bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhancing employment conditions for migrant seasonal workers—Assessing consumer preferences for ‘fair-labour’ apples
Authors: Thiermann Insa , Götze Henrike , Lohmann Uwe-Latacz
Published: May 2024

Criticisms over labour practices in agricultural production often target the living and working conditions of migrant seasonal workers. This article assesses consumer preferences for apples produced under social conditions exceeding current legal standards. The analysis is based on a discrete choice experiment (DCE) with a sample of 204 German consumers, who were asked to choose among domestic ‘fair-labour’ apples and standard apples. The former differed in six attributes describing the social conditions facing migrant seasonal workers on German farms. A mixed logit and latent class model were used to analyse the data. The predicted probability of choosing a ‘fair-labour’ apple was 85 per cent. Consumers valued higher minimum wages, the inclusion of migrant workers in Germany's social security system, and bonus payments for work on Sundays and public holidays. Improved accommodation and limits on the maximum permissible weekly working hours were considered less important. The low-price elasticity suggests that farmers could recoup a large share of the extra costs involved in providing enhanced living and working conditions for their workers.
Lats1 and Lats2 regulate YAP and TAZ activity to control the development of mouse Sertoli cells
Authors: Abou Nader Nour , Charrier Laureline , Meisnsohn Marie‐Charlotte , Banville Laurence , Deffrennes Bérengère , St‐Jean Guillaume , Boerboom Derek , Zamberlam Gustavo , Brind'Amour Julie , Pépin David , Boyer Alexandre
Published: May 2024

Recent reports suggest that the Hippo signaling pathway regulates testis development, though its exact roles in Sertoli cell differentiation remain unknown. Here, we examined the functions of the main Hippo pathway kinases, large tumor suppressor homolog kinases 1 and 2 (Lats1 and Lats2) in developing mouse Sertoli cells. Conditional inactivation of Lats1/2 in Sertoli cells resulted in the disorganization and overgrowth of the testis cords, the induction of a testicular inflammatory response and germ cell apoptosis. Stimulated by retinoic acid 8 (STRA8) expression in germ cells additionally suggested that germ cells may have been preparing to enter meiosis prior to their loss. Gene expression analyses of the developing testes of conditional knockout animals further suggested impaired Sertoli cell differentiation, epithelial‐to‐mesenchymal transition, and the induction of a specific set of genes associated with Yes‐associated protein (YAP) and transcriptional coactivator with PDZ‐binding motif (TAZ)‐mediated integrin signaling. Finally, the involvement of YAP/TAZ in Sertoli cell differentiation was confirmed by concomitantly inactivating Yap/Taz in Lats1/2 conditional knockout model, which resulted in a partial rescue of the testicular phenotypic changes. Taken together, these results identify Hippo signaling as a crucial pathway for Sertoli cell development and provide novel insight into Sertoli cell fate maintenance.
Handedness and Its Impact on a Career in Medicine
Authors: Sonnino Roberta E. , Sonnino Victor G.
Published: May 2024

Left-handedness in a world of right lateral bias can be an invisible barrier both in everyday life as well as in medical career development, and throughout a medical career. Common everyday life actions, including screwing in lightbulbs, inserting a screw, or any action that requires a clockwise rotation, is designed for “righties,” making life for “lefties” a challenge. Other examples include writing without a slant or without smudging. In medicine, the physical examination of a patient is taught using the right hand and standing on the right side of the patient, an awkward situation for left handers. Another major concern in medicine specifically, is handwriting—notoriously poor in lefties—impacting legibility in progress notes, prescriptions, and medical records. In surgery and other procedural specialties in particular, using instruments intended for right-handed individuals, including suturing and positioning at the operating room table, presents left-handed individuals with particular challenges. Left-handed medical students and residents are especially vulnerable, as they may feel uncomfortable requesting special accommodations for their “handedness.” The significance and impact of handedness often go unrecognized, yet may play a substantial role in career choices: the difficulties of being left-handed may dissuade students from pursuing their desired career. Solutions are available, including using instruments designed for left-handers (or learning to use “righty” instruments), and positioning at the operating room or procedure table as preferred by the left-handed individual. These solutions often require a cooperative attitude by colleagues. The authors describe the significance of handedness, including their own personal experiences, and offer some solutions for left-handed individuals who struggle to adapt to a right-handed world.
Nusinersen Initiation After Onset of Weakness Does Not Prevent Progression of Hip Instability
Authors: Kuong Evelyn Eugenie , Ip Hoi Ning Hayley , So Noah Lok Wah , To Michael Kai Tsun , Chow Wang , Wong Janus Siu Him , Chan Sophelia Hoi Shan
Published: May 2024

Background:

We report changes in the natural history of hip instability with nusinersen treatment among patients with spinal muscular atrophy (SMA) type II after onset of weakness, historically wheelchair-bound but now potentially ambulatory in the era of disease-modifying therapy.

Methods:

Patients with genetically confirmed diagnoses of SMA type II who received intrathecal nusinersen from January 1, 2018, to June 30, 2022, were screened for inclusion. Patients with less than 6 months of follow-up, or prior hip surgeries were excluded. Primary clinical outcome measures included scores from Hammersmith motor functional scale expanded (HMFSE), revised upper limb module (RULM), 6-minute walk test (6MWT), and ambulatory status. Radiographic outcomes, including Reimer migration index, the presence of scoliosis, and pelvic obliquity, were also assessed. Secondary outcomes involved comparisons with a historical cohort of SMA type II patients treated at our institution who never received nusinersen.

Results:

Twenty hips from 5 boys and 5 girls were included in the analysis, with a mean follow-up of 3 years and 8 months. The median age at time of nusinersen initiation was 6.8 years old, ranging between 2.5 and 10.3 years. All patients developed lower limb motor weakness before nusinersen initiation. After treatment with nusinersen, 1 previously stable hip (5%) developed subluxation, 15 hips (75%) remain subluxated, 3 hips (15%) remain dislocated, and 1 hip (5%) remained stable, with a statistically significant difference between the pretreatment and posttreatment groups (P<0.01). Six patients (60%) were ambulatory at latest follow-up. Six patients (60%) had improved ambulatory ability; 2 had static ambulatory ability (20%); and 2 had deterioration in their walking ability. The median HFMSE score improved from 18.5 (range 0 to 46) to 22 (range 0 to 49) (P=0.813), whereas the median RULM score improved from 17 (range 2 to 28) to 21.5 (range 5 to 37), which was statistically significant (P=0.007).

Conclusions:

Hip instability persists despite treatment with nusinersen among patients with SMA type II who received nusinersen after onset of lower limb weakness.

Level of Evidence:

Therapeutic Level IV.
Outcomes of Ponseti Method for the Treatment of Clubfeet in Children With Arthrogryposis
Authors: Schaibley Claire , Torres-izquierdo Beltran , Hosseinzadeh Pooya
Published: May 2024

Introduction:

The Ponseti serial casting method is the method of choice in treating children with congenital clubfeet. The arthrogrypotic clubfoot has traditionally been considered challenging to treat, with higher rates of recurrence and the need for more corrective surgeries. However, initial reports have found promising results in using the Ponseti method to treat arthrogrypotic feet. This study aims to compare the outcomes of idiopathic versus arthrogrypotic clubfeet following initial treatment with the Ponseti serial casting method.

Methods:

A retrospective review of medical records from a single institution was conducted. Data was collected from children ages 0 to 18 with idiopathic or arthrogrypotic clubfoot treated from 2002 to 2022 with Ponseti-style serial casting with a minimum 2-year follow-up. Recurrence was defined as the need for additional casting or subsequent surgeries following initial correction. Data was collected on relevant patient demographics, previous treatment, casting records, Achilles tenotomies, and surgical treatments.

Results:

A total of 352 patients (546 feet) met inclusion criteria. In all, 334 idiopathic and 18 arthrogrypotic patients were analyzed with an average follow-up duration of 3.4 and 4.2 years, respectively. Twelve patients had distal arthrogryposis, and 6 had amyoplasia. In all, 93.4% of idiopathic and 72.2% of arthrogrypotic patients successfully achieved correction with Ponseti casting and Achilles tenotomy. Recurrence rates were significantly higher in the arthrogrypotic group at 83.3% compared with 44.6% in the idiopathic group (P=0.001). A posterior or posterior medial release was performed in 35.0% of idiopathic and 66.7% arthrogrypotic feet.

Conclusions:

We report the largest series of arthrogrypotic clubfeet treated by Ponseti casting to the best of our knowledge. In contrast to earlier reports, our investigation underscores that while the Ponseti method may be able to secure initial correction in arthrogrypotic clubfeet, on average, at a 3-year follow-up, the prognosis is less favorable. These patients exhibit higher recurrence and often require operative treatment. Notably, a posterior medial release may eventually be needed in up to 6 of 10 patients.

Level of Evidence:

Level III—therapeutic studies—investigating the results of treatment.
Histological Assessment of the Effectiveness of Microneedling Device-Assisted Filler Delivery
Authors: Ugwu Nelson , Xun Helen , Dover Jeffrey S. , Boustany Ashley N. , Chung Hye Jin
Published: May 2024

BACKGROUND

Microneedling is used to enhance transcutaneous drug delivery. However, the extent to which microneedling devices impact filler delivery and whether this varies by filler type, microneedling device type, and treatment sequence is not known.

OBJECTIVE

To histologically assess and quantify the delivery of commonly used fillers through microneedling, using both a microneedling pen and a microneedling roller. In addition, the authors investigated whether there is a variation in filler delivery based on the sequence of microneedling in relation to topical filler application.

METHODS

Ex vivo human abdominal skin samples were subjected to microneedling pen or microneedling roller treatment. Black tissue marking ink, hyaluronic acid, poly-l-lactic acid, or undiluted calcium hydroxyapatite was topically applied before or immediately after microneedling treatment.

RESULTS

Histological evaluation revealed a notable presence of black ink within channels formed by both microneedling treatments (15.5%–98.1%), whereas there was limited presence of the various filler types tested (0%–6.6%) in all settings. Topical application before microneedling treatment led to relatively higher filler/ink deposition within the channels formed by the microneedling treatments compared with topical application after microneedling.

CONCLUSION

Transcutaneous delivery of fillers was not significantly helped by microneedling treatment, whereas the microneedling devices demonstrated effective delivery of an aqueous solution.
P-selectin and C-reactive protein in relation to home blood pressure and coronary calcification: a SCAPIS substudy
Authors: af Geijerstam Peder , Rådholm Karin , Jonasson Lena , Lindahl Tomas L. , Engvall Jan , Nyström Fredrik H. , Alfredsson Joakim
Published: May 2024

Background:

Soluble P-selectin (sP-selectin) and high-sensitivity C-reactive protein (hsCRP) have previously been associated with hypertension, but the relation with out-of-office blood pressure (BP) and coronary artery calcification score is unknown. We aimed to examine the relationship between sP-selectin, hsCRP and home BP, as well as coronary artery calcification score and carotid artery plaques.

Methods:

In the Swedish CArdioPulmonary bioImage Study (SCAPIS), 5057 randomly selected participants were evaluated with office and home BP using the semi-automatic Omron M10-IT device. For this cross-sectional study, participants with sP-selectin <4 standard deviations above mean and hsCRP <5 mg/l, representing low-grade inflammation, were included. Using generalized linear models, these inflammatory markers were evaluated in relation to BP classifications, as well as coronary artery calcification score and carotid artery plaques.

Results:

Of participants, 4548 were included in the analyses. The median age was 57.2 (53.4–61.2) years, and 775 (17.0%) reported taking medication for hypertension. Participants in the highest quartile of sP-selectin [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.40–1.98, P < 0.001] and hsCRP [OR 2.25, (95% CI 1.89–2.60), P < 0.001] were more likely to have sustained hypertension. Participants in the highest quartile of hsCRP were also more likely to have masked hypertension, OR (95% CI) 2.31 (1.72–3.10), P < 0.001 and carotid artery plaques, OR (95% CI) 1.21 (1.05–1.38), P = 0.007.

Conclusion:

Increased sP-selectin and hsCRP were independently associated with sustained hypertension. These findings indicate an association between hypertension and platelet activity, as expressed by sP-selectin.
Blood pressure variability assessed by office, home, and ambulatory measurements before and during antihypertensive drug treatment: a sub-analysis of the REVERENT randomized trial
Authors: Kyriakoulis Konstantinos G. , Kollias Anastasios , Bilo Grzegorz , Soranna Davide , Liu Chang-Yuan , Pengo Martino F. , Zambon Antonella , Zhang Wei , Destounis Antonios , Wang Ji-Guang , Stergiou George S. , Parati Gianfranco
Published: May 2024

Objectives:

Blood pressure (BP) variability (BPV) can be assessed using office (OBP), home (HBP), or ambulatory BP (ABP) measurements. This analysis investigated the association and agreement between OBP, HBP, and ABP measurements for BPV assessment at baseline and 10 weeks after initiating antihypertensive drug therapy.

Methods:

Untreated hypertensive patients with elevated BPV were randomized to receive an angiotensin-converting enzyme inhibitor (ramipril) or a calcium channel blocker (nifedipine GITS) in a 10-week, open-label, blinded-end point study. BPV was assessed using standard deviation (SD) and coefficient of variation (CV) (reading-to-reading analyses).

Results:

Data from 146 participants from three research centers (Athens/Greece; Milan/Italy; Shanghai/China) were analyzed [mean age 53 ± 10 (SD) years, male individuals 60%, baseline systolic OBP, HBP, and 24 h ABP 144 ± 9, 138 ± 10, and 143 ± 10 mmHg, respectively]. Post-treatment minus pre-treatment systolic CV difference was: OBP: 0.3%, P = 0.28; HBP: −0.2%, P = 0.20; 24 h ABP: 1.1%, P < 0.001. Home and ambulatory (not office) BPV indices presented weak-to-moderate correlation, both before and during treatment (range of coefficients 0.04–0.33). The correlation coefficient between systolic HBP and awake ABP CV was 0.21 and 0.28 before and during treatment, respectively (P < 0.05/< 0.001, respectively). Home and ambulatory (not office) BPV indices presented slight-to-fair agreement (range 64–73%) in detecting participants with high systolic BPV (top quartile of respective distributions) both before and during treatment (kappa range 0.04–0.27).

Conclusion:

These data showed a weak-to-moderate association between out-of-office (but not office) BPV indices both before and during BP-lowering treatment, with reasonable agreement in detecting individuals with high BPV. Out-of-office BP measurements provide more similar and consistent BPV information than office measurements.
TRPV1 signaling of perirenal adipose tissue promotes DOCA-Salt-induced hypertension and kidney injury
Authors: Hua Dongxu , Huang Wanlin , Huang Wen , Xie Qiyang , Tang Lu , Wu Xiaoguang , Gao Min , Xu Tianhua , Zhang Yue , Li Peng , Sun Wei , Kong Xiangqing
Published: May 2024

Background:

Denervation of renal or perirenal adipose tissue (PRAT) can reduce arterial blood pressure in various hypertensive experimental models. Trpv1 (transient receptor potential vanillin 1) channel is highly expressed in the renal sensory nerves and the dorsal root ganglias (DRGs) projected by PRAT. However, it is currently unclear whether Trpv1 in DRGs projected from PRAT can regulate renal hypertension.

Methods:

We used resintoxin (RTX) to block the afferent sensory nerves of rat PRAT. We also constructed Trpv1-/- mice and Trpv1+/- mice or used the injection of AAV2-retro-shTrpv1 to detect the effects of Trpv1 knockout or knockdown of PRAT-projected DRGs on deoxycorticosterone acetate (DOCA)-Salt-induced hypertension and kidney injury.

Results:

Blocking the afferent sensory nerves of PRAT with RTX can alleviate DOCA-Salt-induced hypertension and renal injury in rats. And this blockade reduces the expression of Trpv1 in the DRGs projected by PRAT. Injecting AAV2-retro-shTrpv1 into the PRAT of DOCA-Salt mice also achieved the same therapeutic effect. However, DOCA-Salt-induced hypertension and renal injury can be treated in Trpv1+/- mice but not alleviated or even worsened in Trpv1-/- mice, possibly because of compensatory increase of Trpv5 in DRG of Trpv1-/- mice.

Conclusion:

Reducing, rather than eliminating, Trpv1 in DRG from PRAT-projection can reduce blood pressure and kidney damage in DOCA-Salt in rats or mice. Trpv1 in PRAT-DRGs may serve as a therapeutic target for salt-sensitive hypertension and its renal complications.
Visual assessment of Korotkoff sounds improves the accuracy of a validated professional automated auscultatory blood pressure monitor KOROT P3 Accurate
Authors: Menti Ariadni , Ntineri Angeliki , Kyriakoulis Konstantinos G. , Theodosiadi Aikaterini , Ntousopoulos Vasileios , Stathopoulou Panagiota , Kollias Anastasios , Stergiou George S.
Published: May 2024

Objective:

A novel automated auscultatory upper-arm cuff blood pressure (BP) monitor for office use (KOROT P3 Accurate, previously InBody BPBIO480KV), which displays Korotkoff sound curves for each BP reading was recently developed. This study investigated whether the review of Korotkoff sound curves by healthcare professionals further improves the accuracy of the device by identifying unreliable BP readings.

Methods:

Three observers assessed independently the morphology of Korotkoff sound curves of BP measurements obtained during an ISO 81060-2:2018 validation study, and classified them as of good, fair, or poor quality (low amplitude or sound intensity, aberrant morphology, background noise, signal artifact, auscultatory gap, irregular rhythm). The observers were blinded to the study BP measurements.

Results:

Korotkoff sound curves of 255 BP readings obtained in 85 individuals were analyzed (mean age 57.3 ± 15.0 years, 53 men). Of the SBP readings 80.4/12.2/7.4% were classified as good/fair/poor, and DBP 76.9/12.2/10.9%. Inter-observer agreement in detecting poor-quality curves was 84.7/83.1% (systolic/diastolic). Of poor-quality curves, 10.5/60.7% (systolic/diastolic) clustered in the same individuals. The validation criterion 1 [mean test-reference BP difference ≤5 ± 8 (SD) mmHg] was satisfied for readings with good (0.1 ± 4.9/0.3 ± 3.8 mmHg, systolic/diastolic) and fair-quality curves (−0.4 ± 6.4/0.2 ± 5.0), but not for poor-quality ones (2.7 ± 8.8/3.6 ± 8.1). By excluding poor-quality readings (40 of 255), criterion 1 of the validation study was improved (0.2 ± 4.9/0.2 ± 3.9 versus 0.3 ± 5.5/0.6 ± 4.7 mmHg).

Conclusion:

The visual assessment of Korotkoff sounds generated during automated auscultatory BP measurement by the KOROT P3 Accurate professional monitor identifies unreliable readings and further improves the device accuracy.
Analgesic candidate adenosine A3 receptors are expressed by perineuronal peripheral macrophages in human dorsal root ganglion and spinal cord microglia
Authors: Sapio Matthew R. , Staedtler Ellen S. , King Diana M. , Maric Dragan , Jahanipour Jahandar , Ghetti Andre , Jacobson Kenneth A. , Mannes Andrew J. , Iadarola Michael J.
Published: May 2024

Adenosine receptors are a family of purinergic G protein–coupled receptors that are widely distributed in bodily organs and in the peripheral and central nervous systems. Recently, antihyperalgesic actions have been suggested for the adenosine A3 receptor, and its agonists have been proposed as new neuropathic pain treatments. We hypothesized that these receptors may be expressed in nociceptive primary afferent neurons. However, RNA sequencing across species, eg, rat, mouse, dog, and human, suggests that dorsal root ganglion (DRG) expression of ADORA3 is inconsistent. In rat and mouse, Adora3 shows very weak to no expression in DRG, whereas it is well expressed in human DRG. However, the cell types in human DRG that express ADORA3 have not been delineated. An examination of DRG cell types using in situ hybridization clearly detected ADORA3 transcripts in peripheral macrophages that are in close apposition to the neuronal perikarya but not in peripheral sensory neurons. By contrast, ADORA1 was found primarily in neurons, where it is broadly expressed at low levels. These results suggest that a more complex or indirect mechanism involving modulation of macrophage and/or microglial cells may underlie the potential analgesic action of adenosine A3 receptor agonism.
Monitoring lung recruitment
Authors: Cammarota Gianmaria , Vaschetto Rosanna , Vetrugno Luigi , Maggiore Salvatore M.
Published: May 2024

Purpose of review

This review explores lung recruitment monitoring, covering techniques, challenges, and future perspectives.

Recent findings

Various methodologies, including respiratory system mechanics evaluation, arterial bold gases (ABGs) analysis, lung imaging, and esophageal pressure (Pes) measurement are employed to assess lung recruitment. In support to ABGs analysis, the assessment of respiratory mechanics with hysteresis and recruitment-to-inflation ratio has the potential to evaluate lung recruitment and enhance mechanical ventilation setting. Lung imaging tools, such as computed tomography scanning, lung ultrasound, and electrical impedance tomography (EIT) confirm their utility in following lung recruitment with the advantage of radiation-free and repeatable application at the bedside for sonography and EIT. Pes enables the assessment of dorsal lung tendency to collapse through end-expiratory transpulmonary pressure. Despite their value, these methodologies may require an elevated expertise in their application and data interpretation. However, the information obtained by these methods may be conveyed to build machine learning and artificial intelligence algorithms aimed at improving the clinical decision-making process.

Monitoring lung recruitment is a crucial component of managing patients with severe lung conditions, within the framework of a personalized ventilatory strategy. Although challenges persist, emerging technologies offer promise for a personalized approach to care in the future.
Cognitive Outcomes in Nonacute Patients With Schizophrenia Treated With Long-Acting Injectable Antipsychotics Versus Oral Antipsychotics
Authors: Petric Paula Simina , Teodorescu Andreea , Miron Ana Aliana , Manea Mihnea Costin , Ifteni Petru
Published: May 2024

Background:

Patients with schizophrenia often face challenges related to cognitive function, affecting their daily functioning and overall quality of life. The choice of antipsychotic treatment may play a crucial role in determining cognitive outcomes.

Study Question:

Our study aimed to investigate whether there was a difference in cognitive ability between the patients with schizophrenia receiving oral antipsychotics (OAP) versus long-acting injectable antipsychotics (LAI-APs).

Study Design:

We conducted a cross-sectional study using analytical methods between January 1, 2020, and January 1, 2022. Participants were divided into 2 groups: patients undergoing treatment with OAP and patients undergoing treatment with LAI-AP. All participants underwent version A of Brief Assessment of Cognition in Schizophrenia (BACS).

Measures and Outcomes:

The primary objective was to compare cognitive function in patients with schizophrenia treated with LAI antipsychotics versus OAP using BACS. Primary outcome measures include overall BACS score, with secondary measures focusing on specific cognitive domains. This study contributes to the understanding of the cognitive effects of different antipsychotic formulations in schizophrenia treatment.

Results:

Although there was a slightly higher intelligence quotient in the LAI-AP group (102.2 vs. 101.32, P = 0.5401), it was not statistically significant. Olanzapine was the most commonly prescribed antipsychotic, with 48% of patients in the LAI-AP group and 40% in the OAP group. The LAI-AP group outperformed in all BACS evaluations. The most notable difference was in the token motor task (57.78 ± 17.03 vs. 50.04 ± 18.82, P = 0.0335), while the Tower of London test showed the smallest difference (17.26 ± 2.61 vs. 15.48 ± 3.47, P = 0.0046). Regression analysis revealed no significant variance in intelligence quotient scores; however, a significant discrepancy in BACS scores was evident, favoring the LAI treatment for better cognitive outcomes.

Conclusions:

The use of long-acting antipsychotic treatment in individuals with schizophrenia offers promising advantages in preserving cognitive function.
Edaravone Oral Suspension: A Neuroprotective Agent to Treat Amyotrophic Lateral Sclerosis
Authors: Singh Priya , Belliveau Paul , Towle Jennifer , Neculau Andrea Elena , Dima Lorena
Published: May 2024

Background:

Amyotrophic lateral sclerosis (ALS) is characterized by loss of motor neurons due to degeneration of nerve cells within the brain and spinal cord. Early symptoms include limb weakness, twitching or muscle cramping, and slurred speech. As the disease progresses, difficulty breathing, swallowing, and paralysis can lead to death. Currently, there are no medications that cure ALS, and guidelines recommend treatments focused on symptom management. Intravenous (IV) edaravone was approved by the US Food and Drug Administration (FDA) in 2017 as a treatment to slow the progression of ALS. In May 2022, the FDA approved an oral suspension (ORS) formulation of edaravone.

Mechanism of Action:

The mechanism of action of edaravone is not well defined. However, its neuroprotective effects are thought to result from antioxidant properties occurring through elimination of free radicals.

Pharmacokinetics:

Edaravone ORS (105 mg) has a bioavailability of 57% when compared with edaravone IV (60 mg). The ORS should be taken on an empty stomach in the morning, with water and no food or beverages, for 1 hour. Edaravone is bound to albumin (92%), has a mean volume of distribution of 63.1 L, a half-life of 4.5–9 hours, and a total clearance of 35.9 L/h after intravenous administration. Edaravone is metabolized into nonactive sulfate and glucuronide conjugates.

Clinical Trials:

The FDA approval was based on studies of the pharmacokinetics, safety, tolerability, and bioavailability of edaravone ORS. A phase III, global, multicenter, open-label safety study was conducted on edaravone ORS in 185 patients with ALS over 48 weeks. The most reported treatment-emergent adverse events were falls, muscular weakness, and constipation. Serious treatment-emergent adverse events included disease worsening, dysphagia, dyspnea, and respiratory failure.

Therapeutic advance:

Oral edaravone is an ALS treatment that can be self-administered or administered by a caregiver, precluding the need for administration by a health care professional in an institutional setting.
The Risk of Kidney Injury in Patients With Sickle Cell Disease Treated With Ketorolac for Acute Pain
Authors: Harris Emily M. , Oni Morohuntodun O. , Donado Carolina , Heeney Matthew M. , Solodiuk Jean , Greco Christine , Archer Natasha M.
Published: May 2024

Ketorolac, a nonsteroidal anti-inflammatory drug, is used in combination with opioids to manage vaso-occlusive episodes (VOEs). The relationship between ketorolac use and kidney injury in pediatric patients with sickle cell disease (SCD) remains incompletely understood. We hypothesize that ketorolac is associated with acute kidney injury (AKI) in patients with SCD presenting with pain. All nonsurgical hospitalizations for VOEs treated with ketorolac between January 2014 and December 2022 were included. We used optimal matching methodology to identify control admissions (2:1 ratio) and used nonparametric tests to compare ketorolac administration between cases and controls. A total of 1319 encounters/253 patients were included in this study. AKI was noted in 1.1% of encounters and 5.5% of patients. Cases had significantly higher initial BUN than controls (9.0 vs. 6.0 mg/dL, P=0.012). In cases versus controls, there was significantly lower serum sodium (136.0 vs. 138.0 mmol/L, P=0.021). There was no association between ketorolac dose and development of AKI among children with SCD. Higher BUN and lower sodium in cases suggest that patients with AKI were more volume depleted on admission than controls. This highlights the need for strict assessment of fluid status upon admission for VOE.
The Effect of Socioeconomic Status and Race/Ethnicity on the Risk of Presenting With Advanced Stage at Diagnosis in Embryonal Tumors
Authors: Jung Eun Mi , Kitlinska Joanna B. , Johnson Rebecca A. , Spector Logan G.
Published: May 2024

We evaluated whether socioeconomic status (SES), race/ethnicity, and their interaction were associated with the presentation of advanced stage at diagnosis in embryonal tumors. Children 0 to 19 years of age diagnosed with embryonal tumors between 2006 and 2018 were identified from the US Surveillance, Epidemiology, and End Results program database specialized with Census Tract SES/Rurality. SES quintile was derived from a composite index for census tracts. We performed logistic regression to estimate odds ratios (ORs) and 95% confidence intervals by SES and race/ethnicity, adjusting for sex, age, and diagnosis year. Overall, no significant associations were found between either SES or race/ethnicity and the risk of presenting with advanced stage at diagnosis, although patterns of risk reductions were observed in atypical teratoid/rhabdoid tumors and embryonal rhabdomyosarcoma with increasing SES. In the stratified analysis, decreased odds of presenting with advanced-stage embryonal rhabdomyosarcoma were observed for Hispanics with higher SES (OR: 0.24, 95% Confidence Interval: 0.08-0.75) compared with Hispanics with lower SES. Future studies incorporating individual-level SES, cancer-specific staging information, and potential demographic, clinical, epidemiological, and genetic risk factors are warranted to confirm our findings.
Counting your chickens before they hatch: improvements in an untreated chronic pain population, beyond regression to the mean and the placebo effect
Authors: Sean Monica , Coulombe-Lévêque Alexia , Nadeau William , Charest Anne-Catherine , Martel Marylie , Léonard Guillaume , Tétreault Pascal
Published: May 2024

Introduction:

Isolating the effect of an intervention from the natural course and fluctuations of a condition is a challenge in any clinical trial, particularly in the field of pain. Regression to the mean (RTM) may explain some of these observed fluctuations.

Objectives:

In this paper, we describe and quantify the natural trajectory of questionnaire scores over time, based on initial scores.

Methods:

Twenty-seven untreated chronic low back pain patients and 25 healthy controls took part in this observational study, wherein they were asked to complete an array of questionnaires commonly used in pain studies during each of 3 visits (V1, V2, V3) at the 2-month interval. Scores at V1 were classified into 3 subgroups (extremely high, normal, and extremely low), based on z-scores. The average delta (∆ = V2 − V1) was calculated for each subgroup, for each questionnaire, to describe the evolution of scores over time based on initial scores. This analysis was repeated with the data for V2 and V3.

Results:

Our results show that high initial scores were widely followed by more average scores, while low initial scores tended to be followed by similar (low) scores.

Conclusion:

These trajectories cannot be attributable to RTM alone because of their asymmetry, nor to the placebo effect as they occurred in the absence of any intervention. However, they could be the result of an Effect of Care, wherein participants had meaningful improvements simply from taking part in a study. The improvement observed in patients with high initial scores should be carefully taken into account when interpreting results from clinical trials.
Intramuscular Granular Cell Tumor Detected on 68Ga-PSMA PET/CT
Authors: Engin Muge N. , Boz Adil
Published: May 2024

Finding of the prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer (PC) cells that have made it possible to evaluate the patients with PC with a single imaging method. 68Ga-PSMA PET/CT is now part of the routine in patients with PC. After several years of clinical experience with PSMA tracers, the specificity is satisfactory; however, concerns about the specificity are raising day by day due to the newly laid out nonprostatic malignant and benign lesions with high PSMA expression. Herein, we present an incidental 68Ga-PSMA uptake in an intramuscular granular cell tumor.
PSMA and FDG PET/CT Findings in Patient With Dedifferentiated Liposarcoma and Prostate Cancer Metastases
Authors: Liao Xuhe , Sun Hongwei , Chen Xueqi , Fan Yan , Zhang Jianhua
Published: May 2024

Dedifferentiated liposarcoma is an extremely rare and highly malignant tumor. We demonstrated a case of a 75-year-old man with significantly PSMA-avid and mildly FDG uptake–dedifferentiated liposarcoma in the retroperitoneal area. The double-tracer (PSMA and FDG) PET scans could further contribute to differential diagnosis and the following treatment strategy for patients who were suspected with prostate cancer metastases and other malignant tumors simultaneously.
Gender Is a Spectrum: Evaluating Current and Novel Ways to Inquire About Gender Identity in the Health Care Setting
Authors: Song Siyou , Phong Kiet T. , Davis Greta , Kim Esther A.
Published: May 2024

Purpose

The use of visuals to inquire about gender in the clinical setting has been rare. We developed a survey that included a visual spectrum to assess perceptions about the most and least inclusive ways of inquiring about gender in patients with gender dysphoria.

Methods

The survey included a multiple-choice question (MCQ), free-response question, and a visual spectrum on which respondents were asked to select one box that best depicts their gender. The survey was administered to all patients diagnosed with gender dysphoria at our institution between April and June 2022.

Results

A total of 223 of 856 patients responded. Those with more masculine gender identities selected boxes near the visual spectrum corner of “man,” whereas responses were more variable for more feminine genders. The free-response question was identified by 59% of respondents as the most inclusive. The MCQ was identified as least inclusive by 70.4%. The visual spectrum was considered the most inclusive method by the majority of patients who self-identified as woman and demiwoman/demifemale. Being asked about pronouns was extremely or very important in the health care setting for 52% of respondents, but 68.6% indicated that they are rarely or sometimes asked about their pronouns in this setting.

Conclusions

The traditional MCQ format for self-identifying gender may be lacking in inclusivity and fails to represent the nuances of gender identity. Free response was considered the most inclusive way to inquire about gender among our respondents. These findings highlight the importance of formatting gender identity questionnaires to foster inclusivity for transgender patients.
Current diagnosis and management of necrotizing soft tissue infections: What you need to know
Authors: Bisgaard Erika K. , Bulger Eileen M.
Published: May 2024

Necrotizing soft tissue infections are rare bacterial infections of the skin and soft tissues with a high morbidity and mortality rate, requiring prompt diagnosis and surgical intervention. These represent a spectrum of disease resulting in tissue necrosis that is rapidly progressive; however, they remain a diagnostic challenge because the average surgeon or emergency medicine provider may only see one or two over the course of their career. Diagnosis is largely clinical and based on subtle physical examination findings, physiologic instability, and laboratory derangements. Aids to diagnosis such as scoring systems and cross-sectional imaging may be used; however, the findings are not specific, so management should not be based on these alone. The most common cause of necrotizing soft tissue infection is polymicrobial infection; however, specific bacteria such as clostridial species, group A streptococcal, methicillin resistantStaphylococcus aureus, and aquatic bacteria may also be causative. Initial management includes broad spectrum antibiotics, fluid resuscitation for severe sepsis, and early aggressive surgical debridement. Often, these patients require multiple operative debridement to achieve source control, and a low threshold for repeat debridement should be maintained because these infections can progress rapidly. Once source control is achieved, patients may be left with extensive wounds requiring multidisciplinary care and wound management. Necrotizing infections have long been viewed based on mortality outcomes alone because of their rarity and severity. Over recent years, more reports have shown a decrease in the mortality rates from those previously reported, allowing for a focus on methods to improve morbidity of these infections.
Could the 14q23.2 microdeletion or AKAP5 haploinsufficiency be a potential cause of intellectual disability?
Authors: Maden Bedel Fayize , Balasar Özgür , Şimşek Ayşe , Tokgöz Hüseyin , Çaksen Hüseyin
Published: May 2024

Intellectual disability is characterized by impairment in at least two of the following areas: social skills, communication skills, self-care tasks, and academic skills. These impairments are evaluated in relation to the expected standards based on the individual’s age and cultural levels. Additionally, intellectual disability is typically defined by a measurable level of intellectual functioning, represented by an intelligence quotients core of 70 or below. Autism spectrum disorder is a developmental disability resulting from differences in the brain, often characterized by problems in social communication and interaction, and limited or repetitive behaviors or interests. Hereditary spherocytosis is a disease characterized by anemia, jaundice, and splenomegaly as a result of increased tendency to hemolysis with morphological transformation of erythrocytes from biconcave disc-shaped cells with central pallor to spherocytes lacking central pallor due to hereditary injury of cellular membrane proteins. An 11-year-old female patient was referred to Pediatric Genetics Subdivision due to the presence of growth retardation and a diagnosis of hereditary spherocytosis. Since she also had dysmorphic facial features, such as frontal bossing, broad and prominent forehead, tubular nasal structure, and thin vermillion, genetic tests were performed. Chromosomal microarray analysis revealed a 2.5 Mb deletion in the 14q23.2q23.3 region. Deletion was also identified in the same region in her father, who had the same phenotypic characteristics, including hereditary spherocytosis and learning difficulties. We propose that the PLEKHG3 and AKAP5 genes, which are located in this region, may contribute to the development of intellectual disability.
Whole-exome-based single nucleotide variants and copy number analysis for prenatal diagnosis of compound heterozygosity of SMPD4
Authors: Du Jun , Li Lin , Fu Dinghu
Published: May 2024

Background

Biallelic loss-of-function variants in SMPD4 cause a rare and severe neurodevelopmental disorder. These variants have been identified in a group of children with neurodevelopmental disorders with microcephaly, arthrogryposis, and structural brain anomalies. SMPD4 encodes a sphingomyelinase that hydrolyzes sphingomyelin into ceramide at neutral pH and can thereby affect membrane lipid homeostasis. SMPD4 localizes to the membranes of the endoplasmic reticulum and nuclear envelope and interacts with nuclear pore complexes.

Materials and methods

For the efficient prenatal diagnosis of rare and undiagnosed diseases, the parallel detection of copy number variants (CNVs) and single nucleotide variants using whole-exome analysis is required. A physical examination of the parents was performed. Karyotype and whole-exome analysis were performed for the fetus and the parents.

Results

A fetus with microcephaly and arthrogryposis; biallelic null variants (c.387-1G>A; Chr2[GRCh38]: g.130142742_130202459del) were detected by whole-exome sequencing (WES). We have reported for the first time the biallelic loss-of-function mutations in SMPD4 in patients born to unrelated parents in China.

Conclusion

WES could replace chromosomal microarray analysis and copy number variation sequencing as a more cost-effective genetic test for detecting CNVs and diagnosing highly heterogeneous conditions.
Breeding density affects the movements of gull chicks, the size of their home ranges and their association with neighbours
Authors: Salas R. , Müller W. , Stienen E. , Matheve H. , Vanden Broecke B. , Verbruggen F. , Lens L.
Published: May 2024

Colonies of ground-nesting species often have heterogeneous nest densities and their offspring experience different social conditions depending on the size and location of the breeding territory. For example, unintentional territory crossing by mobile chicks can trigger strong aggression from neighbouring adults, as observed in semi-precocial gulls. This would be expected to shape chicks’ movement tendencies, exploratory behaviour and propensity for social contact through aversive feedback learning or pre-natal maternal effects, as mothers may pre-adapt their offspring’s behaviour to the expected early life conditions. Therefore, we hypothesize that lesser black-backed gull chicks reared in denser areas of the breeding colony will move less, have smaller home ranges and have fewer social contacts with chicks from neighbouring nests. To test this, we first cross-fostered full clutches between and within high- and low-density parts of the colony, and then used ultra-wideband tags to track free-ranging chicks. In line with our predictions, we found that chicks reared in denser areas had a lower movement activity and smaller home ranges. However, these chicks still had more social contacts, although not necessarily with a higher number of unique individuals. Pre-natal breeding density had no significant effect on any of the parameters. We conclude that parental nest choice strongly affects the early social environment of their chicks, which can shape the development of their (social) phenotype, with potentially long-lasting consequences.
Context-dependent multimodal behaviour in a coral reef fish
Authors: Davidson Isla Keesje , Williams Ben , Stratford John E. , Chapuis Lucille , Simpson Stephen D. , Radford Andrew N.
Published: May 2024

Animals are expected to respond flexibly to changing circumstances, with multimodal signalling providing potential plasticity in social interactions. While numerous studies have documented context-dependent behavioural trade-offs in terrestrial species, far less work has considered such decision-making in fish, especially in natural conditions. Coral reef ecosystems host 25% of all known marine species, making them hotbeds of competition and predation. We conducted experiments with wild Ambon damselfish (
Pomacentrus amboinensis
) to investigate context-dependent responses to a conspecific intruder; specifically, how nest defence is influenced by an elevated predation risk. We found that nest-defending male Ambon damselfish responded aggressively to a conspecific intruder, spending less time sheltering and more time interacting, as well as signalling both visually and acoustically. In the presence of a model predator compared to a model herbivore, males spent less time interacting with the intruder, with a tendency towards reduced investment in visual displays compensated for by an increase in acoustic signalling instead. We therefore provide ecologically valid evidence that the context experienced by an individual can affect its behavioural responses and multimodal displays towards conspecific threats.
Essentiality and dynamic expression of the human tRNA pool during viral infection
Authors: Aharon-Hefetz Noa , Schwartz Michal , Dahan Orna , Stern-Ginossar Noam , Pilpel Yitzhak
Published: May 2024

Human viruses depend on the translation resources of the host cell. A significant translation resource is the tRNA pool of the cell, as human viruses do not encode tRNA genes. Through tRNA sequencing, we inspected the human tRNA pool upon infection of human Cytomegalovirus (HCMV) and SARS-CoV-2. HCMV-induced alterations in tRNA expression were predominantly virus-driven, with minimal influence from the cellular immune response. Notably, specific tRNA post-transcriptional modifications appeared to modulate stability and were susceptible to HCMV manipulation. In contrast, SARS-CoV-2 infection did not significantly impact tRNA expression or modifications. We compared the codon usage of viral genes to the proliferation-differentiation codon-usage signatures of human genes. We found a marked difference between the viruses, with HCMV genes aligning with differentiation codon usage and SARS-CoV-2 genes reflecting proliferation codon usage. We further found that codon usage of structural and gene expression-related viral genes displayed high adaptation to host cell tRNA pools. Through a systematic CRISPR screen targeting human tRNA genes and modification enzymes, we identified specific tRNAs and enzymes that improve or reduce HCMV infectivity and cellular growth. These findings highlight the dynamic interplay between the tRNA pool and viral infection dynamics, shedding light on mechanisms governing host-virus interactions.