The mental health of Australians bereaved during the first two years of the COVID-19 pandemic: a latent class analysis.

BACKGROUND: The COVID-19 pandemic disrupted many areas of life, including culturally accepted practices at end-of-life care, funeral rites, and access to social, community, and professional support. This survey investigated the mental health outcomes of Australians bereaved during this time to determine how these factors might have impacted bereavement outcomes. METHODS: An online survey indexing pandemic and bereavement experiences, levels of grief, depression, anxiety, and health, work, and social impairment. Latent class analysis (LCA) was used to identify groups of individuals who shared similar symptom patterns. Multinomial regressions identified pandemic-related, loss-related, and sociodemographic correlates of class membership. RESULTS: 1911 Australian adults completed the survey. The LCA identified four classes: low symptoms (46.8%), grief (17.3%), depression/anxiety (17.7%), and grief/depression/anxiety (18.2%). The latter group reported the highest levels of health, work, and social impairment. The death of a child or partner and an inability to care for the deceased due to COVID-19 public health measures were correlated with grief symptoms (with or without depression and anxiety). Preparedness for the person's death and levels of pandemic-related loneliness and social isolation differentiated all four classes. Unemployment was associated with depression/anxiety (with or without grief). CONCLUSIONS: COVID-19 had profound impacts for the way we lived and died, with effects that are likely to ricochet through society into the foreseeable future. These lessons learned must inform policymakers and healthcare professionals to improve bereavement care and ensure preparedness during and following future predicted pandemics to prevent negative impacts.

Skeletal muscle IL-15/IL-15Rα and myofibrillar protein synthesis after resistance exercise.

In vitro and in vivo studies described the myokine IL-15 and its receptor IL-15Rα as anabolic/anti-atrophy agents, however, the protein expression of IL-15Rα has not been measured in human skeletal muscle and data regarding IL-15 expression remain inconclusive. The purpose of the study was to determine serum and skeletal muscle IL-15 and IL-15Rα responses to resistance exercise session and to analyze their association with myofibrillar protein synthesis (MPS). Fourteen participants performed a bilateral leg resistance exercise composed of four sets of leg press and four sets of knee extension at 75% 1RM to task failure. Muscle biopsies were obtained at rest, 0, 4 and 24 hours post-exercise and blood samples at rest, mid-exercise, 0, 0.3, 1, 2, 4 and 24 hours post-exercise. Serum IL-15 was increased by ~5.3-fold immediately post-exercise, while serum IL-15Rα decreased ~75% over 1 hour post-exercise (P<.001). Skeletal muscle IL-15Rα mRNA and protein expression were increased at 4 hours post-exercise by ~2-fold (P<.001) and ~1.3-fold above rest (P=.020), respectively. At 24 hours post-exercise, IL-15 (P=.003) and IL-15Rα mRNAs increased by ~2-fold (P=.002). Myofibrillar fractional synthetic rate between 0-4 hours was associated with IL-15Rα mRNA at rest (r=.662, P=.019), 4 hours (r=.612, P=.029), and 24 hours post-exercise (r=.627, P=.029). Finally, the muscle IL-15Rα protein up-regulation was related to Leg press 1RM (r=.688, P=.003) and total weight lifted (r=.628, P=.009). In conclusion, IL-15/IL-15Rα signaling pathway is activated in skeletal muscle in response to a session of resistance exercise.

Effects of leucine and its metabolite ß-hydroxy-ß-methylbutyrate on human skeletal muscle protein metabolism.

Maintenance of skeletal muscle mass is contingent upon the dynamic equilibrium (fasted losses-fed gains) in protein turnover. Of all nutrients, the single amino acid leucine (Leu) possesses the most marked anabolic characteristics in acting as a trigger element for the initiation of protein synthesis. While the mechanisms by which Leu is 'sensed' have been the subject of great scrutiny, as a branched-chain amino acid, Leu can be catabolized within muscle, thus posing the possibility that metabolites of Leu could be involved in mediating the anabolic effect(s) of Leu. Our objective was to measure muscle protein anabolism in response to Leu and its metabolite HMB. Using [1,2-(13)C2]Leu and [(2)H5]phenylalanine tracers, and GC-MS/GC-C-IRMS we studied the effect of HMB or Leu alone on MPS (by tracer incorporation into myofibrils), and for HMB we also measured muscle proteolysis (by arteriovenous (A-V) dilution). Orally consumed 3.42 g free-acid (FA-HMB) HMB (providing 2.42 g of pure HMB) exhibited rapid bioavailability in plasma and muscle and, similarly to 3.42 g Leu, stimulated muscle protein synthesis (MPS; HMB +70% vs. Leu +110%). While HMB and Leu both increased anabolic signalling (mechanistic target of rapamycin; mTOR), this was more pronounced with Leu (i.e. p70S6K1 signalling 90 min vs. 30 min for HMB). HMB consumption also attenuated muscle protein breakdown (MPB; -57%) in an insulin-independent manner. We conclude that exogenous HMB induces acute muscle anabolism (increased MPS and reduced MPB) albeit perhaps via distinct, and/or additional mechanism(s) to Leu.

The novel toluidine sulphonamide EL102 shows pre-clinical in vitro and in vivo activity against prostate cancer and circumvents MDR1 resistance.

BACKGROUND: Taxanes are routinely used for the treatment of prostate cancer, however the majority of patients eventually develop resistance. We investigated the potential efficacy of EL102, a novel toluidine sulphonamide, in pre-clinical models of prostate cancer. METHODS: The effect of EL102 and/or docetaxel on PC-3, DU145, 22Rv1 and CWR22 prostate cancer cells was assessed using cell viability, cell cycle analysis and PARP cleavage assays. Tubulin polymerisation and immunofluorescence assays were used to assess tubulin dynamics. CWR22 xenograft murine model was used to assess effects on tumour proliferation. Multidrug-resistant lung cancer DLKPA was used to assess EL102 in a MDR1-mediated drug resistance background. RESULTS: EL102 has in vitro activity against prostate cancer, characterised by accumulation in G2/M, induction of apoptosis, inhibition of Hif1α, and inhibition of tubulin polymerisation and decreased microtubule stability. In vivo, a combination of EL102 and docetaxel exhibits superior tumour inhibition. The DLKP cell line and multidrug-resistant DLKPA variant (which exhibits 205 to 691-fold greater resistance to docetaxel, paclitaxel, vincristine and doxorubicin) are equally sensitive to EL102. CONCLUSION: EL102 shows potential as both a single agent and within combination regimens for the treatment of prostate cancer, particularly in the chemoresistance setting.

An experimental study to determine the optimal access route for renal artery interventions.

OBJECTIVE: The standard approach for endovascular treatment of the renal artery is access via the common femoral artery. However, approximately one in eight patients have a renal artery take-off angle that is less than 50°. In these patients approaching via a femoral access site can be technically challenging. The goal of this study was to design and implement a set of experiments that could empirically determine the critical renal artery take-off angle at which a superior approach would be employed. METHODS: An experimental model of the abdominal aorta, iliac arteries and the renal arteries was constructed using averaged CT angiography data from 10 patients. A number of guide catheter and guide wire combinations were advanced into this model and the force/displacement response was established. RESULTS: Our results demonstrate that a renal artery take-off angle less than 30° has a reduced probability of achieving stable guide wire placement in comparison with the base 90° anatomy (p ≤ .0001). Additionally, our results indicate that the probability of achieving stable guide wire access is increased if the stiffness mismatch between the guide catheter and guide wire is minimised. CONCLUSIONS: In conclusion, we recommend a superior approach to the renal artery if the renal artery take-off angle is within the range of 33-38° and a stiff guide wire platform (e.g. an Amplatz stiff) is required to complete the procedure. Finally, we report an equation that can be used to determine the difficulty associated with accessing the renal artery in comparison to the base 90° anatomy.

Rural health professionals' perspectives on providing grief and loss support in cancer care.

Research demonstrates considerable inequalities in service delivery and health outcomes for people with cancer living outside large metropolitan cities. Semi-structured interviews with 11 professionals providing grief and loss support for people with cancer and their families in rural, regional, and remote areas Western Australia revealed the challenges they faced in delivering such support. The data are presented in four themes - Inequity of regional versus metropolitan services, Strain of the 'Jack of all trades' role, Constraints to accessing professional development, and Challenges in delivering post-bereavement services. These challenges are likely to be of growing concern given that populations are declining in rural areas as Australia becomes increasingly urban. The findings have implications in enhancing the loss and grief support services available in rural, regional, and remote Western Australia, including those grieving the death of a loved one through cancer.

Increased arterial stiffness in patients with chronic obstructive pulmonary disease: a mechanism for increased cardiovascular risk.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with a 2-3-fold increase in the risk of ischaemic heart disease, stroke and sudden death. The mechanisms responsible for this association are not clear and appear to be independent of smoking history. OBJECTIVE: We test the hypothesis that patients with COPD have increased arterial stiffness and blood pressure in comparison with age and smoking matched controls. METHODS: In a prospective case control study, we recruited 102 patients with COPD and 103 healthy controls matched for age and smoking status. Patients were assessed by clinical history and spirometry, with arterial stiffness and blood pressure determined using radial artery applanation tonometry and sphygmomanometry. RESULTS: Patients with COPD had increased arterial stiffness compared with matched controls, with elevated augmentation pressure (17 (1) vs 14 (1) mm Hg; p = 0.005) and a reduced time to wave reflection (131 (1) vs 137 (2) ms; p = 0.004). These differences were associated with increases in both diastolic (82 (1) vs 78 (1) mm Hg; p = 0.005) and systolic blood pressure (147 (2) vs 132 (2) mm Hg; p<0.001). Serum C reactive protein concentrations were threefold higher in patients (6.1 (0.9) vs 2.3 (0.4) mg/l; p = 0.001). Data are presented as mean (SEM). CONCLUSIONS: Patients with COPD have increased arterial stiffness and blood pressure in comparison with controls matched for age and smoking status. We speculate that increased systemic inflammation and vascular dysfunction could potentially explain the excess cardiovascular morbidity and mortality associated with COPD.

Recollision dynamics and time delay in strong-field double ionization.

Three-dimensional classical ensembles are employed to study recollision dynamics in double ionization of atoms by 780-nm intense lasers. After recollision one electron typically remains bound to the atom for a portion of a laser cycle, during which time the nucleus strongly influences its direction of motion. The electron then escapes over a suppressed barrier, with its final momentum depending critically on the laser phase at escape. The other electron remains unbound after collision, and typically drifts out in a momentum hemisphere opposite from its motion just after the collision. Several example trajectories at intensity 0.4 PW/cm(2) with various time delays between recollision and ionization are presented.

Novel localization of CD38 in perivascular sympathetic nerve terminals.

Using high performance liquid chromatography fraction analysis we have recently established that numerous smooth muscle preparations, including the canine mesenteric artery and vein, release beta-nicotinamide adenine dinucleotide upon short-pulse electrical field stimulation in tetrodotoxin- and omega-conotoxin GVIA-sensitive manners [ Release of beta-nicotinamide adenine dinucleotide upon stimulation of postganglionic nerve terminals in blood vessels and urinary bladder. J Biol Chem 279:48893-48903.]. The beta-nicotinamide adenine dinucleotide metabolites ADP-ribose and cyclic ADP-ribose are also present in the tissue superfusates. CD38 is a multifunctional enzyme involved in the degradation of beta-nicotinamide adenine dinucleotide to ADP-ribose and cyclic ADP-ribose. Western immunoblot analysis revealed that CD38 is expressed in both artery and vein. Confocal laser scanning microscopy established colocalization of CD38 with tyrosine hydroxylase, synaptotagmin and synaptic vesicle protein in both blood vessels. High performance liquid chromatography with fluorescence detection demonstrated that whole tissue segments metabolize 1,N(6)-etheno-nicotinamide adenine dinucleotide to 1,N(6)-etheno-ADP-ribose and nicotinamide-guanine dinucleotide to cyclic GDP-ribose, suggesting the presence of both nicotinamide adenine dinucleotide-glycohydrolase and ADP-ribosyl cyclase activities in these blood vessels. Both enzymes appear to be associated with the membrane fraction, and therefore might be attributed to CD38. These data demonstrate a previously uncharacterized localization of CD38 in perivascular autonomic nerve terminals. Therefore, the beta-nicotinamide adenine dinucleotide/CD38 system may provide new mechanisms in autonomic neurovascular control.

The role of the locus coeruleus in corticotropin-releasing hormone and stress-induced suppression of pulsatile luteinizing hormone secretion in the female rat.

Despite a wealth of evidence for CRH mediating stress-induced suppression of the hypothalamic GnRH pulse generator, and hence reproductive dysfunction, the site and mechanism of action remains elusive. The locus coeruleus (LC), a prominent noradrenergic brain stem nucleus, is innervated by CRH neurons, mediates several behavioral stress responses, and is implicated in the control of pulsatile LH secretion. The aim of this study was to test the hypothesis that LC CRH has a critical role in mediating stress-induced suppression of pulsatile LH secretion in the rat. Ovariectomized rats with 17beta-estradiol or oil-filled s.c. capsules were implanted with bilateral LC and i.v. cannulae. Central administration of CRH (10 ng to 1 microg) resulted in a dose-dependent suppression of LH pulses, which was reversed by a CRH receptor antagonist (alpha-helical CRF(9-41), 1 microg). The induction of c-fos expression in glutamic acid decarboxylase67 immunostained neurons in the preoptic area suggests activation of the secretion of gamma-aminobutyric acid in response to intracoerulear administration of CRH; 17beta-estradiol further increased the percentage of glutamic acid decarboxylase67-positive neurons that expressed fos and augmented suppression of LH pulses. Furthermore, intracoerulear administration of alpha-helical CRF(9-41) completely blocked restraint stress-induced suppression of LH pulses, without affecting the inhibitory response to hypoglycemia. These results suggest that CRH innervation of the LC may play a pivotal, but differential, role in the normal physiological response of stress-induced suppression of the GnRH pulse generator and hence the reproductive system.

Effect of growth hormone (GH) on glycerol and free fatty acid metabolism during exhaustive exercise in GH-deficient adults.

GH is an important regulator of fat metabolism at rest, but it is not known whether it regulates fat metabolism during exercise. To determine whether physiologic concentrations of GH influence fat metabolism during exercise, we randomized 16 GH-deficient adults, receiving long-term (mean duration, 5 yr) GH replacement, to either continue GH (n = 8) or receive identical placebo (n = 8) for a 3-month period. Metabolic studies, at rest, during and following exhaustive exercise were carried out at baseline and at the end of the 3 months. The rate of appearance of glycerol (glycerol Ra, an index of lipolysis) and free fatty acids (FFA, FFA Ra) and the rate of disappearance of FFA (FFA Rd) in the plasma were measured using infusions of (2)H(5)-glycerol and 1-(13)C-palmitic acid. Changes in body composition were assessed using dual-energy x-ray absorptiometry scanning and anthropometric measurements. In the baseline studies, exercise resulted in an increase in plasma glycerol and FFA concentrations, glycerol Ra, FFA Ra, and FFA Rd (P < 0.001). Three months of GH withdrawal resulted in reductions in plasma glycerol and FFA, glycerol Ra, FFA Ra, and FFA Rd at rest (P < 0.05 vs. baseline) and during exercise (P < 0.05 vs. baseline and vs. GH treated). Lean body mass decreased after 3 months of GH withdrawal, but total body fat, trunk fat, waist circumference, and the sum of skinfold thicknesses increased after 3 months of GH withdrawal (P < 0.05 vs. baseline and vs. GH treated). Fasting insulin and homeostasis model assessment of insulin resistance decreased after 3 months of GH withdrawal (P < 0.05 vs. baseline and vs. GH treated). In summary, GH withdrawal for 3 months resulted in reductions in release of glycerol and FFA into the circulation and uptake of FFA into the tissues during intense exercise. These changes were accompanied by reduced lean body mass and increased total body and trunk fat. Further studies are required to determine whether reduced mobilization of fat during exercise contributes to reduced exercise capacity and increased body fat in GH-deficient adults.

Juvenile Niemann-Pick disease with vertical supranuclear ophthalmoplegia. Two cases reports and review of the literature.

Examination of two siblings who had histories of progressive decline in speech, intelligence, and coordination disclosed vertical supranuclear ophthalmoplegia, hepatosplenomegaly, and signs of diffuse CNS dysfunction. Niemann-Pick "foam cells" were found in the bone marrow of both patients. The features of these cases correlate in appearance and clinical findings with those of 21 other previously reported cases, which are reviewed in this article. Knowledge of the clinical manifestations of this particular variety of Niemann-Pick disease should aid in its earlier diagnosis.

Pupil-sparing oculomotor nerve palsy due to midbrain infarction.

Vasculopathic oculomotor nerve palsies with pupillary sparing are thought to be due to ischemic damage to the nerve in the subarachnoid space or the cavernous sinus. We present two cases of patients with isolated pupil-sparing oculomotor nerve palsies due to midbrain infarcts. Focal ischemic midbrain lesions should be considered in cases of pupil-sparing oculomotor nerve palsies.

Relationship between diabetes control and pulmonary function in insulin-dependent diabetes mellitus.

PURPOSE: To evaluate the effect of different levels of glycemic control on the pulmonary function of subjects with type I insulin-dependent diabetes mellitus. PATIENTS AND METHODS: Eighteen subjects with type I insulin-dependent diabetes mellitus with no history or physical findings of respiratory disease. Patients were given insulin therapy with a standard twice-daily insulin injection regimen (standard treatment group) or a subcutaneous insulin infusion device (insulin pump) (intensive treatment group). Glycosylated hemoglobin (HbA1c) levels were determined at quarterly intervals in both groups of patients (standard treatment group, n = 10; intensive treatment group, n = 8). Pulmonary function and diffusing capacity for carbon monoxide (DLCO) were measured after 6 years of continuous follow-up. RESULTS: The average HbA1c in the standard treatment group was significantly higher than that of the intensive treatment group throughout the 6 years of follow-up (p less than 0.001). The forced vital capacity of the standard treatment group was 85 +/- 3% of predicted as compared with 106 +/- 4% of predicted in the intensive treatment group (p less than 0.001). The DLCO was also significantly diminished in the standard treatment group as compared with that in the intensive treatment group (65 +/- 2% versus 87 +/- 4% of predicted) (p less than 0.001). CONCLUSION: These data confirm previous reports of abnormal respiratory function in subjects with insulin-dependent diabetes mellitus and suggest that long-term near-normoglycemia may be beneficial in preventing the deterioration of pulmonary function associated with diabetes mellitus.

A double blind comparison of the effects of amlodipine and enalapril on insulin sensitivity in hypertensive patients.

This study compares the effects of a calcium channel blocker (amlodipine) and an angiotensin converting enzyme inhibitor (enalapril) on in vivo insulin sensitivity in patients with essential hypertension. Forty-six patients with mild and moderate hypertension were studied. After a 2-week single-blind placebo phase, they were randomly assigned to double-blind therapy with either amlodipine (2.5 to 10 mg/day) or enalapril (5 to 40 mg/day) for 16 weeks. Both groups were comparable in terms of demographic characteristics, degree of obesity, metabolic parameters, and arterial blood pressure. Insulin sensitivity was measured at baseline and at week 16 during the active phase using euglycemic hyperinsulinemic clamps. Arterial blood pressure decreased similarly in both groups. Whole body glucose uptake (M-value) increased with amlodipine from 3.63 +/- 0.32 (mean +/- SEM) to 3.97 +/- 0.31 mg/kg/min (P = .02). A similar tendency was observed with enalapril: from 3.59 +/- 0.32 to 3.94 +/- 0.30 mg/kg/min (P = .09). A trend to lower steady-state insulin level during the second clamp (compared to baseline) was observed in both groups. The clamp-derived insulin sensitivity index (that corrects for steady-state insulin levels and glucose levels during the clamp) increased similarly in both groups: from 1.15 +/- 0.11 to 1.39 +/- 0.13 with amlodipine (P = .03) and from 1.25 +/- 0.13 to 1.49 +/- 0.16 with enalapril (P = .01). LDL cholesterol decreased with amlodipine (mean change, -11.3 mg/dL, P = .004). Amlodipine and enalapril were associated with increments in insulin sensitivity. Amlodipine provided an additional benefit with decreased low density lipoprotein cholesterol levels.

Relationship between insulin sensitivity, hyperinsulinemia, and insulin-mediated sympathetic activation in normotensive and hypertensive subjects.

The adrenergic response to high physiological hyperinsulinemia was studied in 39 hypertensive subjects (28 men and 11 women) and 25 normal volunteers (15 men and 10 women), using the euglycemic clamp technique. Control studies using 0.45% saline infusions (sham studies) were also performed. Before and during the clamp procedure, plasma norepinephrine (NE) and epinephrine (E) were measured using a high performance liquid chromatographic method (HPLC). The association between the increment in NE and E levels and insulin sensitivity, steady-state insulin level during the clamps, waist to hip ratio (WHR), baseline NE levels and gender was studied. NE levels increased during the hyperinsulinemic period (mean increase 46 +/- 6 pmol P < .001 upsilon baseline and P < .01 upsilon sham studies). E levels did not differ between the insulin clamps and the sham studies. Insulin sensitivity was not significantly associated with the increment in NE. Hypertensive subjects had a higher NE increase than the normotensive individuals (55 +/- 7 upsilon 30 +/- 10 pmol, P = .03), but also had higher insulin levels during the clamps (839 +/- 43 upsilon 522 +/- 38 pmol, P < .001). Insulin levels accounted for most of the differences in NE increase between the normotensive and hypertensive groups. Gender, adiposity and WHR were also associated with NE increment. We conclude that the insulin mediated sympathetic activation is not affected in the presence of decreased insulin sensitivity for glucose utilization. The greater degree of sympathetic activation observed in hypertensive subjects is a function of the level of insulinemia obtained during the clamps.

Disk edema and peripheral neuropathy.

A 55-year-old woman presented with an eight-year history of progressive gait dysfunction and a 2-3 week history of horizontal diplopia. Examination of the patient revealed acute papilledema, intermittent esotropia, and upper and lower motor neuron findings in her lower extremities. CT scan of the head showed communicating hydrocephalus. A spinal cord tumor extending from T11 to L3 was visualized by MR imaging of the spine. All of her symptoms, except for a left foot drop, resolved with aggressive removal of the tumor, which was a myxopapillary ependymoma. Mechanisms of the neuro-ophthalmic picture and treatment of this syndrome are discussed.