Effects of a fixed-dose ACE inhibitor-diuretic combination on ambulatory blood pressure and arterial properties in isolated systolic hypertension

The ideal therapy for patients with isolated systolic hypertension remains unclear; diuretics, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors are all used in clinical practice. The aim of this study was to determine whether a fixed-dose ACE inhibitor/diuretic combination would reduce ambulatory blood pressures (BP) and arterial stiffness in isolated systolic hypertension more than antihypertensive monotherapy. In this randomized, double-blind study, 8 weeks of fosinopril/hydrochlorothiazide combination (10/12.5 mg titrated up to 20/12.5 mg) was compared with the calcium channel blocker (amlodipine, 5 mg titrated up to 10 mg) and diuretic (indapamide, 2.5 mg) monotherapy in 28 patients with isolated systolic hypertension. Each patient received all 3 therapies. Assessments included 24-hour ambulatory BP, clinic BP, and applanation tonometry-derived augmentation index. At 8 weeks, the fall in average 24-hour systolic BP and night time systolic BP were significantly greater in the fosinopril-hydrochlorothiazide group, compared to amlodipine and indapamide. The decrease in augmentation index and central aortic systolic BP was also greater in the fosinopril-hydrochlorothiazide group, compared to either amlodipine or indapamide. There was no difference between therapies in decrease in clinic systolic or diastolic BP, or diastolic ABP (average 24-h, diurnal, or nocturnal). Compared with either calcium channel blocker or diuretic therapy, a fixed-dose ACE inhibitor-diuretic combination induces greater reductions in systolic ABP, particularly at night, favorable effects that may be related to a decrease in the intensity of or delay in arterial wave reflections. ACE inhibitor-diuretic combination therapy is a useful approach to cardiovascular risk reduction in isolated systolic hypertension.     

Successful bone marrow transplantation in a pediatric patient with chronic myeloid leukemia from a HLA-identical sibling selected by preimplantation HLA testing

We report successful bone marrow transplantation in an 11-year-old male with chronic myeloid leukemia from his HLA-identical sibling selected by preimplantation HLA testing. Because collection of cord blood failed, the transplantation was performed when the donor reached the age of 19 months, and sufficient bone marrow could be harvested safely. The patient was BCR/ABL negative at the time of transplantation after complete molecular response to imatinib. Currently, 16 months post-transplantation he is well and in complete molecular remission. This report describes preimplantation HLA-genotyping to deliver a matched sibling donor for successful transplantation of a malignant disorder.     

Human papillomavirus DNA and mRNA positivity of the anal canal in women with lower genital tract HPV lesions: predictors and clinical implications

Objective

Women with HPV related pathology of the lower genital tract are at higher risk for AIN and anal cancer than the general population. A strategy to identify anal disease in these women has not been formulated. The aim of this study is to examine the feasibility of HPV related biomarker testing on anal smears, to identify the risk factors for anal HPV positivity and to provide information of the clinical implications of anal HPV infection in this population.

Methods

In women referred for colposcopy because of HPV related pathology of the lower genital tract (cervical cancer, CIN, VIN, warts) a detailed questionnaire, an anal smear and a cervical smear were taken. On each sample morphological cytology, flow cytometric evaluation of E6&7 mRNA, and HPV DNA detection and typing were performed. Women with a positive anal result were referred for high resolution anoscopy.

Results

So far 235 women have been included (mean age 34.3). HPV DNA, high-risk HPV DNA, high-risk mRNA was detected in 45%, 31% and 8% of the anal smears and in 56%, 39% and 25% of the cervical smears respectively. Absolute or partial concordance of the types between the cervix and the anus was seen in 74%. Positivity for mRNA was significantly lower in the anus than the cervix (8% vs 25%). Logistic regression analysis revealed risk factors for the presence of anal HPV DNA (> 3 lifetime sexual partners and presence of cervical HPV DNA), hr HPV DNA (presence of cervical hr HPV DNA), and hr mRNA (presence of cervical hr mRNA). Twelve months after LLETZ 53% of women were cervical HPV negative, but 25% of those were still HPV positive in the anus.

Conclusions

HPV infection of the anus is common in this group and is interlinked with the cervical infection. Anal HPV E6&7 mRNA expression is less common than in the cervix. Possible clinical implications of anal infection could be the development of AIN and recurrence of CIN after treatment due to cervical reinfection from the anal reservoir. The use of HPV biomarkers is feasible in anal smears, although especially DNA testing as triage method for referral to anoscopy is probably inappropriate due to high positivity rate.     

Paradigm shifts,peregrinations and pixies in ophthalmology

Human ingenuity is challenged by defending vision, our highest bandwidth sense. Special challenges are presented by the replacement or repair of highly specialized but scarce tissue within the constraints of transparency, tissue shape and alignment, tissue borders and pressure maintenance. Many, mostly destructive, surgical procedures were developed prior to an understanding of underlying pathophysiology. For a number of conditions, both reconstructive and destructive procedures co‐exist, yet there are few guidelines as to the better approach. Because the consequences of these procedures may take many years to surface (consistent with a stem cell role in long‐term tissue maintenance), guidance may be provided by the elucidation of underlying principles from these approaches. Illustrative examples from clinical, basic research and biotechnology, particularly relating to pterygium, ocular surface squamous neoplasia, dry‐eye syndrome, corneal rehabilitation and replacement, cataract surgery, strabismus surgery and bionic eye research, are described. An unexpected consequence of bionic device development has been an appreciation of the sophistication of tissues being replaced, given the limitations of available biomaterials. Examples of how this has provided insights into ocular disease will be illustrated. Stem cell and biomaterial technologies are starting to impact at a time when cost‐effectiveness is under scrutiny. Both efficacy and cost will need to be considered as these interventions are introduced. It appears that the paradigm shift rate is accelerating and there is evidence of this in ophthalmology. Lessons learned from the areas of destructive versus reconstructive surgery and the limitations of development of bionic replacements will be used to illustrate how new procedures and technologies can be developed.     

Androgen receptor signaling–mitochondrial DNA–oxidative phosphorylation: A critical triangle in early prostate cancer

Mitochondria are more than just the cellular powerhouse. They also play key roles in vital functions such as apoptosis, metabolism regulation, and other intracellular interactions. The mitochondrial DNA (mtDNA) encodes for 12 subunits of the oxidative phosphorylation (OXPHOS) system. Depletion of mtDNA in androgen-dependent prostate cancer (PCa) cell lines renders them androgen-independent and more aggressive. Paradoxically, pharmaceutical inhibition of OXPHOS is lethal for subsets of PCa cells, whereas others become dependent on androgen receptor (AR) signaling for survival. Given that the AR-mitochondria interaction is critical for early PCa, it is crucial to understand the details of this interaction. Technical hurdles have made mitochondria traditionally difficult to study, with many techniques used for isolation masking the properties of given individual mitochondria. Although the isolation of mitochondria enables us to study OXPHOS, we miss the context in which mitochondria interact with the rest of the cell. Both AR signaling and mtDNA affect apoptosis, metabolism regulation, cellular calcium storage and homeostasis, intracellular calcium signaling, and redox homeostasis. In this review, we will attempt to understand how the crosstalk between AR-mtDNA-OXPHOS is responsible for “life or death” decisions inside the cells. Our aim is to point toward potential vulnerabilities that can lead to the discovery of novel therapeutic targets.     

A population-level application of a method for estimating the timing of HIV acquisition among migrants to Australia

Introduction

Australia has set the goal for the virtual elimination of HIV transmission by the end of 2022, yet accurate information is lacking on the level of HIV transmission occurring among residents. We developed a method for estimating the timing of HIV acquisition among migrants, relative to their arrival in Australia. We then applied this method to surveillance data from the Australian National HIV Registry with the aim of ascertaining the level of HIV transmission among migrants to Australia occurring before and after migration, and to inform appropriate local public health interventions.

Methods

We developed an algorithm incorporating CD4⁺ T-cell decline back-projection and enhanced variables (clinical presentation, past HIV testing history and clinician estimate of the place of HIV acquisition) and compared it to a standard algorithm which uses CD4⁺ T-cell back-projection only. We applied both algorithms to all new HIV diagnoses among migrants to estimate whether HIV infection occurred before or after arrival in Australia.

Results

Between 1 January 2016 and 31 December 2020, 1909 migrants were newly diagnosed with HIV in Australia, 85% were men, and the median age was 33 years. Using the enhanced algorithm, 932 (49%) were estimated to have acquired HIV after arrival in Australia, 629 (33%) before arrival (from overseas), 250 (13%) close to arrival and 98 (5%) were unable to be classified. Using the standard algorithm, 622 (33%) were estimated to have acquired HIV in Australia, 472 (25%) before arrival, 321 (17%) close to arrival and 494 (26%) were unable to be classified.

Conclusions

Using our algorithm, close to half of migrants diagnosed with HIV were estimated to have acquired HIV after arrival in Australia, highlighting the need for tailored culturally appropriate testing and prevention programmes to limit HIV transmission and achieve elimination targets. Our method reduced the proportion of HIV cases unable to be classified and can be adopted in other countries with similar HIV surveillance protocols, to inform epidemiology and elimination efforts.     

Patient and nursing experience of flash glucose monitoring following kidney transplantation

Flash glucose monitoring (FGM) is increasingly used for blood glucose assessment due to ease of use and is now subsidized in Australia for blood glucose measurement for patients with Type 1 Diabetes Mellitus. Dysglycaemia is common following kidney transplantation and is associated with worse outcomes and there are data to support the use of FGM post-transplant to better detect and manage changes in blood glucose levels. There is, however, no data on patient or staff perceptions of FGM, or resource implications in this setting. We prospectively evaluated patients and nursing staff experiences of FGM compared to traditional capillary glucose measurement in the immediate post-transplant setting, along with resource utilization, cost of testing, staff time taken to test and accuracy. Twenty-one kidney transplant recipients had a FGM sensor applied in the post-operative period and results compared to capillary blood glucose monitoring (CBGM) measured at least four times a day. Six-hundred-fifty-six glucose measurements were obtained, median per patient of 30 readings (IQR 10). Pearson's correlation between FGM and CBGM readings is 0.95 (p < .001). FGM readings were lower than CBGM by an average of 1.2 mmol/L (SD 0.7). Using a 5-point preference questionnaire (with ratings varying from strongly disagree-strongly agree), both patients and nurses were highly satisfied with the usability and convenience of FGM, with all preferring FGM over CBGM. Average time to perform FGM was 3.6 s versus 64 s for CBGM. In average, cost of FGM was $58 less than traditional testing per patient. FGM is an accurate, convenient and cost-effective tool that may support optimal management of glycaemic control in the post-transplant period.