PREDICT-GTN 1: Can we improve the FIGO scoring system in gestational trophoblastic neoplasia?

Gestational trophoblastic neoplasia (GTN) patients are treated according to the eight-variable International Federation of Gynaecology and Obstetrics (FIGO) scoring system, that aims to predict first-line single-agent chemotherapy resistance. FIGO is imperfect with one-third of low-risk patients developing disease resistance to first-line single-agent chemotherapy. We aimed to generate simplified models that improve upon FIGO. Logistic regression (LR) and multilayer perceptron (MLP) modelling (n = 4191) generated six models (M1-6). M1, all eight FIGO variables (scored data); M2, all eight FIGO variables (scored and raw data); M3, nonimaging variables (scored data); M4, nonimaging variables (scored and raw data); M5, imaging variables (scored data); and M6, pretreatment hCG (raw data) + imaging variables (scored data). Performance was compared to FIGO using true and false positive rates, positive and negative predictive values, diagnostic odds ratio, receiver operating characteristic (ROC) curves, Bland-Altman calibration plots, decision curve analysis and contingency tables. M1-6 were calibrated and outperformed FIGO on true positive rate and positive predictive value. Using LR and MLP, M1, M2 and M4 generated small improvements to the ROC curve and decision curve analysis. M3, M5 and M6 matched FIGO or performed less well. Compared to FIGO, most (excluding LR M4 and MLP M5) had significant discordance in patient classification (McNemar's test P < .05); 55-112 undertreated, 46-206 overtreated. Statistical modelling yielded only small gains over FIGO performance, arising through recategorisation of treatment-resistant patients, with a significant proportion of under/overtreatment as the available data have been used a priori to allocate primary chemotherapy. Streamlining FIGO should now be the focus.     

Reading the unique DNA methylation landscape of the brain: Non-CpG methylation,hydroxymethylation, and MeCP2

DNA methylation at CpG dinucleotides is an important epigenetic regulator common to virtually all mammalian cell types, but recent evidence indicates that during early postnatal development neuronal genomes also accumulate uniquely high levels of two alternative forms of methylation, non-CpG methylation and hydroxymethylation. Here we discuss the distinct landscape of DNA methylation in neurons, how it is established, and how it might affect the binding and function of protein readers of DNA methylation. We review studies of one critical reader of DNA methylation in the brain, the Rett syndrome protein methyl CpG-binding protein 2 (MeCP2), and discuss how differential binding affinity of MeCP2 for non-CpG and hydroxymethylation may affect the function of this methyl-binding protein in the nervous system.     

How physiotherapists perceive,interpret, and respond to the ethical dimensions of practice: A qualitative study

The profile and reach of physiotherapy has expanded in areas of extended scope of practice, and broader engagement with population needs beyond the individual treatment encounter. These changes raise increasingly complex ethical challenges evidenced by growth in physiotherapy-based ethics studies and discussions. This paper examines how a broad cross section of Australian physiotherapists perceive, interpret, and respond to ethical challenges in their work contexts and how professional codes of conduct are used in their practice. Using an interpretive qualitative methodology, purposive sampling of 88 members of national clinical special interest groups were recruited for focus group discussions. Narrative-based and thematic data analysis identified ethical challenges as emerging from specific clinical contexts, and influenced by health organizations, funding policies, workplace relationships, and individually held perspectives. Five themes were developed to represent these findings: (1) the working environment, (2) balancing diverse needs and expectation, (3) defining ethics, (4) striving to act ethically, and (5) talking about ethics. The results portray a diverse and complex ethical landscape where therapists encounter and grapple with ethical questions emerging from the impact of funding models and policies affecting clinical work, expanding boundaries and scope of practice and changing professional roles and relationships. Codes of conduct were described as foundational ethical knowledge but not always helpful for “in the moment” ethical decision-making. Based on this research, we suggest how codes of conduct, educators, and professional associations could cultivate and nurture ethics capability in physiotherapy practitioners for these contemporary challenges.     

HIV Protease: Historical Perspective and Current Research

The retroviral protease of human immunodeficiency virus (HIV) is an excellent target for antiviral inhibitors for treating HIV/AIDS. Despite the efficacy of therapy, current efforts to control the disease are undermined by the growing threat posed by drug resistance. This review covers the historical background of studies on the structure and function of HIV protease, the subsequent development of antiviral inhibitors, and recent studies on drug-resistant protease variants. We highlight the important contributions of Dr. Stephen Oroszlan to fundamental knowledge about the function of the HIV protease and other retroviral proteases. These studies, along with those of his colleagues, laid the foundations for the design of clinical inhibitors of HIV protease. The drug-resistant protease variants also provide an excellent model for investigating the molecular mechanisms and evolution of resistance.     

Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies

Background

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS).

Methods

This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation.

Results

The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT.

Conclusions

These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS.

Plain Language Summary

• Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.
• Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.
• Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.
• Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

     

Use of an in vitro model of tissue-engineered human skin to study keratinocyte attachment and migration in the process of reepithelialization

To produce a stable epidermis, keratinocytes need to be firmly attached to the basement membrane. However, following wounding, keratinocytes are required to develop a migratory phenotype in order to reepithelialize the wound. To investigate some of the issues underlying reepithelialization, we have developed a three-dimensional in vitro model of tissue-engineered skin, comprising sterilized human dermis seeded with human keratinocytes and dermal fibroblasts. Using this model, we have shown that the inclusion of fibroblasts within the model increases the stability of keratinocyte attachment. We have also demonstrated that keratinocyte migration occurs most effectively in the absence of a basement membrane and following the inclusion of fibroblasts in the model. In addition, subjecting the keratinocyte layer to mechanical trauma induces a migratory phenotype. We conclude that this three-dimensional in vitro wound model can be used to increase our understanding of the factors that enhance keratinocyte migration and hence wound healing in vivo.     

Death due to anaesthesia at Groote Schuur Hospital, Cape Town--1956-1987. Part II. Causes and changes in aetiological pattern of anaesthetic-contributory death

A general analysis of the clinical failures that were responsible for deaths attributable to anaesthesia over a 30-year period, 1956-1987, is presented. Four particular general failures in clinical management were responsible for 80% of anaesthetic-contributory deaths (ACD). These were in descending order of frequency: (i) failures in airway management, of which the majority were associated with the complications of endotracheal intubation (27% of ACD); (ii) failures in pulmonary ventilation management (20% of ACD); (iii) failures in blood volume control (19% of ACD); and (iv) failures in arrhythmia control (17% of ACD). Computation of these groups of causes by the decade reveals a distinct and progressive change in the aetiological pattern of these deaths with time. While the incidence of ACD over the period decreased 6-fold from 0.43 to 0.07/1,000 anaesthetics, that proportion due to failures in airway management, in general, and complications of intubation, in particular, has progressively increased. This has been accompanied by a reciprocal decrease in deaths due to circulatory factors. It is postulated that this change arises from the fact that the physical skills, manual dexterity and clinical judgement demanded by the former have not changed with time, whereas the latter depend on intellectual responses to information derived from ever-improving vital function monitoring.     

Experience with the 'skew flap' below-knee amputation

A review of 353 lower limb amputations over the last 7 years has been performed to assess the results of the skew flap myoplastic below-knee amputation which was introduced in April 1983 because of reported advantages in terms of wound healing and earlier ambulation. Comparing the first 3 1/2 year period with the second, the total number of amputations decreased by 31 per cent. The number of above-knee amputations remained similar in the two periods (82,62), whilst the number of Gritti-Stokes amputations fell from 79 to 21 (0.001 greater than P greater than 0.01). The proportion of below-knee (BK) amputations increased from 50 (23.7 per cent) to 59 (41.5 per cent) (0.01 greater than P greater than 0.025). The groups were comparable in terms of previous vascular surgery and co-existing medical conditions. The time to full stump healing was significantly shorter in the skew flap group compared with the earlier Burgess type BK amputation (P = 0.001), and there was a trend to fewer stump failures in the skew flap group. We therefore feel that the skew flap amputation gives superior results to the Burgess BK amputation in terms of healing and a lower complication rate, allowing a higher proportion of BK amputations to be performed. A prospective randomized trial of the two techniques is in hand to determine the accuracy of this hypothesis.     

Leptin, lipid and lipid metabolism-related hormones in chronic renal failure in Arabia

SUMMARY: In patients with chronic renal failure (CRF), hyperleptinaemia has been widely reported, but the exact mechanisms leading to elevated leptin levels are unclear. Impaired renal clearance of leptin and the influence of other hormones may be important. In this study, we measured serum leptin levels in 150 patients on haemodialysis, peritoneal dialysis or in the predialysis phase of CRF. Furthermore, we measured plasma levels of insulin, growth hormone (GH) and insulin-like growth factor 1 (IGF-1), as well as plasma levels of triacylglycerols and total low density lipoprotein (LDL)- and high density lipoprotein (HDL)-cholesterol. We observed significantly elevated levels of leptin, particularly in female patients, and leptin was shown to correlate significantly with insulin, total and LDL-cholesterol and log triacylglycerols. Leptin was inversely correlated with GH concentrations, but was not correlated with IGF-1 levels. Despite the multiple correlations established between leptin levels and other variables, only hyperinsulinaemia in CRF seems to be important as a determinator of leptin levels.     

Baclofen-induced disinhibition in area CA1 of rat hippocampus is resistant to extracellular Ba

The mechanism of disinhibition produced by (±)-baclofen was studied using intracellular recording in area CA1 of rat hippocampal slices. Baclofen reversibly depressed monosynaptic IPSPs evoked by direct activation of interneurons in the presence of the excitatory amino acid receptor antagonists 6,7-dinitroquinoxaline-2,3-dione (DNQX) andd,l-2amino-5-phosphonovalerate (APV). Ba²⁺ prevented baclofen-induced hyperpolarization of pyramidal neurons but not depression of monosynaptic IPSPs by baclofen. Baclofen reversibly depressed monosynaptic IPSPs when applied close to the recording site, but was ineffective when applied close to the stimulating site in stratum radiatum. These results suggest that baclofen disinhibits pyramidal neurons in area CA1 of the rat hippocampus by activating receptors on the terminals of inhibitory neurons that are coupled to a Ba²⁺-insensitive effector mechanism.