Expanded access to investigational drugs in psychiatry: A systematic review.

Some psychiatric patients have exhausted all approved treatment options. Numerous investigational drugs are currently being developed and tested in clinical trials. However, not all patients can participate in clinical trials. Expanded access programs may provide an opportunity for patients who cannot participate in clinical trials to use investigational drugs as a therapeutic option outside of clinical trials. It is unknown to what extent expanded access occurs in psychiatry. We conducted a systematic literature search on PubMed, Embase, and PscyInfo, with additional information from ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform and FDA/EMA approvals, in order to find all expanded access programs ever conducted, globally, in the field of psychiatry. This resulted in a total of fourteen expanded access programs ever conducted in psychiatry. Given the prevalence of psychiatric disorders, the activity in clinical research in psychiatry, the regulatory framework enabling expanded access, and the impact of psychiatric disorders on patients, their families, and society, we had expected a higher utilization of expanded access. We propose that the psychiatric community, with pharmaceutical industry, should consider establishing and optimizing expanded access programs.

The effect of fatigue on spike jump biomechanics in view of patellar tendon loading in volleyball.

BACKGROUND AND OBJECTIVE: Patellar tendinopathy (PT) is a highly prevalent overuse injury in volleyball and is often linked with overloading of the patellar tendon. Little is known, however, about whether and how patellar tendon loading is affected by fatigue during the most challenging jump activity in volleyball. Therefore, this study investigates the effect of a high-intensity, intermittent fatigue protocol on movement alterations in terms of patellar tendon loading during a volleyball spike jump. METHODS: Forty-three male volleyball players participated in this study. Three-dimensional full-body kinematics and kinetics were collected when performing a spike jump before and after the fatigue protocol. Sagittal plane joint angles, joint work and patellar tendon loading were calculated and analyzed with curve analyses using paired sample t-tests to investigate fatigue effects (p < 0.05). RESULTS: Fatigue induced a stiffer lower extremity landing strategy together with prolonged pelvis-trunk flexion compared to baseline (p = 0.001-0.005). Decreased patellar tendon forces (p = 0.001-0.010) and less eccentric knee joint work (-5%, p < 0.001) were observed after the fatigue protocol compared to baseline. CONCLUSION: Protective strategies seem to be utilized in a fatigued state to avoid additional tensile forces acting on the patellar tendon, including proximal compensations and stiff lower extremity landings. We hypothesize that players might be more prone for developing PT if eccentric patellar tendon loads are high in the non-fatigued state and/or these loads are somehow not decreased after fatigue.

The Effect of Fatigue on Trunk and Pelvic Jump-Landing Biomechanics in View of Lower Extremity Loading: A Systematic Review.

Fatigue has often been considered a risk factor for developing sports injuries, modulating lower extremity jump-landing biomechanics. The impact of fatigue on proximal trunk and pelvic biomechanics has been suggested to play an important role in lower extremity loading and injury risk, yet the available evidence remains ambiguous as the trunk and pelvis were often not the primary focus of research. Therefore, the purpose of this systematic review was to determine how fatigue affects trunk and pelvic three-dimensional jump-landing biomechanics. PubMed (MEDLINE), Web of Science, Embase, CINAHL and SPORTDiscus were consulted up to and including April 2022 for potential studies investigating the effect of fatigue on trunk and pelvic kinematics, kinetics and/or muscular activity during jump-landing tasks in healthy, physically active populations. Methodological quality of the studies was assessed by the modified Downs and Black checklist. Twenty-one studies were included and methodological quality was moderate to high among these studies. The results indicate prevailing evidence for more trunk flexion during standardized jump-landing tasks after lower extremity muscle fatigue. Otherwise, lumbo-pelvic-hip muscle fatigue does not seem to elicit major detrimental changes to these jump-landing biomechanics. Although a wide variability of trunk and pelvic jump-landing strategies was observed, the results provide evidence for increased trunk flexion after lower extremity muscle fatigue. This proximal strategy is suggested to help unload fatigued lower extremity structures and lack of this compensation might increase knee injury risk.

Do Physicians Have a Duty to Discuss Expanded Access to Investigational Drugs with their Patients? A Normative Analysis.

Drawing on ethical and legal frameworks in the Netherlands, the United States and France, we examine whether physicians are expected to inform patients about potentially relevant opportunities for expanded access to investigational drugs. While we found no definitive legal obligation, we argue that physicians have a moral obligation to discuss opportunities for expanded access with patients who have run out of treatment options to prevent inequality, to promote autonomy, and to achieve beneficence.

The 'false hope' argument in discussions on expanded access to investigational drugs: a critical assessment.

When seriously ill patients reach the end of the standard treatment trajectory for their condition, they may qualify for the use of unapproved, investigational drugs regulated via expanded access programs. In medical-ethical discourse, it is often argued that expanded access to investigational drugs raises 'false hope' among patients and is therefore undesirable. We set out to investigate what is meant by the false hope argument in this discourse. In this paper, we identify and analyze five versions of the false hope argument which we call: (1) the limited chance at benefit argument, (2) the side effects outweighing benefits argument, (3) the opportunity costs argument, (4) the impossibility of making informed decisions argument, and (5) the difficulty of gaining access argument. We argue that the majority of these five versions do not provide normative ground for disqualifying patients' hopes as false. Only when hope is rooted in a mistaken belief, for example, about the likelihood of benefits or chances on medical risks, or when hope is directed at something that cannot possibly be obtained, should it be considered false. If patients are adequately informed about their odds of obtaining medical benefit, however small, and about the risks associated with an investigational treatment, it is unjustified to consider patients' hopes to be false, and hence, to deny them access to investigational drug based on that argument.

The development of a clinical screening tool to evaluate unilateral landing performance in a healthy population.

OBJECTIVES: To develop a clinical tool to evaluate unilateral landing quality in a healthy population. The reliability of the novel tool was evaluated, and the influence of gender and leg-dominance was investigated. DESIGN: An experimental study for developing a test protocol, scoring criteria, and scoring method, based on observable landing errors, for the novel Unilateral Landing Error Scoring System (ULESS). SETTING: Controlled lab environment. PARTICIPANTS: Healthy participants (25♂ and 25♀) performed the ULESS. MAIN OUTCOME MEASURES: The ULESS was scored with video analysis. Unilateral landing performance, measured with the ULESS, was compared to bilateral landing performance. RESULTS: Sixteen items to assess trunk, pelvic, and lower limb movement patterns during a unilateral landing task resulted in a composite score on an interval scale. Moderate to excellent intra- and inter-tester reliability (ICC(2,1) = 0.77-0.90) was determined. The ULESS was able to identify moderate to poor unilateral landing quality in subjects with good to excellent bilateral landing quality. No main effect of gender (p = 0.19) or leg-dominance (p = 0.65) on ULESS scores was found. CONCLUSION: Moderate to excellent reliability can be expected when using the newly developed protocol and scoring method. The ULESS is feasible to perform with limited materials.

Altered Multisegment Ankle and Foot Kinematics During Gait in Patients With Hypermobile Ehlers-Danlos Syndrome/Hypermobility Spectrum Disorder: A Case-Control Study.

OBJECTIVE: Ankle-foot problems have a considerable impact on daily functioning in patients with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorder (hEDS/HSD). Therefore, the objective of this study was to identify alterations in multisegment ankle and foot kinematics during gait and to assess foot function and pain in these patients. METHODS: Twenty-three women with hEDS/HSD and 23 healthy controls participated in this 3-dimensional gait analysis. Multisegment ankle and foot kinematics were collected using the Ghent Foot Model and analyzed with Statistical Parametric Mapping. Foot function and pain were assessed using visual analog scale scores, the Margolis Pain Diagram, and the Foot Function Index. RESULTS: Levels of pain and foot dysfunction were significantly higher in subjects with hEDS/HSD (P < 0.001). Kinematic curve analyses provide evidence for a hypermobile first ray, represented by a significantly increased eversion position of the medial forefoot during stance phase (P < 0.001) in subjects with hEDS/HSD compared to controls. In addition, significantly more dorsiflexion was found in the medial and lateral forefoot and the rearfoot (P < 0.001). At the midfoot, an increased plantar flexion (P < 0.001) and at the level of the hallux a decreased dorsiflexion (P = 0.037) and increased inversion (P < 0.001) and abduction (P = 0.016) were found in subjects with hEDS/HSD. CONCLUSION: This study is the first to apply a multisegment foot model during gait in hEDS/HSD, which confirms the characteristic hypermobility throughout the foot, especially the hypermobile first ray.

Evaluation of the Stability of Bacteriophages in Different Solutions Suitable for the Production of Magistral Preparations in Belgium.

In Belgium, the incorporation of phages into magistral preparations for human application has been permitted since 2018. The stability of such preparations is of high importance to guarantee quality and efficacy throughout treatments. We evaluated the ability to preserve infectivity of four different phages active against three different bacterial species in five different buffer and infusion solutions commonly used in medicine and biotechnological manufacturing processes, at two different concentrations (9 and 7 log pfu/mL), stored at 4 °C. DPBS without Ca2+ and Mg2+ was found to be the best option, compared to the other solutions. Suspensions with phage concentrations of 7 log pfu/mL were unsuited as their activity dropped below the effective therapeutic dose (6-9 log pfu/mL), even after one week of storage at 4 °C. Strong variability between phages was observed, with Acinetobacter baumannii phage Acibel004 being stable in four out of five different solutions. We also studied the long term storage of lyophilized staphylococcal phage ISP, and found that the titer could be preserved during a period of almost 8 years when sucrose and trehalose were used as stabilizers. After rehydration of the lyophilized ISP phage in saline, the phage solutions remained stable at 4 °C during a period of 126 days.

A Case of Phage Therapy against Pandrug-Resistant Achromobacter xylosoxidans in a 12-Year-Old Lung-Transplanted Cystic Fibrosis Patient.

Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic fibrosis patient received two rounds of phage therapy because of persistent lung infection with pandrug-resistant A. xylosoxidans. Clinical tolerance was perfect, but initial bronchoalveolar lavage (BAL) still grew A. xylosoxidans. The patient's respiratory condition slowly improved and oxygen therapy was stopped. Low-grade airway colonization by A. xylosoxidans persisted for months before samples turned negative. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. Whole genome sequencing indicated that the eight A. xylosoxidans isolates, collected during phage therapy, belonged to four delineated strains, whereby one had a stop mutation in a gene for a phage receptor. The dynamics of lung colonisation were documented by means of strain-specific qPCRs on different BALs. We report the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. The dynamics of airway colonization was more complex than deduced from bacterial culture, involving phage susceptible as well as phage resistant strains.

The role of core stability in the development of non-contact acute lower extremity injuries in an athletic population: A prospective study.

OBJECTIVES: Stability of the core is associated with lower extremity functioning. Consequently, impaired core stability might play a role in developing non-contact acute lower extremity sports injuries. The objective was to investigate components of core stability as potential risk factors for acute lower extremity injuries. DESIGN: A cohort study was set up with a follow-up and injury registration period of 1.5 years. PARTICIPANTS: 142 male and female physical education students were included. MAIN OUTCOME MEASURES: Measures of isometric hip and core muscular strength, endurance, proprioception and neuromuscular control of the core, and postural control were taken at the start of the study. Sports-related injury occurrence was registered during follow-up. RESULTS: 27 (19%) injuries of interest occurred during follow-up. After multivariate model building, a significant predictive effect was found for side-to-side hip abduction strength asymmetry (p = .007). The hazard of developing an acute lower extremity injury increased with 6.2% with a 1 unit increase in side-to-side strength imbalance, regardless of gender. CONCLUSION: Hip abduction strength imbalance was determined as a risk factor for the development of non-contact, acute lower extremity injuries. Normalizing hip strength imbalances might be beneficial for injury prevention. However, further research is needed to support this claim.

Relationship Between Jump-Landing Kinematics and Lower Extremity Overuse Injuries in Physically Active Populations: A Systematic Review and Meta-Analysis.

BACKGROUND: Lower extremity overuse injuries are common in athletes participating in sports with repeated bouts of landing manoeuvres. Biomechanical alterations during landing may be associated with these types of injuries. The objective of this systematic review with meta-analysis was to summarise and determine the relationship between kinematic alterations during a landing task and the development of lower extremity overuse injuries in physically active populations. METHODS: PubMed, Embase, Web of Science, CINAHL, and SPORTDiscus were consulted up to and including February 2020. Cohort, cross-sectional or case-control studies were included if they investigated the relationship between three-dimensional (3D) landing kinematics in physically active populations and either new incidence or a history of lower extremity overuse injuries. RESULTS: Twenty-three studies that investigated 3D landing kinematics in subjects with either patellar tendinopathy (PT), patellofemoral pain (PFP), exertional medial tibial pain (EMTP) or groin overuse injury met the inclusion criteria. Based on this systematic review, there is evidence for decreased knee flexion range of motion (ROM) and increased knee abduction ROM during landing as risk factors for PFP. For PT, risk factors are poorly understood. Furthermore, the meta-analysis demonstrated significantly greater hip adduction at initial contact (IC) (p = 0.02), greater knee internal rotation at IC (p < 0.001), greater peak knee external rotation (p = 0.05) and less ankle dorsiflexion at peak vertical ground reaction force (vGRF) (p = 0.05) in subjects with knee overuse injuries compared to healthy controls. There is evidence of increased trunk, hip and knee transversal ROM as risk factors for EMTP. Groin injuries are associated with greater pelvic and hip frontal and transversal plane ROM in the injured group compared to the healthy controls. CONCLUSION: The results of this systematic review and meta-analysis provide preliminary evidence for impaired landing kinematics associated with lower extremity overuse injuries. Excessive frontal and transversal plane movements during landing manoeuvres might increase impact and tensile forces resulting in lower extremity overuse injuries. REGISTRATION: This systematic review was registered in the PROSPERO international prospective register of systematic reviews (ID = CRD42019135602).

Comparison of procedures for RNA-extraction from peripheral blood mononuclear cells.

RNA quality and quantity are important factors for ensuring the accuracy of gene expression analysis and other RNA-based downstream applications. Thus far, only a limited number of methodological studies have compared sample storage and RNA extraction procedures for human cells. We compared three commercially available RNA extraction kits, i.e., (NucliSENS) easyMAG, RNeasy (Mini Kit) and RiboPure (RNA Purification Kit-blood). In addition, additional conditions, such as storage medium and storage temperature of human peripheral blood mononuclear cells were evaluated, i.e., 4 °C for RNAlater or -80 °C for QIAzol and for the respective cognate lysis buffers; easyMAG, RNeasy or RiboPure. RNA was extracted from aliquots that had been stored for one day (Run 1) or 83 days (Run 2). After DNase treatment, quantity and quality of RNA were assessed by means of a NanoDrop spectrophotometer, 2100 Bioanalyzer and RT-qPCR for the ACTB reference gene. We observed that high-quality RNA can be obtained using RNeasy and RiboPure, regardless of the storage medium, whereas samples stored in RNAlater resulted in the least amount of RNA extracted. In addition, RiboPure combined with storage of samples in its cognate lysis buffer yielded twice as much RNA as all other procedures. These results were supported by RT-qPCR and by the reproducibility observed for two independent extraction runs.

Development of a qPCR platform for quantification of the five bacteriophages within bacteriophage cocktail 2 (BFC2).

To determine phage titers accurately, reproducibly and in a non-laborious and cost-effective manner, we describe the development of a qPCR platform for molecular quantification of five phages present in bacteriophage cocktail 2 (BFC2). We compared the performance of this molecular approach, with regard to quantification and reproducibility, with the standard culture-based double agar overlay method (DAO). We demonstrated that quantification of each of the five phages in BFC2 was possible by means of qPCR, without prior DNA extraction, but yields were significantly higher in comparison to DAO. Although DAO is assumed to provide an indication of the number of infective phage particles, whereas qPCR only provides information on the number of phage genomes, the difference in yield (qPCR/DAO ratio) was observed to be phage-dependent and appeared rather constant for all phages when analyzing different (freshly prepared) stocks of these phages. While DAO is necessary to determine sensitivity of clinical strains against phages in clinical applications, qPCR might be a valid alternative for rapid and reproducible quantification of freshly prepared stocks, after initial establishment of a correction factor towards DAO.

Primary hyperparathyroidism associated to thrombocytopenia: an issue to consider?

Primary hyperparathyroidism (PHPT) is probably the most common endocrine disorder of the parathyroid glands, causing hypercalcemia. It is diagnosed often in persons with elevated serum calcium levels. However, hematological manifestations, such as thrombocytopenia are less known. In this case we describe the possible association of PHPT with reversible thrombocytopenia after parathyroidectomy. This hematological abnormality can be included in the spectrum of possible causes, including seemingly non-specific symptoms, in the decision tree towards surgical assessment.

Anaerobic bacteraemia: a 10-year retrospective epidemiological survey.

In order to identify current trends in anaerobic bacteraemia, a 10-year retrospective study was performed in the University Hospital Brussel, Belgium. All clinically relevant bacteraemia detected from 2004 until 2013 were included. Medical records were reviewed in an attempt to define clinical parameters that might be associated with the occurrence of anaerobic bacteraemia. 437 of the isolated organisms causing anaerobic bacteraemia were thawed, subcultured and reanalyzed using matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF). There were an average of 33 cases of anaerobic bacteraemia per year during 2004-2008 compared to an average of 27 cases per year during 2009-2013 (P = 0.017), corresponding to a decrease by 19% between the first and the latter period. Also, the total number of cases of anaerobic bacteraemia per 100,000 patient days decreased from 17.3 in the period from 2004 to 2008 to 13.7 in the period 2009 to 2013 (P = 0.023). Additionally, the mean incidence of anaerobic bacteraemia decreased during the study period (1.27/1000 patients in 2004 vs. 0.94/1000 patients in 2013; P = 0.008). In contrast, the proportion of isolated anaerobic bacteraemia compared to the number of all bacteraemia remained stable at 5%. Bacteroides spp. and Parabacteroides spp. accounted for 47.1% of the anaerobes, followed by 14.4% Clostridium spp., 12.6% non-spore-forming Gram-positive rods, 10.5% anaerobic cocci, 8.2% Prevotella spp. and other Gram-negative rods and 7.1% Fusobacterium spp. The lower gastrointestinal tract (47%) and wound infections (10%) were the two most frequent sources for bacteraemia, with the origin remaining unknown in 62 cases (21%). The overall mortality rate was 14%. Further studies focusing on the antimicrobial susceptibility and demographic background of patients are needed to further objectify the currently observed trends.

Quantitative and Functional Requirements for Bioluminescent Cancer Models.

BACKGROUND: Bioluminescent cancer models are widely used but detailed quantification of the luciferase signal and functional comparison with a non-transfected control cell line are generally lacking. In the present study, we provide quantitative and functional tests for luciferase-transfected cells. MATERIALS AND METHODS: We quantified the luciferase expression in BLM and HCT8/E11 transfected cancer cells, and examined the effect of long-term luciferin exposure. The present study also investigated functional differences between parental and transfected cancer cells. RESULTS: Our results showed that quantification of different single-cell-derived populations are superior with droplet digital polymerase chain reaction. Quantification of luciferase protein level and luciferase bioluminescent activity is only useful when there is a significant difference in copy number. Continuous exposure of cell cultures to luciferin leads to inhibitory effects on mitochondrial activity, cell growth and bioluminescence. These inhibitory effects correlate with luciferase copy number. Cell culture and mouse xenograft assays showed no significant functional differences between luciferase-transfected and parental cells. CONCLUSION: Luciferase-transfected cells should be validated by quantitative and functional assays before starting large-scale experiments.

Radiation-induced lung damage promotes breast cancer lung-metastasis through CXCR4 signaling.

Radiotherapy is a mainstay in the postoperative treatment of breast cancer as it reduces the risks of local recurrence and mortality after both conservative surgery and mastectomy. Despite recent efforts to decrease irradiation volumes through accelerated partial irradiation techniques, late cardiac and pulmonary toxicity still occurs after breast irradiation. The importance of this pulmonary injury towards lung metastasis is unclear. Preirradiation of lung epithelial cells induces DNA damage, p53 activation and a secretome enriched in the chemokines SDF-1/CXCL12 and MIF. Irradiated lung epithelial cells stimulate adhesion, spreading, growth, and (transendothelial) migration of human MDA-MB-231 and murine 4T1 breast cancer cells. These metastasis-associated cellular activities were largely mimicked by recombinant CXCL12 and MIF. Moreover, an allosteric inhibitor of the CXCR4 receptor prevented the metastasis-associated cellular activities stimulated by the secretome of irradiated lung epithelial cells. Furthermore, partial (10%) irradiation of the right lung significantly stimulated breast cancer lung-specific metastasis in the syngeneic, orthotopic 4T1 breast cancer model.Our results warrant further investigation of the potential pro-metastatic effects of radiation and indicate the need to develop efficient drugs that will be successful in combination with radiotherapy to prevent therapy-induced spread of cancer cells.

Validation of High Resolution Melting Analysis (HRM) of the Amplified ITS2 Region for the Detection and Identification of Yeasts from Clinical Samples: Comparison with Culture and MALDI-TOF Based Identification.

AIM: Candida species are known as opportunistic pathogens, and a possible cause of invasive infections. Because of their species-specific antimycotic resistance patterns, reliable techniques for their detection, quantification and identification are needed. We validated a DNA amplification method for direct detection of Candida spp. from clinical samples, namely the ITS2-High Resolution Melting Analysis (direct method), by comparing it with a culture and MALDI-TOF Mass Spectrometry based method (indirect method) to establish the presence of Candida species in three different types of clinical samples. MATERIALS AND METHODS: A total of 347 clinical samples, i.e. throat swabs, rectal swabs and vaginal swabs, were collected from the gynaecology/obstetrics, intensive care and haematology wards at the Ghent University Hospital, Belgium. For the direct method, ITS2-HRM was preceded by NucliSENS easyMAG DNA extraction, directly on the clinical samples. For the indirect method, clinical samples were cultured on Candida ID and individual colonies were identified by MALDI-TOF. RESULTS: For 83.9% of the samples there was complete concordance between both techniques, i.e. the same Candida species were detected in 31.1% of the samples or no Candida species were detected in 52.8% of the samples. In 16.1% of the clinical samples, discrepant results were obtained, of which only 6.01% were considered as major discrepancies. Discrepancies occurred mostly when overall numbers of Candida cells in the samples were low and/or when multiple species were present in the sample. DISCUSSION: Most of the discrepancies could be decided in the advantage of the direct method. This is due to samples in which no yeast could be cultured whereas low amounts could be detected by the direct method and to samples in which high quantities of Candida robusta according to ITS2-HRM were missed by culture on Candida ID agar. It remains to be decided whether the diagnostic advantages of the direct method compensate for its disadvantages.

Rapid and accurate identification of isolates of Candida species by melting peak and melting curve analysis of the internally transcribed spacer region 2 fragment (ITS2-MCA).

Rapid identification of clinically important yeasts can facilitate the initiation of anti-fungal therapy, since susceptibility is largely species-dependent. We evaluated melting peak and melting curve analysis of the internally transcribed spacer region 2 fragment (ITS2-MCA) as an identification tool for distinguishing between 16 Candida spp., i.e. Candida albicans, Candida bracarensis, Candida dubliniensis, Candida famata, Candida glabrata, Candida guilliermondii, Candida inconspicua, Candida kefyr, Candida krusei, Candida lipolytica, Candida lusitaniae, Candida nivariensis, Candida norvegensis, Candida parapsilosis, Candida tropicalis and Candida sojae, and Saccharomyces cerevisiae and one species pair, i.e. Candida metapsilosis/Candida orthopsilosis. Starting from a cultured isolate, ITS2-MCA led to differentiation of these species within 6 h. According to our findings, ITS2-MCA offers a simple, rapid and cost-effective method for identification of cultured isolates of the clinically most relevant and prevalent Candida species. Further studies will be necessary to evaluate how it performs on mixed samples and clinical samples.