Expectations and outcomes of varying treatment strategies for CML presenting during pregnancy.

Diagnosing chronic myeloid leukaemia (CML) during pregnancy is rare. Tyrosine kinase inhibitors (TKIs) have traditionally been contraindicated owing to their teratogenicity. Management decisions should consider the risks to mother and foetus of uncontrolled disease and teratogenic medications. Further cases are required to build upon the paucity of current literature. We report 22 cases of CML diagnosed during pregnancy from 2002 to date. Twenty-one pregnancies resulted in healthy babies and one patient miscarried. Some patients remained untreated throughout pregnancy but the majority received one or both of interferon-α and leucapheresis. One patient was started on imatinib at Week 26, and one on hydroxycarbamide in the third trimester. We report haematological parameters during pregnancy to provide clinicians with realistic expectations of management. There were no fetal abnormalities related to treatment during pregnancy. Seventeen patients achieved at least major molecular response on first-line TKI. A diagnosis of CML during pregnancy can be managed without significant consequences for mother or child. Leucapheresis and interferon-α are generally safe throughout pregnancy. Despite having been avoided previously, there is growing evidence that certain TKIs may be used in particular circumstances during the later stages of pregnancy. Future work should aim to further elucidate this safety profile.

Managing women of childbearing age with chronic myeloid leukemia: safety and treatment considerations.

INTRODUCTION: TKIs are paradigmatic in CML management and offer patients the prospect of a normal life expectancy. As a consequence, the focus of both the clinician and patient has shifted to considerations of quality of life, including the ability to parent children. Unfortunately, TKIs are teratogenic so that alternative treatment options may be required during pregnancy to adequately control disease and minimize risk. AREAS COVERED: In this review, we summarize and provide an overview of the literature on the management of CML in women of childbearing age. We discuss the various treatment options as well as their advantages, disadvantages, and safety considerations. We discuss CML in the context of: 1) planned pregnancies with CML; 2) unplanned pregnancies with CML; 3) CML diagnosed during pregnancy. EXPERT OPINION: Confidence in managing pregnancy and CML continues to grow. In the majority of cases, with careful planning and counseling, no treatment is required and disease control can be safely regained after pregnancy ends. For those who require treatment, various options are available and there is growing evidence to suggest that some TKIs may be safe in the later stages of pregnancy.

Cardiopulmonary exercise testing for heart failure: pathophysiology and predictive markers.

Despite the numerous recent advancements in therapy, heart failure (HF) remains a principle cause of both morbidity and mortality. HF with preserved ejection fraction (HFpEF), a condition that shares the prevalence and adverse outcomes of HF with reduced ejection fraction, remains poorly recognised in its initial manifestations. Cardiopulmonary exercise testing (CPET), defined as a progressive work exercise test that includes non-invasive continuous measurement of cardiovascular and respiratory parameters, provides a reliable mode to evaluate for early features and for the assessment of prognostic features of both forms of HF. While CPET measurements are standard of care for advanced HF and transplant programmes, they merit a broader clinical application in the early diagnosis and assessment of patients with HFpEF. In this review, we provide an overview of the pathophysiology of exercise intolerance in HF and discuss key findings in CPETs used to evaluate both severity of impairment and the prognostic implications.

A new experimental model for the investigation of sequential hermaphroditism.

The stunning sexual transformation commonly triggered by age, size or social context in some fishes is one of the best examples of phenotypic plasticity thus far described. To date our understanding of this process is dominated by studies on a handful of subtropical and tropical teleosts, often in wild settings. Here we have established the protogynous New Zealand spotty wrasse, Notolabrus celidotus, as a temperate model for the experimental investigation of sex change. Captive fish were induced to change sex using aromatase inhibition or manipulation of social groups. Complete female-to-male transition occurred over 60 days in both cases and time-series sampling was used to quantify changes in hormone production, gene expression and gonadal cellular anatomy. Early-stage decreases in plasma 17ß-estradiol (E2) concentrations or gonadal aromatase (cyp19a1a) expression were not detected in spotty wrasse, despite these being commonly associated with the onset of sex change in subtropical and tropical protogynous (female-to-male) hermaphrodites. In contrast, expression of the masculinising factor amh (anti-Müllerian hormone) increased during early sex change, implying a potential role as a proximate trigger for masculinisation. Collectively, these data provide a foundation for the spotty wrasse as a temperate teleost model to study sex change and cell fate in vertebrates.

In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial.

BACKGROUND: Loss of mitochondrial function contributes to fatigue, exercise intolerance and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial. METHODS: Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling (ATP supply per O2 uptake; P/O) at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions. RESULTS: A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo (ΔATPmax; P = 0.055, %ΔATPmax; P = 0.045) immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI. CONCLUSIONS: These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.

Blood biomarkers for memory: toward early detection of risk for Alzheimer disease, pharmacogenomics, and repurposed drugs.

Short-term memory dysfunction is a key early feature of Alzheimer's disease (AD). Psychiatric patients may be at higher risk for memory dysfunction and subsequent AD due to the negative effects of stress and depression on the brain. We carried out longitudinal within-subject studies in male and female psychiatric patients to discover blood gene expression biomarkers that track short term memory as measured by the retention measure in the Hopkins Verbal Learning Test. These biomarkers were subsequently prioritized with a convergent functional genomics approach using previous evidence in the field implicating them in AD. The top candidate biomarkers were then tested in an independent cohort for ability to predict state short-term memory, and trait future positive neuropsychological testing for cognitive impairment. The best overall evidence was for a series of new, as well as some previously known genes, which are now newly shown to have functional evidence in humans as blood biomarkers: RAB7A, NPC2, TGFB1, GAP43, ARSB, PER1, GUSB, and MAPT. Additional top blood biomarkers include GSK3B, PTGS2, APOE, BACE1, PSEN1, and TREM2, well known genes implicated in AD by previous brain and genetic studies, in humans and animal models, which serve as reassuring de facto positive controls for our whole-genome gene expression discovery approach. Biological pathway analyses implicate LXR/RXR activation, neuroinflammation, atherosclerosis signaling, and amyloid processing. Co-directionality of expression data provide new mechanistic insights that are consistent with a compensatory/scarring scenario for brain pathological changes. A majority of top biomarkers also have evidence for involvement in other psychiatric disorders, particularly stress, providing a molecular basis for clinical co-morbidity and for stress as an early precipitant/risk factor. Some of them are modulated by existing drugs, such as antidepressants, lithium and omega-3 fatty acids. Other drug and nutraceutical leads were identified through bioinformatic drug repurposing analyses (such as pioglitazone, levonorgestrel, salsolidine, ginkgolide A, and icariin). Our work contributes to the overall pathophysiological understanding of memory disorders and AD. It also opens new avenues for precision medicine- diagnostics (assement of risk) as well as early treatment (pharmacogenomically informed, personalized, and preventive).

Correction to: Oral propranolol in prevention of severe retinopathy of prematurity: a systematic review and meta-analysis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Oral propranolol in prevention of severe retinopathy of prematurity: a systematic review and meta-analysis.

OBJECTIVE: To systematically assess the efficacy of oral beta blockage treatment in primary (before established) and secondary (in threshold stages) prevention of severe retinopathy of prematurity (ROP) in premature infants born ≤32 weeks gestational age. STUDY DESIGN: Following the PRISMA guidelines, published literature was systematically assessed up to April 27, 2018. Trials and observational studies, in which beta blockage was used to prevent severe ROP (defined as stage ≥3, or requiring treatment) were included. Meta-analyses including random effects models were conducted to determine the overall effect of oral beta blockage on prevention of ROP. RESULTS: Six studies (five clinical trials and one observational study) including 461 infants met inclusion criteria using propranolol. The pooled relative risk (RR) of severe ROP in the primary and secondary prophylaxis groups were 0.65 (95% CI 0.43-0.98, NNT = 7) and 0.48 (95% CI 0.35-0.65, NNT = 6) in RCTs, respectively. The RR of severe ROP in one observational study was 0.21 (95% CI 0.08-0.55) with a NNT of 3. There were low heterogeneity and publication bias. Side effects occurred in 8.4% of participants on propranolol. CONCLUSIONS: Systematic assessment of studies showed that prophylactic oral propranolol appeared to be effective in preventing severe ROP in premature infants ≤32 weeks gestational age. Additional well powered, multinational, randomized control trials reporting on long-term outcomes are needed.

Double-lumen tracheal tubes and bougies: a bench study to investigate factors that influence the risk of shearing.

Tracheal intubation with a double-lumen tube can be more challenging than with a single-lumen tube. A bougie can be used to facilitate intubation. Case reports have described fragment shearing from bougies when they are removed from the tube after intubation. These fragments have the potential to cause harm. It has even been suggested that bougies and double-lumen tubes should not be used together. We conducted a benchtop trial to investigate factors that influence the risk of shearing. We investigated three brands of double-lumen tube (each in three sizes and both lateralities) and four brands of bougie. We simulated one intubation and 29 further insertions/removals of bougie with every bougie-double-lumen tube combination. We inspected the inside of the tube for evidence of shearing after first, tenth and thirtieth removals. We found that brand of bougie, brand of double-lumen tube and size of double-lumen tube (but not its laterality) all influenced the degree of shearing. Certain bougie-double-lumen tube combinations produced a particularly high degree of shearing, so these should be avoided.

Extended duration regional analgesia for total knee arthroplasty: a randomised controlled trial comparing five days to three days of continuous adductor canal ropivacaine infusion.

There is a growing body of evidence in favour of continuous adductor canal block (CACB) for total knee arthroplasty. However, there are no studies describing the optimal duration of the infusion. At our institution the usual practice was to stop the infusion on day three. Our hypothesis was that extending the infusion to five days would improve analgesia and quality of recovery. A prospective, non-blinded, randomised trial was undertaken. Patients received a continuous infusion of 0.2% ropivacaine via an adductor canal catheter for either three or five days. Primary outcome was pain while walking during the 24-hour period up to day five (numeric rating scale from 0 to 10). The minimum clinically important difference was set at 1.5 on the numeric rating scale. Secondary outcome measures included quality of recovery, mobility, pain while walking on postoperative day six, Oxford Knee Scores, and complications. Eighty-six patients were recruited with 43 randomised to each group. Seventy-eight were analysed. Median pain scores reported on day five were significantly better in the intervention group (1 versus 3, P=0.003). Furthermore, quality of recovery (QOR-15) scores were significantly better in the intervention group (133.6 versus 123.4, P=0.017). No statistically significant difference between groups was identified for other secondary outcome measures. CACB prolonged to five days provides superior analgesia and a higher quality of recovery on postoperative days four and five compared to a three-day infusion. This benefit did not extend beyond the period of infusion.

Lateralized microstructural changes in early-stage Parkinson's disease in anterior olfactory structures, but not in substantia nigra.

Parkinson's disease (PD) is a progressive neurological disorder characterized by motor symptoms as well as severe deficits in olfactory function and microstructural changes in olfactory brain regions. Because of the evidence of asymmetric neuropathological features in early-stage PD, we examined whether lateralized microstructural changes occur in olfactory brain regions and the substantia nigra in a group of early-stage PD patients. Using diffusion tensor imaging (DTI) and the University of Pennsylvania Smell Identification Test (UPSIT), we assessed 24 early-stage PD patients (Hoehn and Yahr stage 1 or 2) and 26 healthy controls (HC). We used DTI and a region of interest (ROI) approach to study the microstructure of the left and right anterior olfactory structures (AOS; comprising the olfactory bulbs and anterior end of the olfactory tracts) and the substantia nigra (SN). PD patients had reduced UPSIT scores relative to HC and showed increased mean diffusivity (MD) in the SN, with no lateralized differences. Significant group differences in fractional anisotropy (FA) and MD were seen in the AOS, but these differences were restricted to the right side and were not associated with the primary side of motor symptoms amongst PD patients. No associations were observed between lateralized motor impairment and lateralized microstructural changes in AOS. Impaired olfaction and microstructural changes in AOS are useful for early identification of PD but asymmetries in AOS microstructure seem unrelated to the laterality of PD motor symptoms.

Clinical outcomes for the obese hospital inpatient: An observational study.

OBJECTIVES: The prevalence of obesity presents a burden for Australian health care. The aim of this study was to determine whether severely obese hospital inpatients have worse outcomes. METHODS: This is an observational cohort study, using data from all adult patients admitted to hospital for all elective and emergency admissions of patients aged over 18 years to two large Australian urban hospitals. We measured their length of stay, intensive care unit admission rate, intensive care unit length of stay, mortality and readmission rates within 28 days of discharge and compared these outcomes in the severely obese and non-severely obese subjects using t-test or chi-square test as appropriate. RESULTS: Between February 2008 and February 2012, 120,872 were admitted to hospital 193,800 times; 2701 patients were identified as severely obese (2.23%) and 118,171 patients were non-severely obese. If admitted as an emergency, severely obese patients have worse outcomes and consume more resources than other patients. These outcomes are still worse, but less so, if the obese patient is admitted as an elective patient suggesting that anticipation of any obesity-specific problems can have a beneficial effect. CONCLUSION: Upon admission or discharge of severely obese hospital inpatients, health care plans should be even more carefully laid than usual to reduce the risk of readmission.

Quantitative trait locus mapping and functional genomics of an organophosphate resistance trait in the western corn rootworm, Diabrotica virgifera virgifera.

The western corn rootworm, Diabrotica virgifera virgifera, is an insect pest of corn and population suppression with chemical insecticides is an important management tool. Traits conferring organophosphate insecticide resistance have increased in frequency amongst D. v. virgifera populations, resulting in the reduced efficacy in many corn-growing regions of the USA. We used comparative functional genomic and quantitative trait locus (QTL) mapping approaches to investigate the genetic basis of D. v. virgifera resistance to the organophosphate methyl-parathion. RNA from adult methyl-parathion resistant and susceptible adults was hybridized to 8331 microarray probes. The results predicted that 11 transcripts were significantly up-regulated in resistant phenotypes, with the most significant (fold increases ≥ 2.43) being an α-esterase-like transcript. Differential expression was validated only for the α-esterase (ST020027A20C03), with 11- to 13-fold greater expression in methyl-parathion resistant adults (P < 0.05). Progeny with a segregating methyl-parathion resistance trait were obtained from a reciprocal backcross design. QTL analyses of high-throughput single nucleotide polymorphism genotype data predicted involvement of a single genome interval. These data suggest that a specific carboyxesterase may function in field-evolved corn rootworm resistance to organophosphates, even though direct linkage between the QTL and this locus could not be established.

Treating depression with botulinum toxin: a pooled analysis of randomized controlled trials.

INTRODUCTION: Botulinum toxin A (BTA) injection into the glabellar region is currently being studied as a treatment for major depressive disorder (MDD). Here we explore efficacy data of this novel approach in a pooled analysis. METHODS: A literature search revealed 3 RCTs on this topic. Individual patient data and clinical end points shared by these 3 trials were pooled and analyzed as one study (n=134) using multiple regression models with random effects. RESULTS: In the pooled sample, the BTA (n=59) and the placebo group (n=75) did not differ in the baseline variables. Efficacy outcomes revealed BTA superiority over placebo: Improvement in the Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale 6 weeks after baseline was 45.7% for BTA vs. 14.6% for placebo (p<0.0001), corresponding to a BTA response rate of 54.2% (vs. 10.7%) and a BTA remission rate of 30.5% (vs. 6.7%). DISCUSSION: Equalling the status of a meta-analysis, this study increases evidence that a single treatment of BTA into the glabellar region can reduce symptoms of MDD. Further studies are needed to better understand how BTA exerts its mood-lifting effect.

Performance of influenza-specific triage tools in an H1N1-positive cohort: P/F ratio better predicts the need for mechanical ventilation and critical care admission.

BACKGROUND: Pandemic influenza presents a major threat to global health and socioeconomic well-being. Future demand for critical care may outstrip supply and force clinicians to triage patients for admission. We evaluated the Simple Triage Scoring System (STSS), Ontario Health Plan for an Influenza Epidemic (OHPIP) and PaO2 /FiO2  (P/F) ratio to determine utility in predicting need for mechanical ventilation. METHODS: We conducted a retrospective case note review of patients admitted to two centres, Royal Liverpool University Hospital and Countess of Chester Hospital, during the UK influenza pandemic of 2010-11. Demand for critical care during this period forced hospitals in Cheshire and Merseyside to implement escalation policies and increase capacity. Inclusion criteria were polymerase chain reaction-confirmed H1N1 influenza and age >18 years. Exclusion criteria were no evidence of treatment for influenza, patient not admitted to hospital or the inability to locate case notes. RESULTS: One hundred and one patients were included, 29 were admitted to critical care and 23 required mechanical ventilation. The P/F ratio predicted the need for mechanical ventilation with a receiver operating characteristic area under the curve (ROC AUC) of 0.885 (CI 0.817-0.952). Predictive ability was not reduced when the P/F ratio had to be estimated using the Pandharipande tool. The STSS score predicted the need for mechanical ventilation [ROC AUC 0.798 (CI 0.704-0.891)]. The reverse triage component of the OHPIP tool was a poor predictor of patient outcome. CONCLUSIONS: The P/F ratio was a better predictor of need for mechanical ventilation than STSS. The P/F ratio is a simple and accepted determinant of hypoxaemia and should be used if secondary triaging becomes necessary during future influenza pandemics.

Dead space: the physiology of wasted ventilation.

An elevated physiological dead space, calculated from measurements of arterial CO2 and mixed expired CO2, has proven to be a useful clinical marker of prognosis both for patients with acute respiratory distress syndrome and for patients with severe heart failure. Although a frequently cited explanation for an elevated dead space measurement has been the development of alveolar regions receiving no perfusion, evidence for this mechanism is lacking in both of these disease settings. For the range of physiological abnormalities associated with an increased physiological dead space measurement, increased alveolar ventilation/perfusion ratio (V'A/Q') heterogeneity has been the most important pathophysiological mechanism. Depending on the disease condition, additional mechanisms that can contribute to an elevated physiological dead space measurement include shunt, a substantial increase in overall V'A/Q' ratio, diffusion impairment, and ventilation delivered to unperfused alveolar spaces.

Association of run-in periods with weight loss in obesity randomized controlled trials.

Study-level design characteristics that inform the optimal design of obesity randomized controlled trials (RCTs) have been examined in few studies. A pre-randomization run-in period is one such design element that may influence weight loss. We examined 311 obesity RCTs published between 1 January 2007 and 1 July 2009 that examine d weight loss or weight gain prevention as a primary or secondary end-point. Variables included run-in period, pre-post intervention weight loss, study duration (time), intervention type, percent female and degree of obesity. Linear regression was used to estimate weight loss as a function of (i) run-in (yes/no) and (ii) run-in, time, percent female, body mass index and intervention type. Interaction terms were also examined. Approximately 19% (18.6%) of the studies included a run-in period, with pharmaceutical studies having the highest frequency. Although all intervention types were associated with weight loss (Mean = 2.80 kg, SD = 3.52), the inclusion of a pre-randomization run-in was associated with less weight loss (P = 0.0017) compared with studies that did not include a run-in period. However, this association was not consistent across intervention types. Our results imply that in trials primarily targeting weight loss in adults, run-in periods may not be beneficial for improving weight loss outcomes in interventions.

Odorant receptors of a primitive hymenopteran pest, the wheat stem sawfly.

The wheat stem sawfly, Cephus cinctus, is an herbivorous hymenopteran that feeds exclusively on members of the Graminae family. Synanthropically, it has become one of the most important insect pests of wheat grown in the northern Great Plains region of the USA and Canada. Insecticides are generally ineffective because of the wheat stem sawfly's extended adult flight period and its inaccessible larval stage, during which it feeds within the wheat stems, making it virtually intractable to most pest management strategies. While research towards integrated pest management strategies based on insect olfaction has proved promising, nothing is known about the molecular basis of olfaction in this important pest species. In this study we identified 28 unique odorant receptor (Or) transcripts from an antennal transcriptome. A phylogenetic analysis with the predicted Ors from the honey bee and jewel wasp genomes revealed at least four clades conserved amongst all three Hymenoptera species. Antennal expression levels were analysed using quantitative real-time PCR, and one male-biased and five female-biased Ors were identified. This study provides the basis for future functional analyses to identify behaviourally active odours that can be used to help develop olfactory-mediated pest management tools.