique questionnaires that have been used to assess the quality of continuous relationships between patients and primary care providers. The decision to use one of the questionnaires in future work requires careful consideration, including the scope, length, validation testing, accessibility of the questionnaires and their alignment with the initiative being evaluated.

Establishing a new model of integrated primary and secondary care based around general practice: a case study of lessons learned and challenges.

This case study describes the development and implementation of an innovative integrated primary-secondary model of care for people with complex diabetes. The aim of the paper is to present the experiences of clinicians and researchers involved in implementing the 'Beacon' model by providing a discussion of the contextual factors, including lessons learned, challenges and solutions. Beacon-type models of community care for people with chronic disease are well placed to deliver on Australia's health care reform agenda, and this commentary provides rich contextual information relevant to the translation of such models into policy and practice.

Cephalosporin-3'-Diazeniumdiolate NO Donor Prodrug PYRRO-C3D Enhances Azithromycin Susceptibility of Nontypeable Haemophilus influenzae Biofilms.

PYRRO-C3D is a cephalosporin-3-diazeniumdiolate nitric oxide (NO) donor prodrug designed to selectively deliver NO to bacterial infection sites. The objective of this study was to assess the activity of PYRRO-C3D against nontypeable Haemophilus influenzae (NTHi) biofilms and examine the role of NO in reducing biofilm-associated antibiotic tolerance. The activity of PYRRO-C3D on in vitro NTHi biofilms was assessed through CFU enumeration and confocal microscopy. NO release measurements were performed using an ISO-NO probe. NTHi biofilms grown on primary ciliated respiratory epithelia at an air-liquid interface were used to investigate the effects of PYRRO-C3D in the presence of host tissue. Label-free liquid chromatography-mass spectrometry (LC/MS) proteomic analyses were performed to identify differentially expressed proteins following NO treatment. PYRRO-C3D specifically released NO in the presence of NTHi, while no evidence of spontaneous NO release was observed when the compound was exposed to primary epithelial cells. NTHi lacking ß-lactamase activity failed to trigger NO release. Treatment significantly increased the susceptibility of in vitro NTHi biofilms to azithromycin, causing a log fold reduction (10-fold reduction or 1-log-unit reduction) in viability (P < 0.05) relative to azithromycin alone. The response was more pronounced for biofilms grown on primary respiratory epithelia, where a 2-log-unit reduction was observed (P < 0.01). Label-free proteomics showed that NO increased expression of 16 proteins involved in metabolic and transcriptional/translational functions. NO release from PYRRO-C3D enhances the efficacy of azithromycin against NTHi biofilms, putatively via modulation of NTHi metabolic activity. Adjunctive therapy with NO mediated through PYRRO-C3D represents a promising approach for reducing biofilm-associated antibiotic tolerance.