Development of an automated production process of [64Cu][Cu (ATSM)] for positron emission tomography imaging and theranostic applications

Cyclotron-produced copper-64 radioisotope tracers offer the possibility to perform both diagnostic investigation by positron emission tomography (PET) and radiotherapy by a theranostic approach with bifunctional chelators. The versatile chemical properties of copper add to the importance of this isotope in medicinal investigation. [⁶⁴Cu][Cu (ATSM)] has shown to be a viable candidate for imaging of tumor hypoxia; a critical tumor microenvironment characteristic that typically signifies tumor progression and resistance to chemo-radiotherapy. Various production and radiosynthesis methods of [⁶⁴Cu][Cu (ATSM)] exist in labs, but usually involved non-standardized equipment with varying production qualities and may not be easily implemented in wider hospital settings. [⁶⁴Cu][Cu (ATSM)] was synthesized on a modified GE TRACERlab FXN automated synthesis module. End-of-synthesis (EOS) molar activity of [⁶⁴Cu][Cu (ATSM)] was 2.2–5.5 Ci/μmol (HPLC), 2.2–2.6 Ci/μmol (ATSM-titration), and 3.0–4.4 Ci/μmol (ICP-MS). Radiochemical purity was determined to be >99% based on radio-HPLC. The final product maintained radiochemical purity after 20 h. We demonstrated a simple and feasible process development and quality control protocols for automated cyclotron production and synthesis of [⁶⁴Cu][Cu (ATSM)] based on commercially distributed standardized synthesis modules suitable for PET imaging and theranostic studies.     

Long-term follow-up of camouflage effects following resin infiltration of post orthodontic white-spot lesions in vivo

Objectives:To reassess the long-term camouflage effects of resin infiltration (Icon, DMG, Hamburg, Germany) of white spot lesions (WSL) and sound adjacent enamel (SAE) achieved in a previous trial. The null hypothesis was tested that there were no significantly different CIE-L*a*b*-ΔE-values between WSL and SAE areas of assessment after at least 24 months (T24) compared to those at baseline (T0).Materials and Methods:Of twenty subjects who received previous resin infiltration treatment of n_teeth = 111 nonrestored, noncavitated postorthodontic WSL after multibracket treatment during a randomized controlled trial and were contacted 20 months after baseline, eight subjects (trial teeth n_teeth = 40; m/f ratio 1/7; age range (mean; SD) 12–17 [15.25; 2.12] years); response rate: 40%) were available for follow-up after at least 24 months (T24). CIE-L*a*b* differences between summarized color and lightness values (ΔE_WSL/SAE) of WSL and SAE were assessed using a spectrophotometer and compared to baseline data assessed prior to infiltration (T0), and those after 6 (T6), and 12 (T12) months using paired t tests at a significance level of α = 5%.Results:T24 assessments were performed after a mean 33.86 (SD: 8.64; Min: 24; Max: 45) months following T0. Mean (SD) ΔE_WSL/SAE units of available teeth were 8.76 (5.33) at baseline; 5.5 (2.75) at T6; 5.2 (2.41) at T12; and 5.57 (2.6) at T24. Comparisons of T6, T12, and T24 with T0 yielded highly significant differences, whereas T6–T24 and T12–T24 differences were found to be not significant.Conclusions:Assimilation of infiltrated WSL to the color of adjacent enamel by resin infiltration is considered to be suitable for the long-term improvement in the esthetic appearance of postorthodontic WSL.     

Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia (COVID STEROID) trial—Protocol and statistical analysis plan

Introduction

Severe acute respiratory syndrome coronavirus-2 has caused a pandemic of coronavirus disease (COVID-19) with many patients developing hypoxic respiratory failure. Corticosteroids reduce the time on mechanical ventilation, length of stay in the intensive care unit and potentially also mortality in similar patient populations. However, corticosteroids have undesirable effects, including longer time to viral clearance. Clinical equipoise on the use of corticosteroids for COVID-19 exists.

Methods

The COVID STEROID trial is an international, randomised, stratified, blinded clinical trial. We will allocate 1000 adult patients with COVID-19 receiving ≥10 L/min of oxygen or on mechanical ventilation to intravenous hydrocortisone 200 mg daily vs placebo (0.9% saline) for 7 days. The primary outcome is days alive without life support (ie mechanical ventilation, circulatory support, and renal replacement therapy) at day 28. Secondary outcomes are serious adverse reactions at day 14; days alive without life support at day 90; days alive and out of hospital at day 90; all-cause mortality at day 28, day 90, and 1 year; and health-related quality of life at 1 year. We will conduct the statistical analyses according to this protocol, including interim analyses for every 250 patients followed for 28 days. The primary outcome will be compared using the Kryger Jensen and Lange test in the intention to treat population and reported as differences in means and medians with 95% confidence intervals.

Discussion

The COVID STEROID trial will provide important evidence to guide the use of corticosteroids in COVID-19 and severe hypoxia.

     

Localized proton magnetic resonance spectroscopy of a cerebellar tumor in a two-year-old child

Noninvasive localized proton magnetic resonance spectroscopy (MRS) was used for differential diagnosis of a focal brain lesion in a 2.5-year-old girl. The clinical signs were a mild head tilt and neck pain. Magnetic resonance imaging (MRI) revealed a lesion in the right hemisphere of the cerebellum, but its nature remained obscure. In this lesion quantitative determinations of cerebral metabolites by fully relaxed, short-echo-time proton MRS revealed markedly lowered N-acetylaspartate (NAA) and pronounced elevations of choline-containing compounds (Cho) and myo-inositol (Ins), whereas metabolite concentrations in cortical gray matter and white matter were within normal ranges. The metabolite pattern of the lesion indicated loss of vital neuroaxonal tissue (low NAA) and enhanced glial proliferation (high Cho and Ins), which, together with the MRI morphology, suggested a brain tumor. The diagnosis was established by neurosurgical exploration and total extirpation of the tumor. Histology confirmed an astrocytoma (WHO II). After 2 weeks' recovery the child was discharged with no neurological signs.     

Balance and gait improved in patients with MS after physiotherapy based on the Bobath concept

Background and Purpose . Patients with multiple sclerosis (MS) tend to have movement difficulties, and the effect of physiotherapy for this group of patients has been subjected to limited systematic research. In the present study physiotherapy based on the Bobath concept, applied to MS patients with balance and gait problems, was evaluated. The ability of different functional tests to demonstrate change was evaluated. Method . A single‐subject experimental study design with ABAA phases was used, and two patients with relapsing–remitting MS in stable phase were treated. Tests were performed 12 times, three at each phase: A (at baseline); B (during treatment); A (immediately after treatment); and A (after two months). The key feature of treatment was facilitation of postural activity and selective control of movement. Several performance and self‐report measures and interviews were used. Results . After intervention, improved balance was shown by the Berg Balance Scale (BBS) in both patients, and improved quality of gait was indicated by the Rivermead Visual Gait Assessment (RVGA). The patients also reported improved balance and gait function in the interviews and scored their condition as ‘much improved’. Gait parameters, recorded by an electronic walkway, changed, but differently in the two patients. Among the physical performance tests the BBS and the RVGA demonstrated the highest change, while no or minimal change was demonstrated by the Rivermead Mobility Index (RMI) and Ratings of Perceived Exertion (RPE). Conclusion . The findings indicate that balance and gait can be improved after physiotherapy based on the Bobath concept, but this should be further evaluated in larger controlled trials of patients with MS. Copyright © 2006 John Wiley & Sons, Ltd.     

Contribution of genetic factors for melanoma susceptibility in sporadic US melanoma patients

Abstract:  The risks of developing malignant melanoma (MM) include ultraviolet irradiation and genetic factors. To examine the contribution of rare and common variation within known MM genes in sporadic US MM patients, coding regions of known MM susceptibility genes [cyclin-dependent kinase inhibitor 2A ( CDKN2A ), cyclin-dependent kinase 4, melanocortin 1 receptor ( MC1R ) and tyrosinase ( TYR )] were resequenced in 109–135 MM cases. The significance of variants was examined by comparing their frequencies in 390 cancer-free controls. Potential deleterious mutations in CDKN2A were found in two patients and two others had variants of unknown significance. Cases were more likely than controls to harbour the MC1R 'R' variants known or predicted to alter its function ( P  = 0.002), particularly the R160W variant ( P  = 0.0035). The associated TYR R402Q variant (rs1126809*A) was found in 29% of cases, similar to what has been described previously. One MM patient with a family history of MM, who had developed other skin cancers, was homozygous for a novel TYR variant (P406L) of unknown significance. Hence, rare variants in TYR may be important risk factors for skin cancer.     

Effects of growth hormone on glucose and fat metabolism in human subjects.

This article focuses on in vivo data from tests performed in normal subjects and in patients who had abnormal growth hormone (GH) status. Experimental data in human subjects demonstrate that GH acutely inhibits glucose disposal in skeletal muscle. At the same time GH stimulates the turnover and oxidation of free fatty acid (FFA), and experimental evidence suggests a causal link between elevated FFA levels and insulin resistance in skeletal muscle. Observational data in GH-deficient adults do not indicate that GH replacement is associated with significant impairment of glucose tolerance, but it is recommended that overdosing be avoided and glycemic control be monitored.     

Lung function development in the first 2 yr of life is independent of allergic diseases by 2 yr

The aim of the study was to assess if lung function at birth predicts lung function at 2 yr and secondly, if lung function development was influenced by the common phenotypes of recurrent bronchial obstruction (rBO) or atopic eczema (AE) by 2 yr. Lung function was assessed at birth (n = 802) and at 2 yr within the prospective birth cohort study 'the Environment and Childhood Asthma Study' in Oslo. The 135 children with lung function measured at birth by tidal flow volume (TFV) loops and passive respiratory mechanics, who were included in a nested case-control study were reinvestigated at 2 yr with clinical examination, TFV loops (n = 90) (mean age 26.6 (3.7 s.d.) months), skin prick test and parental interview. Children were categorized into quartiles (lower, middle two, upper) according to time to peak tidal expiratory flow/total expiratory time (t(PTEF)/t(E)) at birth as well as clinical phenotype based on the presence of rBO and/or AE (ever) by 2 yr. The observed reduction in mean t(PTEF)/t(E) from birth to 2 yr within the quartiles, were not significantly different after controlling for 'regression to the mean'. t(PTEF)/t(E) at birth correlated significantly with t(PTEF)/t(E) at 2 yr, (r = 0.475, p < 0.001). Children with both rBO and AE by 2 yr had significantly lower t(PTEF)/t(E) at 2 yr (p = 0.002) and at birth (p = 0.027), compared with children with no rBO or AE. Clinical phenotype at 2 yr did not influence the change in t(PTEF)/t(E) from birth to 2 yr. This study demonstrates a clear tracking of lung function from birth, not influenced by rBO or AE by 2 yr.