Successful Trials Research Articles

75 Lung ultrasound severity scores and its utility in predicting success of weaning off respiratory support in neonates born preterm

Abstract Background Preterm infants often require respiratory support in the newborn intensive care unit. Complete trial off around 30-34 weeks post-menstrual age (PMA) is by trial and error based on clinical and physiological variables. Lung ultrasound (LUS) is a reliable adjunct in the diagnosis and management of most neonatal lung conditions. However, its utility in accessing readiness for successful weaning off respiratory pressure support in preterm neonates has not been explored. Objectives To determine the utility of LUS severity score (LUS-sc) in predicting successful weaning off of respiratory pressure support after 32weeks CGA in neonates born ≤32 weeks gestational age (GA). Design/Methods Prospective cohort study involving preterm neonates born ≤32 weeks needing any respiratory pressure support modes, admitted to a single tertiary care center in Canada between Sept 2022-Sept 2023. Eligible neonates were assessed by LUS at two time points- LUS1 at 30-30 + 6 weeks for those born <30weeks GA and between 48-72hours of life for those born at 30-32 + 6 weeks GA; LUS2 within 12hours prior to trial off respiratory pressure support to room air or low flow after 32weeks PMA. LUS were scored for disease severity by two independent reviewers using the LUS-sc by Brat et al. Receiver operator characteristics (ROC) curves analyzed the reliability of LUS-sc to predict the successful cessation of respiratory pressure support to room air or low flow post LUS2. Results Of 50 preterm neonates included in the study, 32 (64%) were successfully weaned from pressure support after LUS2 at a mean (SD) GA of 33.03 (0.29). The mean (SD) GA at birth was 28.78 (0.46) in the successful group and 27.78 (0.62) in the unsuccessful group (p=0.197). The mean (SD) LUS-sc for LUS2 at which cessation of support was possible was significantly lower from those who failed [6.95(0.33) vs 8.69(0.55), p=0.006] (Table 1). The ROC curve (Figure 1) showed AUC of 0.717 (95%CI=0.56-0.86), for a cut-off of LUS-sc of 7.75, with sensitivity of 0.75 (95%CI=0.60-0.90) and specificity of 0.61 (95%CI=0.38-0.84). Independent of GA at birth and at respiratory pressure support trial off, LUS-sc ≤8 was associated with an increased odd of cessation of support by 9.0 (95%CI=1.9-42.6), p=0.005, and each additional week of GA at first trial off increased the odds of cessation by 2.2 (95%CI=1.1-4.4), p=0.031. Conclusion LUS is a reliable tool to assess readiness for successful non-invasive respiratory pressure support trial off. A LUS-sc ≤8 was associated with higher successful weaning off of non-invasive pressure support after 32weeks GA.

First Report of Aspergillus tubingensis Causing Leaf Spot on Pogostemon cablin in China

Patchouli (Pogostemon cablin (Blanco) Benth) is an important medicinal and aromatic plant widely cultivated in China, India, and other Southeast Asian countries. It is renowned for its diverse applications in traditional medicine and its detoxification, antibacterial, anti-inflammatory, and other pharmacological properties (Wu et al. 2016; Fang et al. 2022). In May 2023, a severe leaf spot disease was observed on Pogostemon cablin plants grown in most plantations in Yulin, Guangxi, China (22°26′N; 109°83′E), with over 50% incidence rate. Symptoms began as small, circular, brown spots on leaves, enlarging with yellow halos. Lesions expanded into irregular shapes with necrotic centers. Advanced stages showed extensive yellowing, browning, and leaf senescence. A total of 20 symptomatic plants were sampled from 5 different locations within the detected area, with 4 plants sampled per location. To isolate the pathogen, 20 affected leaves were collected from these plants and preliminarily washed with sterile distilled water (SDW). Five small tissue pieces (5×5 mm) were excised from the lesion edge of each leaf, surface-disinfected with 75% ethanol and 1% NaClO, rinsed thrice with SDW, and placed on potato dextrose agar (PDA) at 28 °C in darkness for 7 days. Out of these, 18 plants (90%) yield fungal isolate with recurrent and similar morphological characteristics. Four representative isolates (X5-1-1, X5-1-3, X5-1-5, and X5-1-7) were selected for further analysis. On PDA, colonies were initially white, gradually turning black on the surface, with light yellow on the reverse side of the plate. Conidia were brown to black, globose, rough-walled, and 2.6 to 5.2 µm in diameter. Conidial heads were brown-black, and conidiophores were smooth and hyaline. Morphological characteristics matched those of Aspergillus sp. (Guo et al. 2017). For molecular identification, the internal transcribed spacer (ITS) region and the β-tubulin (TUB) gene of all four isolates were sequenced (Lim et al. 2019). All four isolates (X5-1-1, X5-1-3, X5-1-5, and X5-1-7) showed consistent morphological characteristics and 100% identical ITS and TUB sequences. Representative sequences from isolate X5-1-5 were submitted to GenBank (ITS: PP789632; TUB: PP798205). The obtained ITS and TUB sequences showed 99% similarity to Aspergillus tubingensis (ITS: OP737633; TUB: MG991377). Based on morphological and molecular analyses, the fungus was identified as A. tubingensis (Palmer et al. 2019). For pathogenicity tests, a spore suspension (1 × 10^6 conidia/mL) was prepared from 7-day-old cultures of A. tubingensis grown on PDA. The suspension was sprayed onto leaves of 10 healthy Pogostemon cablin plants until runoff. Control plants were sprayed with SDW. All plants were kept in a controlled greenhouse (12/12h light/dark, 25 ± 2 °C, 90% humidity). After 7 d, symptoms identical to those observed in the field developed on all pathogen inoculated plants, while control plants remained asymptomatic. The fungus was successfully re-isolated from infected leaves in three successive trials, fulfilling Koch's postulates. Notably, A. tubingensis has previously been reported causing field diseases on strawberry in California, Jatropha curcas and Helleborus species in China (Palmer et al. 2019; Guo et al. 2017, Liaquat et al. 2019), and vine canker on table grape in Italy (Vitale et al. 2012). To our knowledge, this is the first report of A. tubingensis causing leaf spot on Pogostemon cablin in China. This finding provides a foundation for further investigate into the biology, epidemiology, and management of this disease.

Innovation for recycling of organic matter through composter with automatic and sustainable temperature recording accessed via Bluetooth/mobile app.

Compost reactors, commonly used in experiments, industrial assays, and home residue treatment systems, have the potential to facilitate composting. Challenges persist in the realm of small-scale composting, encompassing facets such as temperature monitoring, homogenization of the compost mass, management of moisture with the control of leachate generation, and integration with a renewable energy source. This study assesses a pioneering composter prototype endowed with essential features to ensure a pragmatic and secure composting process. This includes the facilitation of remote access to temperature data via Bluetooth and a mobile application. Across successive trials, the scrutinized composter prototype consistently yielded reproducible outcomes, exhibiting a coefficient of variation below 25% for the majority of appraised parameters. In comparison to a conventional reactor, the decomposing residue mixture within the examined prototype manifested elevated temperatures (p < 0.05). Moreover, the tested prototype demonstrated C/N ratio lower than 20/1 within 45days, a higher final nitrogen concentration, and enhanced germination of seeds that served as phytotoxicity bioindicators. Notably, the prototype needed 46.6% less space, offering improved leachate control, three times faster turning time, temperature monitoring, and reduced fly attraction.

Effects of fMRI neurofeedback of right inferior frontal cortex on inhibitory brain activation in children with ADHD.

We aimed to replicate previous effects of functional magnetic resonance imaging neurofeedback (fMRI-NF) in right inferior frontal cortex (rIFC) on IFC activation during a Stop Task in a larger group of boys with attention-deficit/hyperactivity disorder (ADHD). The present double-blind, randomized controlled trial tested the effects of 15 runs of active versus sham fMRI-NF of rIFC on performance and activation associated with successful and failed inhibition versus Go trials during a tracking Stop task in 88 boys with ADHD (44 active; 44 sham), controlling for age and medication status. No significant group-by-time interaction effects were observed for performance or brain activation during the successful stop trials, and post hoc analysis showed very low numbers of active fMRI-NF learners. Nevertheless, during error monitoring, there was a significant group-by-time interaction effect on post-error reaction time slowing and in left IFC activation, which were both increased after active compared to sham fMRI-NF. The findings are in line with our previous observation of left IFC upregulation after fMRI-NF of rIFC relative to active fMRI-NF of parahippocampal gyrus. This highlights the potentially wider regional effects that fMRI-NF of a particular self-control target region has on other self-regulatory regions in ADHD. This article is part of the theme issue 'Neurofeedback: new territories and neurocognitive mechanisms of endogenous neuromodulation'.

Metformin-mediated protection against doxorubicin-induced cardiotoxicity

BackgroundA phase II clinical trial of metformin (MET) for the treatment of doxorubicin (DOX)-induced cardiotoxicity (NCT02472353) failed. ObjectivesThe aims of this study were to confirm MET-mediated protection against DOX-induced cardiotoxicity and its mechanism using H9C2 cells, and to establish a Wistar rat model of DOX-induced cardiotoxicity. Subsequently, Wistar rats were utilized to identify clinically relevant indicators for evaluating MET-mediated protection against DOX-induced cardiotoxicity, thereby facilitating early transition towards successful clinical trials. MethodsMET-mediated protection was assessed using cell viability and cytotoxicity experiments. Additionally, intramitochondrial reactive oxygen species (ROS) levels were measured using an ROS fluorescent probe (dihydroethidium) to confirm the oxidative stress mechanism. Eighteen Wistar rats were randomly allocated to the control, DOX, and DOX+MET groups; and the body weight, adverse drug reactions (ADRs), myocardial injury, cardiac function, oxidative stress, and histopathology of heart tissues were compared between groups. ResultsH9C2 cells treated with MET/Dexrazoxane demonstrated dose-dependent protection against DOX-induced cardiotoxicity. The fluorescence intensity of H9C2 cells suggested DOX-induced cardiomyocyte toxicity and MET-mediated protection against DOX-induced cardiotoxicity. In vivo experiments confirmed that a rat model of DOX-induced cardiotoxicity was successfully established, but MET-mediated protection against DOX-induced cardiotoxicity was not demonstrated. This was attributed to insufficient energy intake because of ADRs, such as vomiting. ConclusionsWe confirmed the MET-mediated protection against DOX-induced cardiomyocyte toxicity and its mechanism involving the inhibition of oxidative stress in vitro experiments. It is imperative to investigate the optimal conditions for MET-mediated protection against DOX-induced cardiotoxicity in vivo or clinical trials.

Immunotherapy-Based Strategies for Treatment of Type 1 Diabetes.

Type 1 diabetes (T1D) is more than an insulin-deficiency disease-it is an autoimmune disease, and the field is moving towards adopting disease-modifying immunotherapy as part of clinical care during T1D development. Recent successful immunotherapies as well as therapies that missed the mark are reviewed. T cell-directed therapies may allow for the greatest preservation of β cell function but also come with more side effects. Anti-cytokine therapies are very promising but likely need chronic administration. Antigen-specific therapies while safe have not produced meaningful results. Most successful trials have been conducted in adolescents and adults with stage 3 T1D (clinical T1D) with preserved C-peptide (up to 60% more compared to placebo) demonstrated 1-2 years post treatment. HbA1c and total insulin dose are less likely to be significantly different between treated and placebo groups because most participants in studies are meeting glycemic targets and because of the heterogeneous nature of these measures. In the prevention space (delaying progression from stage 2 to stage 3 T1D) the outcome is more discrete, and a T cell-directed therapy, teplizumab, has received FDA approval. Even negative studies with promising mechanistic and safety profiles have added value. What is clear, a single administration or short course of an immunotherapy is unlikely to provide sustained freedom from exogenous insulin.

Neoadjuvant Immunotherapy in Head and Neck Cancers: A Paradigm Shift in Treatment Approach.

Checkpoint inhibitors (ICIs) have demonstrated substantial efficacy in the treatment of numerous solid tumors, including head and neck cancer. Their inclusion in the therapeutic paradigm in metastatic lines of treatment has certainly improved the outcomes of these patients. Starting from this assumption, numerous studies have been conducted on ICIs in other earlier disease settings, including studies conducted in patients in neoadjuvant settings. However, how many and which studies are truly significant? Can they lay concrete foundations for further future studies and therefore allow us to continue to have this interesting future perspective? Through a review of the existing literature, coupled with insights gleaned from clinical practice and from the main recently published studies, we aim to examine the therapeutic potential of ICIs in patients affected by head and neck cancer in a neoadjuvant treatment setting and encourage researchers to set up successful future clinical trials.

Deciphering autism heterogeneity: a molecular stratification approach in four mouse models

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous mouse models, each exhibiting unique autism-like behaviors modeling the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes across the four models. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt, and Oxtr as five robust and discriminant molecular markers that allowed the successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward the potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.

Experimental study on how the settings of plasma affect its effectiveness of suppression of thermoacoustic oscillations in a Rijke tube

Thermoacoustic instabilities, frequent in a wide range of combustors, arise from the intricate coupling between the flame’s unsteady heat release and the combustor acoustic. The application of plasma, characterized by its substantial local energy addition and radical generation, has demonstrated potential in disrupting this coupling and thereby mitigating thermoacoustic oscillations. Notably, open-loop control using discharge plasma has been successfully implemented to suppress self-excited oscillations in a Rijke tube setup. Considering the broader context of a complex system that integrates both thermoacoustic systems and discharge plasma, experiments were done to see its performance in stability under different arrangement and discharge repetition rates of discharge plasma. These experimental investigations identified critical operating conditions essential for complete suppression: (A) the optimal location of discharge actuations, and (B) the minimum energy required for complete suppression. Moreover, the impact of discharge plasma, particularly when tuned to the eigenfrequencies of oscillations within the thermoacoustic system, was thoroughly examined. The insights gained from these successful suppression trials are instrumental in guiding the strategic design of both physical arrangement and electrical configurations for the control of combustion instabilities via discharge plasma. Furthermore, through the photographing of the swinging arcs and their thermal disturbances by high-speed camera and high-speed schlieren, the characteristics of arcs’ thermal disturbances and the reasons affecting its suppression effectiveness were determined.

Optical and optoelectrical characterizations of Cu2ZnSn3S8: A potential nominee for optoelectronic and photovoltaic applications

A successful trial has been accomplished in synthesizing a stable phase of Cu2ZnSn3S8 (CZTS8). The deposited thin films have been obtained by utilizing the chemical bath deposition (CBD) process. Basic characterizations have been applied to check the formation of our new stable material. The formed CZTS8 films disclose the amorphous nature as presented in the x-ray diffraction (XRD) patterns. Also, an enhancement in film morphology has been obtained by expanding the film thickness. Moreover, optoelectrical and linear/nonlinear optical features have been studied for the as-deposited films. Our material has interesting characteristics to be a promising window sheet for thin film solar cells. It reveals a tendency to be an n-type semiconductor material. Further, it shows high optical absorption as well as high optical conductivity. Moreover, it has a direct optical transition, and its energy gap is varied in the range (3.89 eV - 3.94 eV). Additionally, the dispersion and optoelectrical indices were affected by the variation in both film thickness and film roughness. Furthermore, the nonlinear optical indices χ(1),χ(3) and n2 were improved via the increase in film thickness. A satisfactory correlation has been performed between all of the evaluated parameters. The main goal of this study has been achieved by obtaining n-type material by increasing the Tin and Sulfur contents in the CZTS8 as compared with the known p-type material (Cu2ZnSnS4) CZTS4. The revealed findings acknowledge that CZTS8 could be a promising nominee for either optoelectronic or photovoltaic applications.

Integrated Sensing Platform Validated for the Efficient and On-Site Screening of Amine-Containing Illicit Drugs.

Efficient and reliable technologies for the on-site detection of illicit drugs are important in drug-facilitated crime investigations. However, the development of such technologies is challenging. Based on the synthetic optimization, introducing a boron ester functional group to the two furanic indicators endows the stimulus-responsive properties synergistically. The ring-opening reaction of the indicators in the presence of amine-containing illicit drugs generated well-known donor-acceptor Stenhouse adducts, accompanied by strong color changes. A small-size and lightweight laminated sensor was integrated based on the outstanding ratiometric variations of the two active furanic indicators. A prototype platform was fabricated equipped with a circuit control, a mini pump, and a signal processing system. A user-friendly detection and efficient screening of amine-containing illicit drugs, including phenethylamines, amphetamines, cathinones, and tryptamines in the liquid states were conducted. The ratiometric response of the sensor was linear in the concentration range of 2.1-10.6 μg·mL-1 for methamphetamine·HCl and methcathinone ·HCl. The detection limits for the two illicit drugs at the sublevel (ng·mL-1) were found to be 8.4 and 9.0 ng·mL-1, respectively. Double-blind field tests and different illicit drugs were evaluated with good screening capability. Successful trials showed the potential applications of the developed prototype platform for efficient and on-site analytical determination.

Hippocampal representations of alternative possibilities are flexibly generated to meet cognitive demands.

The cognitive ability to go beyond the present to consider alternative possibilities, including potential futures and counterfactual pasts, can support adaptive decision making. Complex and changing real-world environments, however, have many possible alternatives. Whether and how the brain can select among them to represent alternatives that meet current cognitive needs remains unknown. We therefore examined neural representations of alternative spatial locations in the rat hippocampus during navigation in a complex patch foraging environment with changing reward probabilities. We found representations of multiple alternatives along paths ahead and behind the animal, including in distant alternative patches. Critically, these representations were modulated in distinct patterns across successive trials: alternative paths were represented proportionate to their evolving relative value and predicted subsequent decisions, whereas distant alternatives were prevalent during value updating. These results demonstrate that the brain modulates the generation of alternative possibilities in patterns that meet changing cognitive needs for adaptive behavior.

Trial Factors Associated With Completion of Clinical Trials Evaluating AI: Retrospective Case-Control Study.

Evaluation of artificial intelligence (AI) tools in clinical trials remains the gold standard for translation into clinical settings. However, design factors associated with successful trial completion and the common reasons for trial failure are unknown. This study aims to compare trial design factors of complete and incomplete clinical trials testing AI tools. We conducted a case-control study of complete (n=485) and incomplete (n=51) clinical trials that evaluated AI as an intervention of ClinicalTrials.gov. Trial design factors, including area of clinical application, intended use population, and intended role of AI, were extracted. Trials that did not evaluate AI as an intervention and active trials were excluded. The assessed trial design factors related to AI interventions included the domain of clinical application related to organ systems; intended use population for patients or health care providers; and the role of AI for different applications in patient-facing clinical workflows, such as diagnosis, screening, and treatment. In addition, we also assessed general trial design factors including study type, allocation, intervention model, masking, age, sex, funder, continent, length of time, sample size, number of enrollment sites, and study start year. The main outcome was the completion of the clinical trial. Odds ratio (OR) and 95% CI values were calculated for all trial design factors using propensity-matched, multivariable logistic regression. We queried ClinicalTrials.gov on December 23, 2023, using AI keywords to identify complete and incomplete trials testing AI technologies as a primary intervention, yielding 485 complete and 51 incomplete trials for inclusion in this study. Our nested propensity-matched, case-control results suggest that trials conducted in Europe were significantly associated with trial completion when compared with North American trials (OR 2.85, 95% CI 1.14-7.10; P=.03), and the trial sample size was positively associated with trial completion (OR 1.00, 95% CI 1.00-1.00; P=.02). Our case-control study is one of the first to identify trial design factors associated with completion of AI trials and catalog study-reported reasons for AI trial failure. We observed that trial design factors positively associated with trial completion include trials conducted in Europe and sample size. Given the promising clinical use of AI tools in health care, our results suggest that future translational research should prioritize addressing the design factors of AI clinical trials associated with trial incompletion and common reasons for study failure.

Visuomotor predictors of interception.

Intercepting moving targets is a fundamental skill in human behavior, influencing various domains such as sports, gaming, and other activities. In these contexts, precise visual processing and motor control are crucial for adapting and navigating effectively. Nevertheless, there are still some gaps in our understanding of how these elements interact while intercepting a moving target. This study explored the dynamic interplay among eye movements, pupil size, and interceptive hand movements, with visual and motion uncertainty factors. We developed a simple visuomotor task in which participants used a joystick to interact with a computer-controlled dot that moved along two-dimensional trajectories. This virtual system provided the flexibility to manipulate the target's speed and directional uncertainty during chase trials. We then conducted a geometric analysis based on optimal angles for each behavior, enabling us to distinguish between simple tracking and predictive trajectories that anticipate future positions of the moving target. Our results revealed the adoption of a strong interception strategy as participants approached the target. Notably, the onset and amount of optimal interception strategy depended on task parameters, such as the target's speed and frequency of directional changes. Furthermore, eye-tracking data showed that participants continually adjusted their gaze speed and position, continuously adapting to the target's movements. Finally, in successful trials, pupillary responses predicted the amount of optimal interception strategy while exhibiting an inverse relationship in trials without collisions. These findings reveal key interactions among visuomotor parameters that are crucial for solving complex interception tasks.

Platinum(II) complexes based on derivatives of natural chlorins with pyridine-containing chelate groups as prototypes of drugs for combination therapy in oncology

Objectives. To synthesize Pt-containing derivatives of natural chlorins as potential agents for the combination therapy in oncology. Platinum compounds are known to occupy an important place as chemotherapeutic agents in the treatment of oncological diseases. However, Pt(II) complexes are highly toxic to the body and are not selectively accumulated in tumor cells. If photodynamic and chemotherapy methods are combined in a single drug, the pigments are responsible for the selectivity of conjugate accumulation in the tumor, while a chemotherapeutic agent based on Pt(II) complexes is responsible for the cytotoxic effect on tumor cells. This will not affect healthy cells and thereby minimize the systemic toxicity of the drug to the body.Methods. Methods for the synthesis of pyridine-containing derivatives of natural chlorins and their metal complexes for use as potential binary agents in oncology were applied. As part of the study, the structures of the compounds obtained were confirmed by mass spectrometry, nuclear magnetic resonance spectroscopy, ultraviolet spectroscopy, and high-resolution chromatography-mass spectrometry. Preparative methods, including thin-layer and column chromatography, centrifugation and recrystallization, were used to isolate and purify the compounds obtained.Results. Platinum(II) complexes of pyridine-containing derivatives of natural chlorins were obtained for application in combination therapy in oncology. The schemes for synthesizing the target photosensitizers were optimized, in order to increase the yields and for subsequent transfer to industrial sites.Conclusions. It was found that pyridine-containing derivatives of natural chlorins could be obtained in high yields, that they possess chelating properties for platinum, and can be considered as binary agents in cancer therapy after successful preclinical trials.

Optimal level of human intracranial theta activity for behavioral switching in the subthalamo-medio-prefrontal circuit

The ability to switch between rules associating stimuli and responses depend on a circuit including the dorsomedial prefrontal cortex (dmPFC) and the subthalamic nucleus (STN). However, the precise neural implementations of switching remain unclear. To address this issue, we recorded local field potentials from the STN and from the dmPFC of neuropsychiatric patients during behavioral switching. Drift-diffusion modeling revealed that switching is associated with a shift in the starting point of evidence accumulation. Theta activity increases in dmPFC and STN during successful switch trials, while temporally delayed and excessive levels of theta lead to premature switch errors. This seemingly opposing impact of increased theta in successful and unsuccessful switching is explained by a negative correlation between theta activity and the starting point. Together, these results shed a new light on the neural mechanisms underlying the rapid reconfiguration of stimulus-response associations, revealing a Goldilocks’ effect of theta activity on switching behavior.

If You Build It, Patients with Rare Cancers Will Come: A Successful Clinical Trial in Relapsed and Refractory JMML.

Juvenile myelomonocytic leukemia (JMML) is a rare pediatric hematologic malignancy with a high relapse rate and a poor prognosis hallmarked by RAS pathway mutations. Stieglitz and colleagues conducted a phase II clinical trial using the MEK inhibitor trametinib to treat patients with relapsed and refractory juvenile myelomonocytic leukemia and observed an objective response rate of 50% and an overall survival of 80% after 4 years. See related article by Stieglitz et al., p. 1590 (4) .

Qualitative Comparative Analysis of exercise interventions for fall prevention in residential aged care facilities

BackgroundExercise interventions are highly effective at preventing falls in older people living in the community. In residential aged care facilities (RACFs), however, the evidence for effectiveness is highly variable, warranting exploration of drivers of successful trials. This study aims to identify the conditions of randomised controlled trials (RCTs) that are associated with reducing falls in RACFs and test whether it can explain the variability.MethodsRCTs testing exercise interventions in RACFs compared to usual care, reporting rate or risk of falls from the 2018 Cochrane Collaboration review and a search update to December 2022 were included. Two authors independently extracted and coded trial conditions and outcomes according to a theory developed from prior Intervention Component Analysis. Trial outcomes were coded as successful or unsuccessful based on point estimates for the rate or risk ratio for falls, or p value. Qualitative Comparative Analysis (QCA), utilising Boolean minimisation theory, was conducted to determine the key conditions driving trial success. A subgroup meta-analysis and the GRADE approach was applied to the final theory.ResultsEighteen trials undertaken in 11 countries with 2,287 residents were included. Participants were predominately ambulant females aged 70 to 80 with cognitive impairment. Most interventions were fully supervised or supervised at the start of the intervention. QCA identified two configurations as drivers of successful exercise falls prevention programs: (i) group exercise that is moderate or low intensity, or (ii) for independent ambulatory residents, exercise for more than 1 h per week. The combination of configuration (i) and (ii) had consistency and total coverage scores of 1, indicating all trials were explained. This combination was associated with a reduction in falls (rate ratio 0.45, 95%CI 0.34 to 0.59; risk ratio 0.66, 95%CI 0.53 to 0.82; low certainty evidence).ConclusionTo successfully reduce falls in RACFs, exercise programs should provide continuous supervised moderate-intensity group exercise. For programs that mostly include independent ambulatory residents, exercise for at least 80 min per week should be provided. As many current residents are frail, tailored exercise is likely necessary and an individualised dose may be required. Future trials should test exercise interventions for less mobile residents.

"Stamp the tunnel"- Innovative tool - for perfection in manual small incision cataract surgery.

Manual small incision cataract surgery (SICS) is a cost-effective and safe procedure offering comparable outcomes to phacoemulsification. It holds significance for outreach and economically disadvantaged patients in developing countries, while also being important for complex cataracts in developed nations. The SICS technique revolves around a three planar self-sealing sclero corneal tunnel (SCT), a critical element for rapid and suture-less healing. The tunnel's components include the incision, side pocket, internal entry, and depth each affecting astigmatism and successful nucleus delivery.[1-3] Various incision types are explored, with the frown incision yielding minimal astigmatism but posing challenges.[2,4] Inappropriate SCT leads on to high induced astigmatism, post op hypotony, and chances of infection. This video introduces "Tunnel stamp" which is a novel device designed to guide the incision length, internal entry line, and side pocket accuracy thus making a perfect SCT particularly for novice surgeons, who often encounter intraoperative and postoperative complications due to inappropriate SCT. The device is produced through 3D printing with thermoplastic polyurethane (TPU), an easily available and economically feasible material. The prototype's practicality is demonstrated through successful wet lab trials on goat eyes and subsequently on human eyes. The device is aligned using a limbus-matching step and a sterilized marker pen. This device has unique advantage to take care of the three aspects of SCT, that is, incision, side pocket, and internal entry. One can have custom-made guarded knife to perform scleral groove in optimum depth, which is another important dimension of SCT. Future developments involve creating the tunnel stamp in transparent flexible silicon to enhance alignment accuracy. Given the diversity of cataract types, multiple sizes of the device are envisioned to accommodate nucleus size variability and different stages of cataract development. To aid novice surgeons, two variations of incision guides (straight and frown) are proposed for immature and harder cataracts reducing induced astigmatism. Overall, this innovative tunnel stamp aims to enhance SICS outcomes, enabling more precise and consistent SCT creation while addressing challenges posed by various cataract types and surgeon experience levels. https://youtu.be/yzV-UC4jwPg.

Addressing At-the-Moment Defenses against Painful Affects: A Core Mechanism of Change in Psychodynamic Treatment.

There is an ongoing tension in the psychodynamic field between interpreting the meaning of a patient's verbal productions or actions and addressing the defenses utilized by the patient. Some authors maintain that implicit interactions between analyst and patient may be more important than the verbal interventions by the analyst. This article stresses the importance of observing and appropriately addressing how patients manage painful affects in the sessions. Focusing the patients' attention on their at-the-moment defenses as they occur in the session is an experience-near intervention and minimizes interventions that address issues far from the patient's consciousness and that require a high level of conjecture by the therapist. This technique can be utilized at any point in treatment, regardless of its duration and intensity. Several vignettes are provided that suggest that addressing defenses against painful affect is a pantheoretical construct and may be a common factor in psychodynamic treatment. A successful randomized control trial utilizing this technique with children (regulation-focused psychotherapy) is described. There have been limited empirical studies of the impact of therapists addressing defenses in sessions, but the work of J. Christopher Perry and colleagues, particularly the development of the Psychodynamic Intervention Rating Scales, offers an opportunity to further study the impact of defense interpretations and other interventions.