A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis.

Objective: To determine whether a combination therapy with abatacept (CTLA4-Ig) and interleukin-2 (IL-2) is safe and suppresses markers of oxidative stress, inflammation, and degeneration in ALS. Methods: In this open-label study, four participants with ALS received subcutaneous injections of low dose IL-2 (1 × 106 IU/injection/day) for 5 consecutive days every 2 weeks and one subcutaneous injection of CTLA4-Ig (125 mg/mL/injection) every 2 weeks coinciding with the first IL-2 injection of each treatment cycle. Participants received a total of 24 treatment cycles during the first 48 weeks in this 56-week study. They were closely monitored for treatment-emergent adverse events (TEAEs) and disease progression with the ALSFRS-R. Phenotypic changes within T cell populations and serum biological markers of oxidative stress [4-hydroxynonenal (4-HNE) and oxidized-LDL (ox-LDL)], inflammation (IL-18), and structural neuronal degeneration [neurofilament light chain (Nf-L)] were assessed longitudinally. Results: CTLA4-Ig/IL-2 therapy was safe and well-tolerated in all four participants over the 56-week study. During the first 24 weeks, the average rate of change in the ALSFRS-R was +0.04 points/month. Over the 48-week treatment period, the average rate of change was -0.13 points/month with one participant improving by 0.9 points/month while the other three participants experienced an average decrease of -0.47 points/month, which is slower than the average - 1.1 points/month prior to initiation of therapy. Treg suppressive function and numbers increased during treatment. Responses in the biological markers during the first 16 weeks coincided with minimal clinical progression. Mean levels of 4-HNE decreased by 30%, ox-LDL decreased by 19%, IL-18 decreased by 23%, and Nf-L remained the same, on average, in all four participants. Oxidized-LDL levels decreased in all four participants, 4-HNE and IL-18 levels decreased in three out of four participants, and Nf-L decreased in two out of four participants. Conclusion: The combination therapy of CTLA4-Ig and IL-2 in ALS is safe and well-tolerated with promising results of clinical efficacy and suppression of biomarkers of oxidative stress, neuroinflammation and neuronal degeneration. In this open-label study, the efficacy as measured by the ALSFRS-R and corresponding biomarkers suggests the therapeutic potential of this treatment and warrants further study in a phase 2 double-blind, placebo-controlled trial. Clinical trial registration: ClinicalTrials.gov, NCT06307301.

From hunter-gatherers to food producers: New dental insights into the Nile Valley population history (Late Paleolithic-Neolithic).

OBJECTIVES: This study presents biological affinities between the last hunter-fisher-gatherers and first food-producing societies from the Nile Valley. We investigate odontometric and dental tissue proportion changes between these populations from the Middle Nile Valley and acknowledge the biological processes behind them. MATERIALS AND METHODS: Dental remains of 329 individuals from Nubia and Central Sudan that date from the Late Pleistocene to the mid-Holocene are studied. Using 3D imaging techniques, we investigated outer and inner metric aspects of upper central incisors, and first and second upper molars. RESULTS: Late Paleolithic and Mesolithic foragers display homogeneous crown dimensions, dental tissue proportions, and enamel thickness distribution. This contrasts with Neolithic trends for significant differences from earlier samples on inner and outer aspects. Finally, within the Neolithic sample differences are found between Nubian and Central Sudanese sites. DISCUSSION: Substantial dental variation appears to have occurred around 6000 bce in the Nile Valley, coinciding with the emergence of food-producing societies in the region. Archeological and biological records suggest little differences in dietary habits and dental health during this transition. Furthermore, the substantial variations identified here would have happened in an extremely short time, a few centuries at most. This does not support in situ diet-related adaptation. Rather, we suggest these data are consistent with some level of population discontinuity between the Mesolithic and Neolithic samples considered here. Complex settlement processes could also explain the differences between Nubia and Central Sudan, and with previous results based on nonmetric traits.

Empagliflozin for treating neutropenia and neutrophil dysfunction in 21 infants with glycogen storage disease 1b.

Empagliflozin has been successfully repurposed for treating neutropenia and neutrophil dysfunction in patients with glycogen storage disease type 1b (GSD 1b), however, data in infants are missing. We report on efficacy and safety of empagliflozin in infants with GSD 1b. This is an international retrospective case series on 21 GSD 1b infants treated with empagliflozin (total treatment time 20.6 years). Before starting empagliflozin (at a median age of 8.1 months with a median dose of 0.3 mg/kg/day) 12 patients had clinical signs and symptoms of neutrophil dysfunction. Six of these previously symptomatic patients had no further neutropenia/neutrophil dysfunction-associated findings on empagliflozin. Eight patients had no signs and symptoms of neutropenia/neutrophil dysfunction before start and during empagliflozin treatment. One previously asymptomatic individual with a horseshoe kidney developed a central line infection with pyelonephritis and urosepsis during empagliflozin treatment. Of the 10 patients who were treated with G-CSF before starting empagliflozin, this was stopped in four and decreased in another four. Eleven individuals were never treated with G-CSF. While in 17 patients glucose homeostasis remained stable on empagliflozin, four showed glucose homeostasis instability in the introductory phase. In 17 patients, no other side effects were reported, while genital (n = 2) or oral (n = 1) candidiasis and skin infection (n = 1) were reported in the remaining four. Empagliflozin had a good effect on neutropenia/neutrophil dysfunction-related signs and symptoms and a favourable safety profile in infants with GSD 1b and therefore qualifies for further exploration as first line treatment.

Associations between 3D-based Left Atrial Volumetric and Blood Flow Parameters in a Single-Site Cohort of the Multi-Ethnic Study of Atherosclerosis.

Purpose To investigate associations between left atrial volume (LAV) and function with impaired three-dimensional hemodynamics from four-dimensional flow MRI. Materials and Methods A subcohort of participants from the Multi-Ethnic Study of Atherosclerosis from Northwestern University underwent prospective 1.5-T cardiac MRI including whole-heart four-dimensional flow and short-axis cine imaging between 2019 and 2020. Four-dimensional flow MRI analysis included manual three-dimensional segmentations of the LA and LA appendage (LAA), which were used to quantify LA and LAA peak velocity and blood stasis (% voxels < 0.1 m/sec). Short-axis cine data were used to delineate LA contours on all cardiac time points, and the resulting three-dimensional-based LAVs were extracted for calculation of LA emptying fractions (LAEFtotal, LAEFactive, LAEFpassive). Stepwise multivariable linear models were calculated for each flow parameter (LA stasis, LA peak velocity, LAA stasis, LAA peak velocity) to determine associations with LAV and LAEF. Results This study included 158 participants (mean age, 73 years ± 7 [SD]; 83 [52.5%] female and 75 [47.4%] male participants). In multivariable models, a 1-unit increase of LAEFtotal was associated with decreased LA stasis (ß coefficient, -0.47%; P < .001), while increased LAEFactive was associated with increased LA peak velocity (ß coefficient, 0.21 cm/sec; P < .001). Furthermore, increased minimum LAV indexed was most associated with impaired LAA flow (higher LAA stasis [ß coefficient, 0.65%; P < .001] and lower LAA peak velocity [ß coefficient, -0.35 cm/sec; P < .001]). Conclusion Higher minimum LAV and reduced LA function were associated with impaired flow characteristics in the LA and LAA. LAV assessment might therefore be a surrogate measure for LA and LAA flow abnormalities. Keywords: Atherosclerosis, Left Atrial Volume, Left Atrial Blood Flow, 4D Flow MRI Supplemental material is available for this article. © RSNA, 2024.

A data set of symptoms and needs of individuals affected by COVID-19.

Here we provide data from an online survey of 639 people diagnosed with COVID-19 and resident in France, who were diagnosed with COVID-19 between 30th Jan 2020 and 29th August 2022. In addition to demographic information the survey includes questions about participants' symptoms (by category), symptom onset and persistence, and the effects these symptoms had on their daily lives. Participants were able to include information related to their perceived medical, social and professional needs. These data are needed in order to create effective care policies addressing post-COVID sequelae. Information related to symptom association & dynamics is expected to be useful to clinicians and may also inform more fundamental studies.

NRG Oncology Assessment of Artificial Intelligence Deep Learning-Based Auto-segmentation for Radiation Therapy: Current Developments, Clinical Considerations, and Future Directions.

Deep learning neural networks (DLNN) in Artificial intelligence (AI) have been extensively explored for automatic segmentation in radiotherapy (RT). In contrast to traditional model-based methods, data-driven AI-based models for auto-segmentation have shown high accuracy in early studies in research settings and controlled environment (single institution). Vendor-provided commercial AI models are made available as part of the integrated treatment planning system (TPS) or as a stand-alone tool that provides streamlined workflow interacting with the main TPS. These commercial tools have drawn clinics' attention thanks to their significant benefit in reducing the workload from manual contouring and shortening the duration of treatment planning. However, challenges occur when applying these commercial AI-based segmentation models to diverse clinical scenarios, particularly in uncontrolled environments. Contouring nomenclature and guideline standardization has been the main task undertaken by the NRG Oncology. AI auto-segmentation holds the potential clinical trial participants to reduce interobserver variations, nomenclature non-compliance, and contouring guideline deviations. Meanwhile, trial reviewers could use AI tools to verify contour accuracy and compliance of those submitted datasets. In recognizing the growing clinical utilization and potential of these commercial AI auto-segmentation tools, NRG Oncology has formed a working group to evaluate the clinical utilization and potential of commercial AI auto-segmentation tools. The group will assess in-house and commercially available AI models, evaluation metrics, clinical challenges, and limitations, as well as future developments in addressing these challenges. General recommendations are made in terms of the implementation of these commercial AI models, as well as precautions in recognizing the challenges and limitations.

Underweight in the first 2 years of life and nutrition risk in later childhood: a prospective cohort study.

BACKGROUND: Children with underweight in the first 2 years have lower body mass index z-score (zBMI) and height-for-age z-score (HAZ) in later childhood. It is not known if underweight in the first 2 years is associated with nutrition risk in later childhood. OBJECTIVE: (1) Determine the relationship between underweight (zBMI < -2) in the first 2 years and nutrition risk measured by the Nutrition Screening for Toddlers and Preschoolers (NutriSTEP) score from 18 months to 5 years. (2) Explore the relationship between underweight in the first 2 years and the NutriSTEP subscores for eating behaviours and dietary intake from 18 months to 5 years. METHODS: This was a prospective study, including healthy full-term children in Canada aged 0-5 years. zBMI was calculated using measured heights and weights and the WHO growth standards. NutriSTEP score was measured using a parent-completed survey and ranged from 0 to 68. Nutrition risk was defined as a score ≥21. Linear mixed effects models were used. RESULTS: Four thousand nine hundred twenty-nine children were included in this study. At enrolment, 51.9% of participants were male. The prevalence of underweight children was 8.8%. Underweight in the first 2 years was associated with higher NutriSTEP (0.79, 95% CI: 0.29,1.29), higher eating behaviour subscore (0.24, 95% CI: 0.03, 0.46) at 3 years and higher odds of nutrition risk (OR: 1.39, 95% CI: 1.07,1.82) at 5 years. CONCLUSIONS: Children with underweight in the first 2 years had higher nutrition risk in later childhood. Further research is needed to understand the factors which influence these relationships.

Overview and Recommendations for Prospective Multi-institutional Spatially Fractionated Radiation Therapy Clinical Trials.

PURPOSE: The highly heterogeneous dose delivery of spatially fractionated radiation therapy (SFRT) is a profound departure from standard radiation planning and reporting approaches. Early SFRT studies have shown excellent clinical outcomes. However, prospective multi-institutional clinical trials of SFRT are still lacking. This NRG Oncology/American Association of Physicists in Medicine working group consensus aimed to develop recommendations on dosimetric planning, delivery, and SFRT dose reporting to address this current obstacle toward the design of SFRT clinical trials. METHODS AND MATERIALS: Working groups consisting of radiation oncologists, radiobiologists, and medical physicists with expertise in SFRT were formed in NRG Oncology and the American Association of Physicists in Medicine to investigate the needs and barriers in SFRT clinical trials. RESULTS: Upon reviewing the SFRT technologies and methods, this group identified challenges in several areas, including the availability of SFRT, the lack of treatment planning system support for SFRT, the lack of guidance in the physics and dosimetry of SFRT, the approximated radiobiological modeling of SFRT, and the prescription and combination of SFRT with conventional radiation therapy. CONCLUSIONS: Recognizing these challenges, the group further recommended several areas of improvement for the application of SFRT in cancer treatment, including the creation of clinical practice guidance documents, the improvement of treatment planning system support, the generation of treatment planning and dosimetric index reporting templates, and the development of better radiobiological models through preclinical studies and through conducting multi-institution clinical trials.

Multicenter Multivendor Evaluation of Dose Volume Histogram Creation Consistencies for 8 Commercial Radiation Therapy Dosimetric Systems.

PURPOSE: To evaluate dose volume histogram (DVH) construction differences across 8 major commercial treatment planning systems (TPS) and dose reporting systems for clinically treated plans of various anatomic sites and target sizes. METHODS AND MATERIALS: Dose files from 10 selected clinically treated plans with a hypofractionation, stereotactic radiation therapy prescription or sharp dose gradients such as head and neck plans ranging from prescription doses of 18 Gy in 1 fraction to 70 Gy in 35 fractions, each calculated at 0.25 and 0.125 cm grid size, were created and anonymized in Eclipse TPS, and exported to 7 other major TPS (Pinnacle, RayStation, and Elements) and dose reporting systems (MIM, Mobius, ProKnow, and Velocity) systems for comparison. Dose-volume constraint points of clinical importance for each plan were collected from each evaluated system (D0.03 cc [Gy], volume, and the mean dose were used for structures without specified constraints). Each reported constraint type and structure volume was normalized to the value from Eclipse for a pairwise comparison. A Wilcoxon rank-sum test was used for statistical significance and a multivariable regression model was evaluated adjusting for plan, grid size, and distance to target center. RESULTS: For all DVH points relative to Eclipse, all systems reported median values within 1.0% difference of each other; however, they were all different from Eclipse. Considering mean values, Pinnacle, RayStation, and Elements averaged at 1.038, 1.046, and 1.024, respectively, while MIM, Mobius, ProKnow, and Velocity reported 1.026, 1.050, 1.033, and 1.022, respectively relative to Eclipse. Smaller dose grid size improved agreement between the systems marginally without statistical significance. For structure volumes relative to Eclipse, larger differences are seen across all systems with a range in median values up to 3.0% difference and mean up to 10.1% difference. CONCLUSIONS: Large variations were observed between all systems. Eclipse generally reported, at statistically significant levels, lower values than all other evaluated systems. The nonsignificant change resulting from lowering the dose grid resolution indicates that this resolution may be less important than other aspects of calculating DVH curves, such as the 3-dimensional modeling of the structure.

A phase 1 open-label pilot study of low-dose interleukine-2 immunotherapy in patients with Alzheimer's disease.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05821153, Registered April 20 2023, Retrospectively registered, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05821153.

Interpretations of meaningful and ambiguous hand gestures in autistic and non-autistic adults: A norming study.

Gestures are ubiquitous in human communication, and a growing but inconsistent body of research suggests that people with autism spectrum disorder (ASD) may process co-speech gestures differently from neurotypical individuals. To facilitate research on this topic, we created a database of 162 gesture videos that have been normed for comprehensibility by both autistic and non-autistic raters. These videos portray an actor performing silent gestures that range from highly meaningful (e.g., iconic gestures) to ambiguous or meaningless. Each video was rated for meaningfulness and given a one-word descriptor by 40 autistic and 40 non-autistic adults, and analyses were conducted to assess the level of within- and across-group agreement. Across gestures, the meaningfulness ratings provided by raters with and without ASD correlated at r > 0.90, indicating a very high level of agreement. Overall, autistic raters produced a more diverse set of verbal labels for each gesture than did non-autistic raters. However, measures of within-gesture semantic similarity among the responses provided by each group did not differ, suggesting that increased variability within the ASD group may have occurred at the lexical rather than semantic level. This study is the first to compare gesture naming between autistic and non-autistic individuals, and the resulting dataset is the first gesture stimulus set for which both groups were equally represented in the norming process. This database also has broad applicability to other areas of research related to gesture processing and comprehension. The video database and accompanying norming data are available on the Open Science Framework.

Primary visual cortex pathology in ALS patients with C9ORF72 expansion.

Poly-GA and poly-GP immunofluorescence studies show conspicuous dipeptide repeat pathology in layers IV and II of primary visual cortex in C9ALS patients.

Blood pressure trajectory of inpatient stroke rehabilitation patients from the Determining Optimal Post-Stroke Exercise (DOSE) trial over the first 12 months post-stroke.

Background: High blood pressure (BP) is the primary risk factor for recurrent strokes. Despite established clinical guidelines, some stroke survivors exhibit uncontrolled BP over the first 12 months post-stroke. Furthermore, research on BP trajectories in stroke survivors admitted to inpatient rehabilitation hospitals is limited. Exercise is recommended to reduce BP after stroke. However, the effect of high repetition gait training at aerobic intensities (>40% heart rate reserve; HRR) during inpatient rehabilitation on BP is unclear. We aimed to determine the effect of an aerobic gait training intervention on BP trajectory over the first 12 months post-stroke. Methods: This is a secondary analysis of the Determining Optimal Post-Stroke Exercise (DOSE) trial. Participants with stroke admitted to inpatient rehabilitation hospitals were recruited and randomized to usual care (n = 24), DOSE1 (n = 25; >2,000 steps, 40-60% HRR for >30 min/session, 20 sessions over 4 weeks), or DOSE2 (n = 25; additional DOSE1 session/day) groups. Resting BP [systolic (SBP) and diastolic (DBP)] was measured at baseline (inpatient rehabilitation admission), post-intervention (near inpatient discharge), 6- and 12-month post-stroke. Linear mixed-effects models were used to examine the effects of group and time (weeks post-stroke) on SBP, DBP and hypertension (≥140/90 mmHg; ≥130/80 mmHg, if diabetic), controlling for age, stroke type, and baseline history of hypertension. Results: No effect of intervention group on SBP, DBP, or hypertension was observed. BP increased from baseline to 12-month post-stroke for SBP (from [mean ± standard deviation] 121.8 ± 15.0 to 131.8 ± 17.8 mmHg) and for DBP (74.4 ± 9.8 to 78.5 ± 10.1 mmHg). The proportion of hypertensive participants increased from 20.8% (n = 15/72) to 32.8% (n = 19/58). These increases in BP were statistically significant: an effect [estimation (95%CI), value of p] of time was observed on SBP [0.19 (0.12-0.26) mmHg/week, p < 0.001], DBP [0.09 (0.05-0.14) mmHg/week, p < 0.001], and hypertension [OR (95%CI): 1.03 (1.01-1.05), p = 0.010]. A baseline history of hypertension was associated with higher SBP by 13.45 (8.73-18.17) mmHg, higher DBP by 5.57 (2.02-9.12) mmHg, and 42.22 (6.60-270.08) times the odds of being hypertensive at each timepoint, compared to those without. Conclusion: Blood pressure increased after inpatient rehabilitation over the first 12 months post-stroke, especially among those with a history of hypertension. The 4-week aerobic gait training intervention did not influence this trajectory.

DROID: Driver-Centric Risk Object Identification.

Identification of high-risk driving situations is generally approached through collision risk estimation or accident pattern recognition. In this work, we approach the problem from the perspective of subjective risk. We operationalize subjective risk assessment by predicting driver behavior changes and identifying the cause of changes. To this end, we introduce a new task called driver-centric risk object identification (DROID), which uses egocentric video to identify object(s) influencing a driver's behavior, given only the driver's response as the supervision signal. We formulate the task as a cause-effect problem and present a novel two-stage DROID framework, taking inspiration from models of situation awareness and causal inference. A subset of data constructed from the Honda Research Institute Driving Dataset (HDD) is used to evaluate DROID. We demonstrate state-of-the-art DROID performance, even compared with strong baseline models using this dataset. Additionally, we conduct extensive ablative studies to justify our design choices. Moreover, we demonstrate the applicability of DROID for risk assessment.

A general urban spreading pattern of COVID-19 and its underlying mechanism.

Currently, the global situation of COVID-19 is aggravating, pressingly calling for efficient control and prevention measures. Understanding the spreading pattern of COVID-19 has been widely recognized as a vital step for implementing non-pharmaceutical measures. Previous studies explained the differences in contagion rates due to the urban socio-political measures, while fine-grained geographic urban spreading pattern still remains an open issue. Here, we fill this gap by leveraging the trajectory data of 197,808 smartphone users (including 17,808 anonymous confirmed cases) in nine cities in China. We find a general spreading pattern in all cities: the spatial distribution of confirmed cases follows a power-law-like model and the spreading centroid human mobility is time-invariant. Moreover, we reveal that long average traveling distance results in a high growth rate of spreading radius and wide spatial diffusion of confirmed cases in the fine-grained geographic model. With such insight, we adopt the Kendall model to simulate the urban spreading of COVID-19 which can well fit the real spreading process. Our results unveil the underlying mechanism behind the spatial-temporal urban evolution of COVID-19, and can be used to evaluate the performance of mobility restriction policies implemented by many governments and to estimate the evolving spreading situation of COVID-19.

Hereditary orotic aciduria identified by newborn screening.

Introduction: Hereditary orotic aciduria is an extremely rare, autosomal recessive disease caused by deficiency of uridine monophosphate synthase. Untreated, affected individuals may develop refractory megaloblastic anemia, neurodevelopmental disabilities, and crystalluria. Newborn screening has the potential to identify and enable treatment of affected individuals before they become significantly ill. Methods: Measuring orotic acid as part of expanded newborn screening using flow injection analysis tandem mass spectrometry. Results: Since the addition of orotic acid measurement to the Israeli routine newborn screening program, 1,492,439 neonates have been screened. The screen has identified ten Muslim Arab newborns that remain asymptomatic so far, with DBS orotic acid elevated up to 10 times the upper reference limit. Urine organic acid testing confirmed the presence of orotic aciduria along with homozygous variations in the UMPS gene. Conclusion: Newborn screening measuring of orotic acid, now integrated into the routine tandem mass spectrometry panel, is capable of identifying neonates with hereditary orotic aciduria.

Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial.

The multimodal activities of farnesoid X receptor (FXR) agonists make this class an attractive option to treat nonalcoholic steatohepatitis. The safety and efficacy of tropifexor, an FXR agonist, in a randomized, multicenter, double-blind, three-part adaptive design, phase 2 study, in patients with nonalcoholic steatohepatitis were therefore assessed. In Parts A + B, 198 patients were randomized to receive tropifexor (10-90 µg) or placebo for 12 weeks. In Part C, 152 patients were randomized to receive tropifexor 140 µg, tropifexor 200 µg or placebo (1:1:1) for 48 weeks. The primary endpoints were safety and tolerability to end-of-study, and dose response on alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hepatic fat fraction (HFF) at week 12. Pruritus was the most common adverse event in all groups, with a higher frequency in the 140- and 200-µg tropifexor groups. Decreases from baseline in ALT and HFF were greater with tropifexor versus placebo at week 12, with a relative decrease in least squares mean from baseline observed with all tropifexor doses for ALT (tropifexor 10-90-µg dose groups ranged from -10.7 to -16.5 U l-1 versus placebo (-7.8 U l-1) and tropifexor 140- and 200-µg groups were -18.0 U l-1 and -23.0 U l-1, respectively, versus placebo (-8.3 U l-1)) and % HFF (tropifexor 10-90-µg dose groups ranged from -7.48% to -15.04% versus placebo (-6.19%) and tropifexor 140- and 200-µg groups were -19.07% and -39.41%, respectively, versus placebo (-10.77%)). Decreases in ALT and HFF were sustained up to week 48; however, similar trends in AST with tropifexor at week 12 were not observed. As with other FXR agonists, dose-related pruritus was frequently observed. Clinicaltrials.gov registration: NCT02855164.

Addition of galactose-1-phosphate measurement enhances newborn screening for classical galactosemia.

Galactosemia is an inborn disorder of carbohydrate metabolism of which early detection can prevent severe illness. Although the assay for galactose-1-phosphate uridyltransferase (GALT) enzyme activity has been available since the 1960s, many issues prevented it from becoming universal. In order to develop the Israeli newborn screening pilot algorithm for galactosemia, flow injection analysis tandem mass spectrometry measurement of galactose-1-phosphate in archived dried blood spots from newborns with classical galactosemia, galactosemia variants, epimerase deficiency, and normal controls, was conducted. Out of 431 330 newborns screened during the pilot study (30 months), two with classical galactosemia and four with epimerase deficiency were identified and confirmed. Five false positives and no false negatives were recorded. Following this pilot study, the Israeli final and routine newborn screening algorithm, as recommended by the Advisory Committee to the National Newborn Screening Program, now consists of galactose-1-phosphate measurement integrated into the routine tandem mass spectrometry panel as the first-tier screening test, and GALT enzyme activity as the second-tier performed to identify only newborns suspected to be at risk for classical galactosemia. The GALT enzyme activity cut-off used in the final algorithm was lowered in order to avoid false positives.

Four-Dimensional Computed Tomography Ventilation Image-Guided Lung Functional Avoidance Radiation Therapy: A Single-Arm Prospective Pilot Clinical Trial.

PURPOSE: The primary objective of this prospective pilot trial was to assess the safety and feasibility of lung functional avoidance radiation therapy (RT) with 4-dimensional (4D) computed tomography (CT) ventilation imaging. METHODS AND MATERIALS: Patients with primary lung cancer or metastatic disease to the lungs to receive conventionally fractionated RT (CFRT) or stereotactic body RT (SBRT) were eligible. Standard-of-care 4D-CT scans were used to generate ventilation images through image processing/analysis. Each patient required a standard intensity modulated RT plan and ventilation image guided functional avoidance plan. The primary endpoint was the safety of functional avoidance RT, defined as the rate of grade ≥3 adverse events (AEs) that occurred ≤12 months after treatment. Protocol treatment was considered safe if the rates of grade ≥3 pneumonitis and esophagitis were <13% and <21%, respectively for CFRT, and if the rate of any grade ≥3 AEs was <28% for SBRT. Feasibility of functional avoidance RT was assessed by comparison of dose metrics between the 2 plans using the Wilcoxon signed-rank test. RESULTS: Between May 2015 and November 2019, 34 patients with non-small cell lung cancer were enrolled, and 33 patients were evaluable (n = 24 for CFRT; n = 9 for SBRT). Median follow-up was 14.7 months. For CFRT, the rates of grade ≥3 pneumonitis and esophagitis were 4.2% (95% confidence interval, 0.1%-21.1%) and 12.5% (2.7%-32.4%). For SBRT, no patients developed grade ≥3 AEs. Compared with the standard plans, the functional avoidance plans significantly (P < .01) reduced the lung dose-function metrics without compromising target coverage or adherence to standard organs at risk constraints. CONCLUSIONS: This study, representing one of the first prospective investigations on lung functional avoidance RT, demonstrated that the 4D-CT ventilation image guided functional avoidance RT that significantly reduced dose to ventilated lung regions could be safely administered, adding to the growing body of evidence for its clinical utility.