Identification and characterization of repeat expansions in neurological disorders: Methodologies, tools, and strategies.

Tandem repeats are a common, highly polymorphic class of variation in human genomes. Their expansion beyond a pathogenic threshold is a process that contributes to a wide range of neurological and neuromuscular genetic disorders, of which over 60 have been identified to date. The last few years have seen a resurgence in repeat expansion discovery propelled by technological advancements, enabling the identification of over 20 novel repeat expansion disorders. These expansions can occur in coding or non-coding regions of genes, resulting in a range of pathogenic mechanisms. In this article, we review strategies, tools and methods that can be used for efficient detection and characterization of known repeat expansions and identification of new expansion disorders. Features that can be used to prioritize repeat expansions include anticipation, which is characterized by increased severity or earlier onset of symptoms across generations, and founder effects, which contribute to higher prevalence rates in certain populations. Classical technologies such as Southern blotting, repeat-primed polymerase chain reaction (PCR) and long-range PCR can still be used to detect known repeat expansions, although they usually have significant limitations linked to the absence of sequence context. Targeted sequencing of known expansions using either long-range PCR or CRISPR-Cas9 enrichment combined with long-read sequencing or adaptive nanopore sampling are usually better but more expensive alternatives. The development of new bioinformatics tools applied to short-read genome data can now be used to detect repeat expansions either in a targeted manner or at the genome-wide level. In addition, technological advances, particularly long-read technologies such as optical genome mapping (Bionano Genomics), Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PacBio) HiFi sequencing, offer promising avenues for the detection of repeat expansions. Despite challenges in specific DNA extraction requirements, computation resources needed and data interpretation, these technologies have an immense potential to advance our understanding of repeat expansion disorders and improve diagnostic accuracy.

A qualitative stakeholder analysis of beliefs, facilitators, and barriers for a feasible prehabilitation program before lung cancer surgery.

BACKGROUND: In order to develop a feasible prehabilitation program before surgery of NSCLC, this study aimed to gain insight into beliefs, facilitators, and barriers of (1) healthcare professionals to refer patients to a prehabilitation program, (2) patients to participate in and adhere to a prehabilitation program, and (3) informal caregivers to support their loved ones. METHODS: Semi-structured interviews were conducted with healthcare professionals, patients who underwent surgery for NSCLC, and their informal caregivers. The capability, opportunity, and motivation for behavior-model (COM-B) guided the development of the interview questions. Results were analyzed thematically. RESULTS: The interviews were conducted with twelve healthcare professionals, seventeen patients, and sixteen informal caregivers. Four main themes were identified: (1) content of prehabilitation and referral, (2) organizational factors, (3) personal factors for participation, and (4) environmental factors. Healthcare professionals mentioned that multiple professionals should facilitate the referral of patients to prehabilitation within primary and secondary healthcare involved in prehabilitation, considering the short preoperative period. Patients did not know that a better preoperative physical fitness and nutritional status would make a difference in the risk of postoperative complications. Patients indicated that they want to receive information about the aim and possibilities of prehabilitation. Most patients preferred a group-based physical exercise training program organized in their living context in primary care. Informal caregivers could support their loved one when prehabilitation takes place by doing exercises together. CONCLUSION: A prehabilitation program should be started as soon as possible after the diagnosis of lung cancer. Receiving information about the purpose and effects of prehabilitation in a consult with a physician seems crucial to patients and informal caregivers to be involved in prehabilitation. Support of loved ones in the patient's own living context is essential for adherence to a prehabilitation program.

Management of obstructive sleep apnea syndrome type 1 in children and adolescents - A French consensus.

This document is the outcome of a group of experts brought together at the request of the French Society of Sleep Research and Medicine to provide recommendations for the management of obstructive sleep apnea syndrome type 1 (OSA1) in children. The recommendations are based on shared experience and published literature. OSA1 is suspected when several nighttime respiratory symptoms related to upper airway obstruction are identified on clinical history taking. A specialist otolaryngologist examination, including nasofibroscopy, is essential during diagnosis. A sleep study for OSA1 is not mandatory when at least two nighttime symptoms (including snoring) are noted. Therapeutic management must be individualized according to the location of the obstruction. Ear, nose, and throat (ENT) surgery is often required, as hypertrophy of the lymphoid tissues is the main cause of OSA1 in children. According to clinical findings, orthodontic treatment generally associated with specialized orofacial-myofunctional therapy might also be indicated. Whatever treatment is chosen, follow-up must be continuous and multidisciplinary, in a network of trained specialists.

Glycogen synthase 1 targeting reveals a metabolic vulnerability in triple-negative breast cancer.

BACKGROUND: Hypoxia-induced glycogen turnover is implicated in cancer proliferation and therapy resistance. Triple-negative breast cancers (TNBCs), characterized by a hypoxic tumor microenvironment, respond poorly to therapy. We studied the expression of glycogen synthase 1 (GYS1), the key regulator of glycogenesis, and other glycogen-related enzymes in primary tumors of patients with breast cancer and evaluated the impact of GYS1 downregulation in preclinical models. METHODS: mRNA expression of GYS1 and other glycogen-related enzymes in primary breast tumors and the correlation with patient survival were studied in the METABRIC dataset (n = 1904). Immunohistochemical staining of GYS1 and glycogen was performed on a tissue microarray of primary breast cancers (n = 337). In four breast cancer cell lines and a mouse xenograft model of triple-negative breast cancer, GYS1 was downregulated using small-interfering or stably expressed short-hairpin RNAs to study the effect of downregulation on breast cancer cell proliferation, glycogen content and sensitivity to various metabolically targeted drugs. RESULTS: High GYS1 mRNA expression was associated with poor patient overall survival (HR 1.20, P = 0.009), especially in the TNBC subgroup (HR 1.52, P = 0.014). Immunohistochemical GYS1 expression in primary breast tumors was highest in TNBCs (median H-score 80, IQR 53-121) and other Ki67-high tumors (median H-score 85, IQR 57-124) (P < 0.0001). Knockdown of GYS1 impaired proliferation of breast cancer cells, depleted glycogen stores and delayed growth of MDA-MB-231 xenografts. Knockdown of GYS1 made breast cancer cells more vulnerable to inhibition of mitochondrial proteostasis. CONCLUSIONS: Our findings highlight GYS1 as potential therapeutic target in breast cancer, especially in TNBC and other highly proliferative subsets.

Validation and discussion of clinical practicability of the 2022 graded prognostic assessment for NSCLC adenocarcinoma patients with brain metastases in a routine clinical cohort.

Introduction: The goal of this analysis is to validate the 2022 graded prognostic assessment (GPA) for patients with brain metastases from adenocarcinoma of the lung and to discuss its clinical practicability. Methods/material: 137 patients with adenocarcinoma of the lung were included in this analysis. The disease specific GPA for NSCLC, Lung-molGPA and the GPA for NSCLC adenocarcinoma were calculated. Overall survival was calculated for each GPA group. Additionally, expected and actual OS in the prognostic groups of the GPA available at the time of the patients' diagnosis was compared. Results: Median overall survival (OS) from diagnosis of brain metastases was 15 months (95% confidence interval (CI) 9.7-20.3 months). The median OS in the three individual prognostic groups was 7 months for GPA 0-1, 16 months for GPA 1.5-2, 33 months for GPA 2.5-3 and not reached for GPA 3.5-4 (p<0.001). Median survival times for the individual groups were similar to those published in the original GPA publication. Regarding the expected and actual OS when using the available GPA at the time of diagnosis there was an underestimation of survival of more than 3 months for all except the worst prognosis group. Conclusion: We were able to validate the 2022 GPA for NSCLC adenocarcinoma patients with brain metastases in a similar cohort from a non-academic center. However, the practical applicability regarding the expected median OS might be limited due to the constantly evolving treatment landscape and the consecutive improvement in overall survival.

French Sleepiness Scale for Adolescents-8 items: A discriminant and diagnostic validation.

The objective of the present study was to validate the Short Version of French Sleepiness Scale for Adolescents (FSSA) with eight items (FSSA8). METHODS: A total of 384 adolescents, aged between 12 and 18 years, completed the FSSA8. These included 269 nonclinical adolescents and 115 adolescents admitted for overnight polysomnography and Multiple Sleep Latency Test (MSLT) because of suspected hypersomnia (85 patients with narcolepsy and 30 with other sleep disorders). Item response theory (IRT) assumptions were tested and psychometric properties were analysed. Matching on sex ratio and age was conducted to estimate concurrent criterion, diagnostic validity and cut-offs. RESULTS: IRT assumptions were validated confirming the one-dimensionality of the FSSA8. The latent continuum sleepiness for which the scale and its items are reliable encompassed most of the clinical subjects. FSSA8 is weakly correlated with MSLT. Distribution of scores for the nonclinical group and the clinical group differed significantly; the FSSA8 had very good screening validity in sleep disorders. The cut-off was seven points. CONCLUSION: The FSSA8 appeared to be more reliable for patients than for nonclinical participants and to be a good tool for screening excessive daytime sleepiness in sleep disorders.

Validation of a data collection set for the psychiatric, addiction, sleep and chronobiological assessments of patients with depression: A Delphi study for the SoPsy-depression French national cohort.

OBJECTIVES: Despite international efforts to identify biomarkers of depression, none has been transferred to clinical practice, neither for diagnosis, evolution, nor therapeutic response. This led us to build a French national cohort (through the clinical and research network named SoPsy within the French biological psychiatry society (AFPBN) and sleep society (SFRMS)), to better identify markers of sleep and biological rhythms and validate more homogeneous subgroups of patients, but also to specify the manifestations and pathogeneses of depressive disorders. Before inclusions, we sought to provide a predefined, standardized, and robust set of data to be collected in all centers. METHODS: A Delphi process was performed to achieve consensus through the independent rating of invited experts, the SoPsy-depression co-investigators (n=34). The initial set open for vote included 94 questionnaires targeting adult and child psychiatry, sleep and addiction. RESULTS: Two questionnaire rounds were completed with 94% participation in the first round and 100% participation in the second round. The results of the Delphi survey incorporated the consensus opinion of the 32 members who completed both rounds. Nineteen of the 94 questionnaires achieved consensus at the first round and seventy of 75 at the second round. The five remaining questionnaires were submitted to three experts involved in the steering committee during a dedicated meeting. At the end, 24 questionnaires were retained in the mandatory and 26 in the optional questionnaire set. CONCLUSIONS: A validated data collection set of questionnaires is now available to assess psychiatry, addiction, sleep and chronobiology dimensions of depressive disorders.

[Therapeutic approaches for sleep and rhythms disorders in children with ASD]. / Approches thérapeutiques des troubles du sommeil et des rythmes chez l'enfant avec TSA.

Sleep disturbances are extremely common (40-86%) in children and adolescents, especially those with autism spectrum disorders (ASD) and are often among the first symptoms identified by parents at a very early stage of their child's development. These abnormalities are among the main parental concerns when having a child with ASD and have a significant impact on the quality of life of patients, their parents, and more broadly their siblings. Sleep disorders are essentially abnormalities of the sleep-wake rhythm - primarily sleep onset insomnia or nocturnal awakenings (with difficulty falling back to sleep). These disturbances can be accompanied by other sleep disorders, requiring notably a systematic elimination of the presence of a sleep apnea or restless legs syndrome - to ensure a personalized and efficient therapeutic approach. Physiologically, the determinants of these sleep disorders are poorly understood, even though several studies point to a significant decrease in melatonin synthesis in people with ASD. Melatonin is a hormone that facilitates falling asleep and maintaining sleep and is also involved in the endogenous synchronization of internal biological clocks. However, the causal factors of this decrease in melatonin synthesis are largely unknown, involving to a small extent the genes involved in melatonin synthesis pathway. The treatment of sleep disorders is relatively systematic: after eliminating other specific sleep disorders associated with the complaint of insomnia, as well as other possible associated comorbidities (such as seizures), a global and graduated therapeutic approach must be put in place. This treatment will be non-pharmacological as a first line, then pharmacological as a second line. A number of non-pharmacological treatment strategies for sleep disorders in typically developing children and adolescents, as well as those with ASD, have been shown to be effective. This treatment requires a combination of: 1) parental education to promote sleep development; 2) setting up bedtime rituals adapted to the child's age and particularities; 3) specific behavioral strategies including bedtime fading, gradual extinction and positive reinforcement of adapted behaviors. It is very essential that the parents are accompanied throughout this therapy. Sleep hygiene and behavioral care must also take into consideration the important role of the zeitgebers of sleep-wake rhythms, i.e. the external environmental factors involved in the synchronization of the biological clocks: regular exposure to light at adapted times, regular meal and wake-up times, social activities and times for going to school. The evidence for the effectiveness of behavioral interventions in the treatment of behavioral insomnia in the typical developmental child is strong, since 94% of children show clinically significant improvements in nighttime sleepiness and waking. By contrast, only about 25% of children with ASD are improved by an approach combining sleep hygiene and behavioral therapy. Melatonin has a special and prominent place in the drug management of sleep disorders associated with ASD. Several clinical trials have shown that melatonin is effective in treating sleep disorders in patients with ASD. This work led to the European Medicines Agency (EMA) granting marketing authorization in September 2018 for a sustained-release paediatric melatonin molecule (Slenyto®). This synthetic molecule is a prolonged release melatonin (PRM) which mimics the physiological pharmacokinetic and secretory characteristics of endogenous melatonin, having a very short blood half-life and prolonged secretion for several hours during the night. A recent study evaluated the efficacy and safety of pediatric PRM (mini-tablets) in 125 children, aged 2 to 17.5 years with mainly ASD. After 15 days on placebo, the children were randomized into two parallel groups, PRM or placebo in a double-blind design for 13 weeks. At endpoint, total sleep time was increased by an average of 57.5 minutes on PRM and only 9.14 minutes on placebo (P=0.034). This difference between the two groups was already significant after three weeks of treatment (P=0.006). Sleep latency was also improved in the PRM group (-39.6 minutes) compared to placebo (-12.51 minutes) (P=0.01). Consolidated sleep duration (uninterrupted by awakenings) was improved by 77.9 minutes for the PRM group and only 25.4 minutes for the placebo group (P<0.001). PRM was well tolerated, the most frequent side effects being headache and daytime drowsiness at the same level with PRM or placebo. In addition, the acceptability by the children for swallowing the mini-tablets was excellent (100% compliance). The efficacy and tolerability of PRM was maintained over the medium and long term in the open phase, over a total study duration of 2 years.

Rewetting does not return drained fen peatlands to their old selves.

Peatlands have been drained for land use for a long time and on a large scale, turning them from carbon and nutrient sinks into respective sources, diminishing water regulation capacity, causing surface height loss and destroying biodiversity. Over the last decades, drained peatlands have been rewetted for biodiversity restoration and, as it strongly decreases greenhouse gas emissions, also for climate protection. We quantify restoration success by comparing 320 rewetted fen peatland sites to 243 near-natural peatland sites of similar origin across temperate Europe, all set into perspective by 10k additional European fen vegetation plots. Results imply that rewetting of drained fen peatlands induces the establishment of tall, graminoid wetland plants (helophytisation) and long-lasting differences to pre-drainage biodiversity (vegetation), ecosystem functioning (geochemistry, hydrology), and land cover characteristics (spectral temporal metrics). The Paris Agreement entails the rewetting of 500,000 km2 of drained peatlands worldwide until 2050-2070. A better understanding of the resulting locally novel ecosystems is required to improve planning and implementation of peatland rewetting and subsequent management.

High-dose re-irradiation of intracranial lesions - Efficacy and safety including dosimetric analysis based on accumulated EQD2Gy dose EQD calculation.

INTRODUCTION: The use of cranial re-irradiation is growing with improving overall survival and the advent of high-precision radiotherapy techniques. Still the value of re-irradiation needs careful evaluation regarding safety and efficacy. We analyzed dosimetric and clinical data of patients receiving cranial re-irradiation using EQD2 sum plans. METHODS AND MATERIAL: We retrospectively analyzed the data of 76 patients who received repeated cranial radiotherapy from 02/2013 to 09/2016. 34 patients suffered from recurrent primary brain tumors, 42 from brain metastases. Dosimetric analysis was performed accumulating EQD2 dose distributions based on rigid image registration. Clinical and radiological data was collected at follow-ups including toxicity, local control and overall survival. RESULTS: In total 76 patients had at least 2 courses of intracranial radiotherapy. The median accumulated prescription EQD2 dose was 96.5 Gy2 for all radiation courses combined. The median D(0.1 cc) of the brain for patients receiving more than 100 Gy2 was 114 Gy2 with a highest dose of 161.5 Gy2. 74% of patients suffered from low grade (G1-G2) acute toxicity, only two high grade (>G3) toxicities were recorded.Median overall survival from the time of first re-irradiation was 57 weeks (range 4-186 weeks). The median time to local failure for patients with a primary brain tumor was not reached and 24 weeks (range 1-77 weeks) for patients with brain metastases. CONCLUSION: Repeated radiotherapy appears both safe and efficient in patients with recurrent primary or secondary brain tumors with doses to the brain up to 120 Gy2 EQD2, doses below 100 Gy2 for brainstem and doses below 75 Gy2 EQD2 to chiasm and optic nerves.

Urgency of surgery as an indicator for the occurrence of surgical site infections: data from over 100,000 surgical procedures.

BACKGROUND: The risk for surgical site infections (SSIs) is influenced by patient- and procedure-related factors. Urgent surgery represents a challenge in operative medicine and is frequently linked to a variety of complications, including SSIs. AIM: We aimed to investigate whether urgency was significantly associated with SSI occurrence, and determine whether collection of this variable provided useful information for SSI surveillance. METHODS: We performed a retrospective data analysis of caesarean sections (C-sections) and colon surgeries conducted between 2017 and 2019 within the German national SSI surveillance network. A multivariable logistic regression model was utilized to determine the influence of urgency on SSI occurrence. For this purpose, data on procedures and SSIs were associated with available department- and patient-related parameters. FINDINGS: A total of 115,648 procedures were included in the analysis: 78,288 C-sections and 37,360 colon surgeries. For C-sections, the SSI rate per 100 procedures was 0.98 (95% confidence interval: 0.85-1.11) for urgent and 0.46 (0.40-0.53) for elective procedures (P<0.001). For open colon surgeries, SSI rates were 9.66 (8.89-10.49) for urgent and 8.60 (8.13-9.11) for elective procedures (P<0.001). For laparoscopic colon surgeries, SSI rates did not differ significantly. Multivariable analysis revealed that urgency significantly increased the likelihood of SSI occurrence only for C-sections. CONCLUSION: Urgency significantly increased the SSI risk of C-sections, but not colon surgeries. Hence, collection of this variable is useful for SSI surveillance of C-sections, but may be dispensable for other procedures. Future analyses on the matter should therefore focus on other procedure types.

No increase in compliance before aseptic procedures in German hospitals. A longitudinal study with data from the national surveillance system over four years.

BACKGROUND: Hand hygiene plays a crucial role in the prevention of healthcare-associated infections and transmission of pathogens. In 2008 the national campaign 'Aktion Saubere Hände' was launched in Germany. It is based on the World Health Organization (WHO) 'Clean Care is Safer Care' initiative. Direct observation and feedback of the results are key components in the improvement of hand hygiene compliance. In 2014 a voluntary national surveillance electronic tool for the documentation of directly observed compliance to hand hygiene was introduced. AIM: Description and evaluation of compliance with the WHO model 'my 5 moments' in German hospitals after implementation. METHODS: Direct observation was performed in the participating hospitals by trained local staff according to the WHO recommendations. We evaluated wards that reported annually at least 150 hand hygiene opportunities (HHOs) of hand hygiene per observation period from January 1st, 2015 until December 31st, 2018. FINDINGS: In all, 1,485,622 HHOs observed on 3337 wards in 525 hospitals were included into analysis. Overall compliance increased from 72% (interquartile range: 61-82) to 76% (66-84). Compliance significantly increased for all individual moments of the WHO model except moment 2. In the multivariate logistic regression analysis the following parameters were independently associated with a high compliance in hand hygiene: intensive care unit, nurse, opportunity observed in 2017 or 2018, as well as all moments except moment 2. CONCLUSION: Overall compliance in German hospitals increased over time. To improve HH compliance 'before aseptic procedures' appears to be difficult and should be addressed explicitly. Underlying reasons need to be the focus of future investigations.

Re-irradiation in the thorax - An analysis of efficacy and safety based on accumulated EQD2 doses.

INTRODUCTION: Thoracic re-irradiation remains a challenge regarding the balance of local efficacy and acceptable toxicities. In this retrospective analysis we analyzed dosimetrical and clinical data of patients treated with thoracic re-irradiation based on accumulated EQD2Gy doses. METHODS AND MATERIAL: We retrospectively analyzed the data of 42 consecutive single-institutional patients treated with repeated courses of thoracic radiotherapy from 12/2011 to 01/2017. Accumulated EQD2 dose distributions were calculated and dose parameters for organs at risk and target volumes were analysed. RESULTS: The median prescription dose was 42.2 Gy (10-70.6 Gy) for all RT courses. The median Dmean of both lungs was 10.1 Gy3 (range: 1.9 Gy3-17.9 Gy3) with a maximum D0.1 cc of 253.86 Gy3. The median D0.1 cc of the esophagus was 62.2 Gy3 with a maximum of 103.78 Gy3. The maximum D0.1 cc for the bronchial tree was 187.33 Gy3 (median 74.35 Gy3) and for the Aorta 216.1 Gy3 (median 70.9 Gy3). Median OS after first re-irradiation was 19 months (range 1-45 months). 12-month local control after a course of re-irradiation was 52.6%. 80% of patients suffered from a G1-G2 toxicity, most frequently coughing. One patient suffered from a G5 complication probably unrelated to re-irradiation. CONCLUSION: Even though several organs at risk received maximum accumulated doses of >100 Gy3, thoracic reirradiation resulted in an acceptable toxicity profile. Local tumor control and overall survival remained encouraging even after multiple courses of thoracic radiotherapy.

[Psychopathological consequences of confinement]. / Conséquences psychopathologiques du confinement.

The psychological effects of isolation have already been described in the literature (polar expeditions, submarines, prison). Nevertheless, the scale of confinement implemented during the COVID-19 pandemic is unprecedented. In addition to reviewing the published studies, we need to anticipate the psychological problems that could arise during or at a distance from confinement. We have gone beyond the COVID-19 literature in order to examine the implications of the known consequences of confinement, like boredom, social isolation, stress, or sleep deprivation. Anxiety, post-traumatic stress disorder, depression, suicidal or addictive behaviours, domestic violence are described effects of confinement, but the mechanisms of emergence of these disorders and their interrelationships remain to be studied. For example, what are the mechanisms of emergence of post-traumatic stress disorders in the context of confinement? We also remind the reader of points of vigilance to be kept in mind with regard to eating disorders and hallucinations. Hallucinations are curiously ignored in the literature on confinement, whereas a vast literature links social isolation and hallucinations. Due to the broad psychopathological consequences, we have to look for these various symptoms to manage them. We quickly summarize the diagnostic and therapeutic approaches already in place, such as telemedicine, which is undergoing rapid development during the COVID-19 crisis.

Distress, problems, referral wish, and supportive health care use in breast cancer survivors beyond the first year after chemotherapy completion.

PURPOSE: We examined distress levels, problems, referral wish, and supportive health care use in a cross-sectional group of breast cancer survivors at two-time points with a 1-year time interval. Also, factors related to continuing elevated distress were explored. METHODS: Breast cancer survivors, 1-5 years after chemotherapy completion, filled in the Dutch Distress Thermometer/Problem List (DT/PL) and questions on background characteristics at study inclusion (T1). DT/PL responses and health care use were discussed during semi-structured interviews. One year later, re-assessment took place (T2). The data were analyzed by descriptive and univariate analyses. Continuing elevated distress was defined as a DT score ≥ 5 at T1 and T2. RESULTS: Seventy-three survivors completed all questionnaires (response = 84.6%). Eighteen (25%) experienced continuing elevated distress. Fatigue (T1 N = 48 (66%); T2 N = 41 (56%)) and lack of physical fitness (T1 N = 44 (60%); T2 N = 36 (49%)) were most often reported. Time since diagnosis, health care use, and practical, social, emotional and physical problems were significantly associated with continuing elevated distress. Between diagnosis and T1, N = 49(67%) used supportive healthcare services, mostly a psychologist and/or a physical/lymphedema therapist, and between T1 and T2, 39 (53%) did. At T1, 8 (11%) expressed a referral wish and at T2, 11 (16%) did. CONCLUSIONS: Screening and management of distress, problems, and referral wish are important, even years after chemotherapy completion as a substantial proportion of breast cancer survivors continue to report elevated distress and problems. Special attention should be paid to survivors reporting physical problems, especially fatigue and lack of physical fitness, since these problems are most strongly related to continuing elevated distress.

Long-term participation of Dutch service members with combat-related injury.

BACKGROUND: After deployment service members need to adapt to civilian life and return to participation in family, vocational and community life. AIMS: To assess the level of activity and participation of service members with combat-related injury after their rehabilitation intervention and to measure the effect of injury severity, adaptive coping, number of deployments and traumatic stress. METHODS: The physical functioning scale of the 36-Item Short Form Health Survey (SF-36 PF), the Assessment of Life Habits short version (LIFE-H), the Impact of Event Scale (IES-R) and the Cognitive Emotion Regulation Questionnaire (CERQ) were administered to service members who sustained combat-related injury. The Injury Severity Score (ISS) was calculated, and the number of deployments was noted. Correlations were calculated between the LIFE-H and ISS, IES-R, number of deployments and adaptive coping and between the SF-PF and ISS, IES-R, number of deployments and adaptive coping. RESULTS: The response rate was 55% (32 service members). A moderate correlation was found between LIFE-H and IES (r = -0.49) and a very weak correlation was found between LIFE-H and injury severity (r = 0.31). No correlation was found between SF-36 PF and ISS, IES, number of deployments or CERQ and between LIFE-H and number of deployments or CERQ. CONCLUSIONS: A moderate correlation was found between level of participation and traumatic stress in service members with combat-related injury in a 5-year follow-up. Therefore, it is advisable to screen for traumatic stress symptoms and monitor these symptoms during the rehabilitation intervention.

Enhanced pulmonary uptake on 18F-FES-PET/CT scans after irradiation of the thoracic area: related to fibrosis?

RATIONALE: The use of 16α-[18F]fluoro-17ß-estradiol (FES) positron emission tomography (PET) in clinical dilemmas and for therapy decision-making in lesions expressing estrogen receptors is growing. However, on a considerable number of FES PET scans, previously performed in a research and clinical setting in our institution, FES uptake was noticed in the lungs without an oncologic substrate. We hypothesized that this uptake was related to pulmonary fibrosis as a result of radiation therapy. This descriptive study therefore aimed to investigate whether radiation therapy in the thoracic area is possibly related to enhanced pulmonary, non-tumor FES uptake. METHODS: All FES-PET/CT scans performed in our institution from 2008 to 2017 were retrospectively analyzed. Scans from patients who had received irradiation in the thoracic area prior to the scan were compared to scans of patients who had never received irradiation in the thoracic area. The primary outcome was the presence of enhanced non-tumor FES uptake in the lungs, defined as visually increased FES uptake in the absence of an oncologic substrate on the concordant (contrast-enhanced) CT scan. All CT scans were evaluated for the presence of fibrosis or oncologic substrates. RESULTS: A total of 108 scans were analyzed: 70 scans of patients with previous irradiation in the thoracic area and 38 of patients without. Enhanced non-tumor FES uptake in the lungs was observed in 39/70 irradiated patients (56%), versus in 9/38 (24%) of non-irradiated patients. Fibrosis was present in 37 of the 48 patients with enhanced non-tumor FES uptake (77%), versus in 15 out of 60 (25%) patients without enhanced non-tumor uptake, irrespective of radiotherapy (p < 0.001). CONCLUSION: After irradiation of the thorax, enhanced non-tumor uptake on FES-PET can be observed in the radiation field in a significant proportion of patients. This seems to be related to fibrosis. When observing enhanced FES uptake in the lungs, this should not be interpreted as metastases. Information on recent radiation therapy or history of pulmonary fibrosis should therefore be taken into consideration.

Clinical burden of illness in patients with phenylketonuria (PKU) and associated comorbidities - a retrospective study of German health insurance claims data.

BACKGROUND: Phenylketonuria (PKU) is an inherited deficiency in the enzyme phenylalanine hydroxylase (PAH), which, when poorly-managed, is associated with clinical features including deficient growth, microcephaly, seizures, and intellectual impairment. The management of PKU should start as soon as possible after diagnosis to prevent irreversible damage and be maintained throughout life. The aim of this study was to assess the burden of illness in PKU patients in general and in PKU patients born before and after the introduction of newborn screening in Germany. METHODS: This retrospective matched cohort analysis used the Institut für angewandte Gesundheitsforschung Berlin (InGef) research database containing anonymized healthcare claims of approximately 4 million covered lives. PKU patients were compared with matched controls from the general population within the same database (1:10 ratio via direct, exact matching on age and gender without replacement). PKU patients were included if they were aged ≥18 years on 01/01/15 and were continuously enrolled from 01/01/10 to 31/12/15. The 50 most commonly reported comorbidities and 50 most commonly prescribed medications in the PKU population were analyzed. Differences between groups were tested using 95% confidence interval (CI) of prevalence ratio (PR) values. RESULTS: The analysis included 377 adult PKU patients (< 5 of which were receiving sapropterin dihydrochloride) and 3,770 matched controls. Of the 50 most common comorbidities in the PKU population, those with a statistically significant PR > 1.5 vs controls included major depressive disorders (PR = 2.3), chronic ischemic heart disease (PR = 1.7), asthma (PR = 1.7), dizziness and giddiness (PR = 1.8), unspecified diabetes mellitus (PR = 1.7), infectious gastroenteritis and colitis (PR = 1.7), and reaction to severe stress and adjustment disorders (PR = 1.6). The most commonly prescribed Anatomical Therapeutic Chemical (ATC) subcodes among PKU patients (vs the control population) are for systemic antibacterials (34.7% vs 32.8%), anti-inflammatory and antirheumatic (29.4% vs 27.5%), renin-angiotensin agents (30.0% vs 27.0%), acid-related disorders (29.4% vs 20.2%), and beta-blockers (24.9% vs 19.9%). CONCLUSION: The overall clinical burden on patients with PKU is exacerbated by a significantly higher risk of numerous comorbidities and hence, prescribing of the requisite medication, both for recognized (e.g. major depressive disorders) and more unexpected comorbidities (e.g. ischemic heart disease).