bluuebunny/crossref_metadata_2025 huggingface dataset:
Recent updates on therapeutic targeting of lipoprotein(a) with RNA interference
Authors: Sekhar Aravind , Kuttan Ashani , Lange Richard A.
Published: March 2024

Purpose

RNA interference (RNAi)-based therapies that target specific gene products have impacted clinical medicine with 16 FDA approved drugs. RNAi therapy focused on reducing plasma lipoprotein(a) [Lp(a)] levels are under evaluation.

Findings

RNAi-based therapies have made significant progress over the past 2 decades and currently consist of antisense oligonucleotides (ASO) and small interfering RNA (siRNA). Chemical modification of the RNA backbone and conjugation of siRNA enables efficient gene silencing in hepatocytes allowing development of effective cholesterol lowering therapies. Multiple lines of evidence suggest a causative role for Lp(a) in atherosclerotic cardiovascular disease, and recent analyses indicate that Lp(a) is more atherogenic than low density lipoprotein- cholesterol (LDL-C). These findings have led to the ‘Lp(a) hypothesis’ that lowering Lp(a) may significantly improve cardiovascular outcomes. Four RNAi-based drugs have completed early phase clinical trials demonstrating >80% reduction in plasma Lp(a) levels. Phase 3 clinical trials examining clinical outcomes with these agents are currently underway.

Currently, four RNAi-based drugs have been shown to be effective in significantly lowering plasma Lp(a) levels. Clinical outcome data from phase 3 trials will evaluate the Lp(a) hypothesis.
Management of hypertension in heart transplant recipients: an ongoing conundrum
Authors: Torres Juan Duarte , Krim Selim R.
Published: March 2024

Purpose of review

Hypertension remains one of the most common clinical problems leading to significant posttransplant complications. This study reviews the pathophysiology of hypertension in the postcardiac transplant phase and provides an update on currently available antihypertensive therapies for heart transplant patients.

Recent findings

The true prevalence of hypertension in the heart transplant population remains unknown. Effective blood pressure (BP) control is key to prevent left ventricular remodeling, diastolic dysfunction and stroke. Calcium channel blockers (CCBs) are the most commonly and preferred agents in the early posttransplant phase and may have renal protective effects. Angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) can all be used as second line antihypertensive agents and may have a role in preventing other long-term complications such as calcineurin-inhibitor induced nephropathy. Although more data are needed, sodium-glucose co-transporter 2 inhibitors (SGLT2i) appeared to be well tolerated and could be considered especially in the presence of type diabetes and chronic kidney disease. Conversely, angiotensin receptor-neprilysin inhibition (ARNI) have not been studied in the heart transplant population therefore cannot be recommended at this time.

Hypertension is very common after heart transplant. Early steroid wean and traditional risk factor modification play an important part in the management of post-heart transplant hypertension. CCB, ACEI, ARB are the preferred antihypertensive agents to improve postcardiac transplant complications. Novel therapies such as SGLT2i appear well tolerated and may have benefits in both BP and glycemic control in heart transplant; however, larger trials are needed.
Mechanical pain sensitivity is associated with hippocampal structural integrity
Authors: Ayoub Lizbeth J. , Honigman Liat , Barnett Alexander J. , McAndrews Mary Pat , Moayedi Massieh
Published: March 2024

Rodents and human studies indicate that the hippocampus, a brain region necessary for memory processing, responds to noxious stimuli. However, the hippocampus has yet to be considered a key brain region directly involved in the human pain experience. One approach to answer this question is to perform quantitative sensory testing on patients with hippocampal damage—ie, medial temporal lobe epilepsy. Some case studies and case series have performed such tests in a handful of patients with various types of epilepsy and have reported mixed results. Here, we aimed to determine whether mechanical pain sensitivity was altered in patients diagnosed with temporal lobe epilepsy. We first investigated whether mechanical pain sensitivity in patients with temporal lobe epilepsy differs from that of healthy individuals. Next, in patients with temporal lobe epilepsy, we evaluated whether the degree of pain sensitivity is associated with the degree of hippocampal integrity. Structural integrity was based on hippocampal volume, and functional integrity was based on verbal and visuospatial memory scores. Our findings show that patients with temporal lobe epilepsy have lower mechanical pain sensitivity than healthy individuals. Only left hippocampal volume was positively associated with mechanical pain sensitivity—the greater the hippocampal damage, the lower the sensitivity to mechanical pain. Hippocampal measures of functional integrity were not significantly associated with mechanical pain sensitivity, suggesting that the mechanisms of hippocampal pain processing may be different than its memory functions. Future studies are necessary to determine the mechanisms of pain processing in the hippocampus.
Elevated white blood cell count and long-term clinical outcomes of patients with vasospastic angina
Authors: Kim Dong-Yeon , Kim Sung Eun , Park Taek Kyu , Choi Ki Hong , Lee Joo Myung , Yang Jeong Hoon , Song Young Bin , Choi Jin-Ho , Gwon Hyeon-Cheol , Hahn Joo-Yong , Choi Seung-Hyuk , Cho Sung Woo
Published: March 2024

Objectives

Inflammation is known as one of key pathophysiologic mechanisms of coronary artery disease. We aimed to investigate the relationship between white blood cell (WBC) count and long-term clinical outcomes of patients with vasospastic angina (VA).

Methods

A total of 823 patients who were diagnosed as VA without significant coronary lesion by coronary angiography with ergonovine provocation test were enrolled for analysis. Patients were divided according to WBC count tertile at the time of diagnosis: group I, tertile 1 and 2 (n = 546, <7490/ml); group II, tertile 3 (n = 277, ≥7490/ml). Primary outcome was defined as major adverse cardiovascular events (MACE), a composite outcome of all-cause death, cardiac death, myocardial infarction (MI), readmission due to cardiac symptoms, and revascularization.

Results

Median follow-up duration was 4.3 years. No significant difference of primary outcome was observed between group I and group II (14.7% vs. 20.2%, hazard ratio (HR) 1.29, confidence interval (CI) 0.90–1.83, P = 0.162), while incidence of cardiac death and MI was significantly higher in group II (1.5% vs. 4.3%, HR 2.86, CI 1.14–7.17), P = 0.025). In multivariate Cox regression model, elevated WBC count at the time of diagnosis of VA was an independent predictor of MI (HR 3.43, CI 1.02–11.59, P = 0.047).

Conclusion

Elevated WBC count at the time of diagnosis was associated with a significantly increased risk of cardiac death and MI during long-term follow-up in VA patients.
The Effect of Reiki on Pain, Functional Status, and Holistic Well-Being in Patients With Knee Osteoarthritis
Authors: Unal Nursemin , Bektaş Akpinar Nilay , Bek Doğan , Yurtsever Sabire
Published: March 2024

Knee osteoarthritis (OA) is a chronic degenerative joint disease that causes pain and adversely affects functional status and holistic well-being. This randomized controlled trial investigated the effect of Reiki on pain, functional status, and holistic well-being in patients with knee OA. The sample consisted of 42 patients. The control group received standardized treatment only, whereas the intervention group received face-to-face Reiki (nine positions; 39 minutes) and distance Reiki on two consecutive days in addition to standardized treatment. The Reiki group had lower pain scores than the control group as measured by the Visual Analog Scale (p < .001) and the Western Ontario and McMaster Universities Arthritis Index pain score (p < .001). Those participating in the Reiki group had improved holistic well-being scores specifically for the subscales of Sadness, Perception of Sadness, Spiritual Disruption, Cognitive Awareness, and General mood. Reiki is a safe, noninvasive, and cost-effective alternative treatment technique that has the potential to reduce symptoms of pain and improve holistic well-being in patients with knee OA.
The impact of Demodex blepharitis on patient symptoms and daily life
Authors: Barnett Melissa , Simmons Blake , Vollmer Patrick , Patel Assem , Whitson William E. , Berdy Gregg J. , Karpecki Paul , Periman Laura M. , Holdbrook Mark , Baba Stephanie N. , Meyer John , Yeu Elizabeth
Published: March 2024

SIGNIFICANCE

Patients with Demodex blepharitis have a considerable symptomatic burden that negatively impacts their daily activities and well-being. Despite chronic manifestations of and problems associated with blepharitis that resulted in multiple visits to eye care providers, Demodex blepharitis remained underdiagnosed or misdiagnosed.

PURPOSE

This study aimed to evaluate the effect of Demodex blepharitis on patients' daily activities and well-being.

METHODS

This prospective, multicenter, observational study recruited 524 patients with Demodex blepharitis from 20 U.S. ophthalmology and optometry practices. Demodex blepharitis was diagnosed based on the presence of the following clinical manifestations in at least one eye: >10 collarettes on the upper lashes, at least mild lid margin erythema of the upper eyelid, and mite density of ≥1.0 mite/lash (upper and lower combined). Patients were asked to complete a questionnaire related to their symptoms, daily activities, and management approaches.

RESULTS

The proportion of patients who experienced blepharitis symptoms for ≥2 years was 67.8%, and for ≥4 years, it was 46.5%. The three most bothersome symptoms ranked were “itchy eyes,” “dry eyes,” and “foreign body sensation.” Overall, 77.4% of patients reported that Demodex blepharitis negatively affected their daily life. One-third (32.3%) of patients had visited a doctor for blepharitis at least two times, including 19.6% who visited at least four times. Despite having clinical manifestations of Demodex blepharitis confirmed by an eye care provider, 58.7% had never been diagnosed with blepharitis. Commonly used management approaches were artificial tears, warm compresses, and lid wipes. Among those who discontinued their regimen, 45.9% had discontinued because of either tolerability issues or lack of effectiveness. Among contact lens wearers, 64.3% of the patients either were uncomfortable wearing contact lenses or experienced vision changes “sometimes” or “frequently.”

CONCLUSION

Demodex blepharitis results in a significant negative impact on daily activities, creating a psychosocial and symptomatic burden on patients.
Repeatability and agreement of the MYAH and Lenstar
Authors: Lal Barsha , Cantrell Amy , Ostrin Lisa A.
Published: March 2024

SIGNIFICANCE

Validation of new biometry instruments against the gold standard and establishing repeatability are important before being utilized for clinical and research applications.

PURPOSE

This study aimed to investigate intersession repeatability of the MYAH optical biometer and corneal topographer and examine agreement with the Lenstar LS900 optical biometer in healthy young adults.

METHODS

Forty participants (mean age, 25.2 ± 3.1 years) presented for two visits, 2 to 4 days apart. At each visit, measurements for right eyes were collected with the MYAH and Lenstar LS 900 and included axial length, corneal power, white-to-white distance, and pupil diameter. Bland-Altman analysis was used to assess the intrasession agreement between the MYAH and Lenstar for each parameter and intersession repeatability for the two devices. For each device, coefficient of variation and intraclass correlation coefficient were calculated, and paired t tests between visits were performed to assess intersession repeatability.

RESULTS

Good agreement (mean difference [95% limits of agreement]) between the MYAH and Lenstar was found for axial length (−0.01 [−0.07 to 0.04] mm), corneal power (−0.02 D [−0.15 to 0.19 d]), white-to-white distance (−0.13 [−0.43 to 0.17] mm), and pupil diameter (−0.27 [−0.79 to 1.33] mm). The limits of agreement, coefficient of variations, and intraclass correlation coefficients for MYAH-measured parameters were −0.04 to 0.04, 0.06%, and >0.99 for axial length; −0.24 to 0.19, 0.18%, and >0.99 for corneal power; −1.05 to 1.15, 0.57%, and 0.96 for white-to-white distance; and −0.17 to 0.21, 7.0%, and 0.76 for pupil diameter, with no significant difference between visits (p>0.05 for all), indicating good intersession repeatability. Similar intersession repeatability was also noted for Lenstar.

CONCLUSIONS

Findings show good intersession repeatability of the MYAH and good agreement with the Lenstar for axial length, corneal power, and white-to-white distance in young adults. Pupil diameter was more variable, likely due to the dynamic nature of the pupil. This study provides validation and supports the use of the MYAH for ocular biometry.
Estrogen Receptor Expression in DICER1-related Lesions is Associated With the Presence of Cystic Components
Authors: Thorner Paul Scott , Chong Anne-Laure , Apellaniz-Ruiz Maria , Benlimame Naciba , Marrano Paula , Brimo Fadi , Shuangshoti Somruetai , Shuangshoti Shanop , Foulkes William D.
Published: March 2024

DICER1 tumor predisposition syndrome results from pathogenic variants in DICER1 and is associated with a variety of benign and malignant lesions, typically involving kidney, lung, and female reproductive system. Over 70% of sarcomas in DICER1 tumor predisposition syndrome occur in females. Notably, pediatric cystic nephroma (pCN), a classic DICER1 tumor predisposition syndrome lesion, shows estrogen receptor (ER) expression in stromal cells. There are also renal, hepatic, and pancreatic lesions unassociated with DICER1 tumor predisposition syndrome that have an adult female predominance and are characterized/defined by ER-positive stromal cells. Except for pCN, the expression of ER in DICER1-associated lesions remains uninvestigated. In the present study, ER expression was assessed by immunohistochemistry in 89 cases of DICER1-related lesions and 44 lesions lacking DICER1 pathogenic variants. Expression was seen in stromal cells in pCN and pleuropulmonary blastoma (PPB) types I and Ir, whereas anaplastic sarcoma of kidney and PPB types II and III were typically negative, as were other solid tumors of non-Müllerian origin. ER expression was unrelated to the sex or age of the patient. Expression of ER showed an inverse relationship to preferentially expressed antigen in melanoma (PRAME) expression; as lesions progressed from cystic to solid (pCN/anaplastic sarcoma of kidney, and PPB types I to III), ER expression was lost and (PRAME) expression increased. Thus, in DICER1 tumor predisposition syndrome, there is no evidence that non-Müllerian tumors are hormonally driven and antiestrogen therapy is not predicted to be beneficial. Lesions not associated with DICER1 pathogenic variants also showed ER-positive stromal cells, including cystic pulmonary airway malformations, cystic renal dysplasia, and simple renal cysts in adult kidneys. ER expression in stromal cells is not a feature of DICER1 perturbation but rather is related to the presence of cystic components.
Patient-Specific Le Fort I Osteotomy Plates Are More Stable than Stock Plates in Patients with Cleft Lip and Palate
Authors: Varidel Alistair , Padwa Bonnie L. , Britt Michael C. , Flanagan Sarah , Green Mark A.
Published: March 2024

Background:

There is evidence that patient-specific plate fixation for Le Fort I osteotomies (LFI) is more stable than traditional plate fixation. The purpose of this study was to evaluate stability of LFI in patients with cleft lip and palate and determine stability differences between patient-specific and stock plates.

Methods:

Consecutive patients with cleft lip and palate who underwent isolated LFI by one surgeon (B.L.P.) between 2016 and 2021 were included. The predictor variable was type of plate used for fixation (patient-specific or stock). The outcome variable was magnitude of relapse in the vertical (nasion to A point) and horizontal planes (basion to A point) at 1 year after LFI using 3-dimensional cone beam computed tomography. Statistical analysis included independent samples t, Mann-Whitney U, Fisher exact, and chi-square tests. Values of P < 0.05 were significant.

Results:

The sample included 63 subjects; 23 in the patient-specific group (36.5%) and 40 in the stock group (63.5%). Groups were comparable by sex, race, age at surgery, cleft type, presence of pharyngeal flap, and magnitude of horizontal movement (P > 0.136 for all). Subjects who underwent patient-specific plate fixation were less likely to have greater than or equal to 1-mm change at 1 year in the horizontal (4.3% versus 50.0%; P < 0.001) and vertical planes (4.3% versus 65.0%; P < 0.001) compared with stock plates. For patients who had greater than 10-mm horizontal advancement, the patient-specific plates had significantly less relapse (patient-specific plates, 0.105 ± 0.317 mm; stock plates, 1.888 ± 1.125 mm; P = 0.003).

Conclusion:

Patient-specific plate fixation of LFI is more stable and demonstrates less relapse after 1 year than stock plates.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, III.
Acellular Dermal Matrix–Assisted Tissue Expansion for Giant Congenital Melanocytic Nevi of the Extremities and Trunk in Pediatric Patients
Authors: Huang Xing , Shan Shengzhou , Lu Lin , Jin Rui , Wang Xiuxia , Yuan Zhaoqi , Sun Di , Chang Mengling , Luo Xusong
Published: March 2024

Background:

Tissue expansion for treating giant congenital melanocytic nevi (GCMN) is a commonly used surgical method. However, the procedure’s efficacy is often hindered by anatomical and histologic characteristics and blood supply, particularly in the extremities and trunk. Enhancing expansion efficiency while reducing complications is thus a topic to be investigated, especially for pediatric patients undergoing rapid physical and psychological development with higher risks of noncompliance to medical instructions. The purpose of this study was to explore the effectiveness of expansion in extremities and trunk by immobilizing the acellular dermal matrix (ADM) in the gravitational force zone of inflating expanders.

Methods:

All patients involved in this research underwent ADM-assisted tissue expansion in either the extremities or trunk. ADM was fully flattened, securely fixed to the lower pole of the expander, and subsequently attached to the inner surface of the expanding flap.

Results:

From 2021 to 2023, a total of 9 pediatric patients with GCMN underwent ADM-assisted tissue expansion. All patients achieved the desired expansion volume without experiencing petechiae, ecchymosis, or skin ulceration in the ADM-covered area. The process was well tolerated by all patients, with no reports of itching, pain, allergic reaction, or fever. During the flap transfer, the ADM was observed to be firmly adhered to the expanding flap with discernible capillary network.

Conclusions:

ADM-assisted tissue expansion demonstrates promise in augmenting expansion efficiency and reducing the time needed for surgical intervention in the extremities and trunk, thereby presenting significant clinical value for pediatric patients with GCMN.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Uncommon Anatomical Causes of Ulnar Compression
Authors: Natroshvili Tinatin , Roorda Adam , van Doorn MATS , Foumani Mahyar
Published: March 2024

Objectives

Some patients develop ulnar nerve compression due to rare anatomical variations or malformations. The aims of this review are to provide a comprehensive overview of anatomical structures and variations that can cause ulnar nerve compression and to evaluate treatment options.

Methods

Case reports and case series about rare cases of unusual ulnar nerve compression published from January 2000 until April 2022 were obtained from databases Embase, MEDLINE, and Web of Science. A total of 48 studies describing 64 patients were included in our study.

Results

The following structures have proven to cause ulnar nerve compression: anconeus epitrochlearis, accessory abductor digiti minimi, vascular anomalies, palmaris longus, fibrous bands, and flexor carpi ulnaris. All cases except one have had a surgical release of the ulnar nerve resulting in diminished symptoms or complete recovery at follow-up.

Conclusions

In addition to considering common compression points, it is important to be aware that proximal compression symptoms, such as pain and a positive Tinel sign at the medial elbow, may be attributed to a hypertrophic AE or vascular anomaly. Distal compression symptoms encompass swelling, along with pain and a positive Tinel sign at the distal forearm. Various structures contributing to distal compression include an accessory abductor digiti minimi muscle, an accessory or anomalous palmaris longus muscle, or an accessory or hypertrophic flexor carpi ulnaris muscle. The occurrence of fibrous bands exhibits variability, manifesting in diverse locations across the arm.

Level of Evidence: IV
Intraoperative Completion Studies and their Associations with Carotid Endarterectomy Outcomes
Authors: Knappich Christoph , Bohmann Bianca , Kirchhoff Felix , Lohe Vanessa , Naher Shamsun , Kallmayer Michael , Eckstein Hans-Henning , Kuehnl Andreas
Published: March 2024

Objective:

This study aimed at assessing outcomes after carotid endarterectomy (CEA) in dependence of center policy with respect to imaging intraoperative completion study (ICSi) usage.

Summary Background Data:

Although randomized controlled studies are missing, a beneficial effect was shown for ICSi techniques (i.e., angiography and intraoperative duplex ultrasound) after CEA.

Methods:

This secondary data analysis is based on the German statutory quality assurance database. Research was funded by Germany’s Federal Joint Committee Innovation Fund (G-BA Innovationsfonds, 01VSF19016 ISAR-IQ). According to their ICSi policy, hospitals were categorized as routine ICS

i
(>90%), selective ICS

i
(10–90%), or sporadic ICS

i
(<10%) centers. Primary study outcome was in-hospital stroke or death. Multivariable regression analyses were performed.

Results:

Between 2012 and 2016, a total of 119,800 patients underwent CEA. In-hospital stroke or death rates were lower in routine ICS

i

centers (1.7%) compared to selective (2.1%) and sporadic ICS

i

centers (2.0%). The multivariable regression analysis showed, that in routine ICS

i

centers, ICSi use was associated with lower rates of stroke or death (aOR 0.64; 95% CI 0.44–0.93). In selective ICS

i

centers, ICSi was not associated with the occurrence of either of the assessed outcomes. In sporadic ICS

i

centers, ICSi was associated with higher rates of stroke or death (aOR 1.91; 95% CI 1.26–2.91).

Conclusions:

Lowest in-hospital stroke or death rates are achieved in routine ICS

i

centers. While ICSi is associated with a lower perioperative risk in routine ICS

i

centers, it might act as a surrogate marker for worse outcomes due to intraoperative irregularities in sporadic ICS

i

centers. Routine use of ICSi is advisable.
Metallo-β-lactamase mediated rapid increase in carbapenem resistance ofPseudomonas aeruginosa
Authors: Anjum Hasnain , Mitu Shomaia Yasmin , Arefin Md. Shamsul , Mitu Meftahul Jannat , Hossain Md. Sabir , Islam Salequl , Rumi M.A. Karim , Rahman M. Hasibur
Published: March 2024

Antibiotic-resistantPseudomonas aeruginosais a common nosocomial pathogen all over the world. We detected the presence ofP. aeruginosain 22% (53 out of 238) of the test samples collected from patients with infections including secondary wound infections, abscesses and urinary tract infections admitted to two academic hospitals in Bangladesh. Resistance to carbapenems (imipenem, and meropenem) was present among 30% (16 out of 53) of these clinicalP. aeruginosaisolates, which is more than 2-fold higher compared to that of previous studies. Such a rapid increase in carbapenem resistance was mediated by metallo-β-lactamase (MBL). Expression of MBL was detected in 90% (14 out of 16) of these resistant isolates. Molecular analyses revealed that the carbapenem-resistant isolates carried at least one of the MBL variants, eitherbla-VIM orbla-NDM-1. All thebla-NDM-1 positives carried a 0.5 MDa plasmid. ERIC-PCR revealed the highly heterogeneous nature of theP. aeruginosaisolates indicating multiple sources of infection within the hospital. However, the majority of XDR isolates belonged to a single cluster of drug-resistant bacterial infections. These findings indicate that Metallo-β-lactamase (MBL) mediated resistance to carbapenem inP. aeruginosaposes a serious threat to the spread of infections among hospitalized patients.
Clinical, psychosocial and demographic factors affect decisions in SLE people
Authors: Miguel Pedraza-Meza Luis , Laura Hernández-Ledesma Ana , Ruiz-Contreras Alejandra E , Alejandra Medina-Rivera , Domingo Martínez
Published: March 2024

Neurological and psychiatric manifestations affect most lupus individuals and include depression, anxiety, mood disorders, and cognitive dysfunction. Although there is evidence supporting suboptimal decision-making in lupus and its association with glucocorticoids consumption, it is not clear what variables impact such decisions. The aim of this study is to explore how social, clinical, psychological, and demographic factors impact social and temporal decision-making in people with lupus. Through a within-subjects experimental-design, our participants responded to social, clinical, psychological, and demographic electronic questionnaires. Then, they participated in two behavioral economics experiments: the third-party dictator game, and the delay discounting task. Our results show that hostility, and age are essential predictors of social decisions, whereas obsessive-compulsiveness and anxiety better predict temporal decisions. These variables behave as expected, but anxiety shows unexpected results: most anxious people act patiently and prefer delayed but bigger rewards. Finally, clinical factors are critical decision predictors for social and temporal decisions. When people are in remission, they tend to impose higher punishment on those who violate the social norm, and they also tend to prefer immediate rewards. When taking glucocorticoids, they also prefer immediate rewards, and as the dosage of glucocorticoids intake increases, they tend to impose higher punishment on norm violators. Clinicians, researchers, and practitioners must consider the side effects of glucocorticoids on decision-making.
Mental Bandwidth is Associated with HIV and Viral Suppression Among Low-Income Women in Philadelphia
Authors: Richterman Aaron , Aitcheson Nancy , Durnwald Celeste , Curley Cara , Short William R. , Louis Mirabelle Jean , Momplaisir Florence , Thirumurthy Harsha
Published: March 2024

Behavioral economics research suggests poverty may influence behavior by reducing mental bandwidth, increasing future discounting, and increasing risk aversion. It is plausible that these decision-making processes are further impaired in the context of HIV or pregnancy. In this cross-sectional study of 86 low-income women in Philadelphia, multivariable models showed that HIV was associated with decreased mental bandwidth (one of two measures) and lower risk aversion. Pregnancy was not associated with any decision-making factors. Viral suppression was associated with greater mental bandwidth (one of two measures), and antenatal care engagement with lower future discounting. Anti-poverty interventions may be particularly beneficial to improve health behaviors in the context of HIV.
Predictive modeling provides insight into the clinical heterogeneity associated withTARS1loss-of-function mutations
Authors: Meyer-Schuman Rebecca , Cale Allison R. , Pierluissi Jennifer A. , Jonatzke Kira E. , Park Young N. , Lenk Guy M. , Oprescu Stephanie N. , Grachtchouk Marina A. , Dlugosz Andrzej A. , Beg Asim A. , Meisler Miriam H. , Antonellis Anthony
Published: March 2024

Aminoacyl-tRNA synthetases (ARSs) are ubiquitously expressed, essential enzymes that complete the first step of protein translation: ligation of amino acids to cognate tRNAs. Genes encoding ARSs have been implicated in myriad dominant and recessive phenotypes, the latter often affecting multiple tissues but with frequent involvement of the central and peripheral nervous system, liver, and lungs. Threonyl-tRNA synthetase (TARS1) encodes the enzyme that ligates threonine to tRNATHRin the cytoplasm. To date,TARS1variants have been implicated in a recessive brittle hair phenotype. To better understandTARS1-related recessive phenotypes, we engineered threeTARS1missense mutations predicted to cause a loss-of-function effect and studied these variants in yeast and worm models. This revealed two loss-of-function mutations, including one hypomorphic allele (R433H). We next used R433H to study the effects of partial loss ofTARS1function in a compound heterozygous mouse model (R433H/null). This model presents with phenotypes reminiscent of patients withTARS1variants and with distinct lung and skin defects. This study expands the potential clinical heterogeneity ofTARS1-related recessive disease, which should guide future clinical and genetic evaluations of patient populations.

SUMMARY STATEMENT

This study leverages an engineered, hypomorphic variant of threonyl-tRNA synthetase (TARS1) to captureTARS1-associated recessive phenotypes. This strategy revealed both known and previously unappreciated phenotypes, expanding the clinical heterogeneity associated withTARS1and informing future genetic and clinical evaluations of patient populations.
Stakeholder Interviews to Inform Best Practice for Public Facing COVID-19 Wastewater Dashboards
Authors: Morales D. , Rhodes T. , O’Reilly K.M.
Published: March 2024

Background

WW-based epidemiology is the detection of pathogens from wastewater, typically sewage systems. Its use gained popularity during the COVID-19 pandemic as a rapid and non-invasive way to assess infection prevalence in a population. Public facing dashboards for SARS-CoV-2 were developed in response to the discovery that RNA biomarkers were being shed in faeces before symptoms. However, there is not a standard template or guidance for countries to follow. The aim of this research is to reflect on how currently available dashboards evolved during the pandemic and identify suitable content and rationale from these experiences.

Methods and Results

Interviews were carried out with implementers and users of dashboards for SARS-CoV-2 WW data across Europe and North America. The interviews addressed commonalities and inconsistencies in displaying epidemiological data of SARS-CoV-2, clinical parameters of COVID-19, data on variants, and data transparency. The thematic analysis identified WW dashboard elements that can facilitate standardization, or at least interoperability. These elements emphasise communication among developers under the same organization, open access for identified stakeholders, and data summarized with a time-intensive graphic analysis through normalizing at least by population. Simultaneous communication of clinical surveillance is recommended. More research is needed on flow and faecal indicators for normalization of WW data, and on the analysis and representation of variants.

Discussion

WW dashboard development between 2020-2023 provided a ‘real-time’ iterative process of data representation, and several recommendations have been identified. Communication of data through dashboards has the potential to support early warning systems for infectious diseases.
Access to Anti-Obesity GLP-1s for Medicare-Aged Adults
Authors: Rodriguez Patricia J. , Zhang Vincent , Gratzl Samuel , Cartwright Brianna M Goodwin , Do Duy , Stucky Nicholas , Emanuel Ezekiel J.
Published: March 2024

Background

Obesity is common among older adults in the US, but Medicare policies prohibit coverage of anti-obesity medications (AOMs) and may limit access to effective treatment.

Objective

To describe first-time prescribing and dispensing of AOM glucagon-like peptide-1 receptor agonists (GLP-1 RA) among eligible older adults, stratified by Medicare age eligibility.

Methods

Adults aged 60-69 with overweight or obesity and without Type II diabetes (T2D) were identified from Truveta Data. Data included EHR (encounters, prescriptions, conditions, BMI) and medication dispensing for a collective of US healthcare systems. Eligibility required an outpatient office encounter between June 2021 and January 2024 with a BMI ≥ 27, a negative history of GLP-1 RA use, and a follow-up ≥60 days later. Patients were stratified by Medicare age eligibility (60-64 vs. 65-69) and the proportions prescribed and subsequently dispensed AOM GLP-1 RA were compared.

Results

In total, 413,833 AOM eligible older adults were included in our cohort, with 208,067 (50.3%) Medicare-aged adults and 205,766 (49.7%) adults aged 60-64. Among eligible patients, 0.2% of Medicare-aged patients and 0.4% of patients aged 60-64 were prescribed AOM GLP-1 RA, a significant difference (p < 0.01). Among those prescribed AOM GLP-1 RA, 15.2% of Medicare-aged patients and 22.7% of patients aged 60-64 were dispensed AOM GLP-1 RA within 60 days, a significant difference (p<0.01). In both age groups, prescribing and dispensing were more common for females and those with higher BMI.

Conclusions

Fewer than 1% of older adults with overweight or obesity and without T2D were prescribed an AOM GLP-1 RA. New use of GLP-1 RA was significantly lower for Medicare-aged adults, compared to 60-64-year-olds, with differences occurring at both medication prescribing and dispensing stages. While coverage of AOMs is limited by many insurers, Medicare’s unique prohibition on AOM coverage may contribute to differentially lower use among Medicare-aged adults.
Design and Evaluation of Nanoscale Materials with Programmed Responsivity towards Epigenetic Enzymes
Authors: Ray Priyanka , Sedigh Abbas , Confeld Matthew , Alhalhooly Lina , Iduoku Kweeni , Casanola-Martin Gerardo M. , Pham-The Hai , Rasulev Bakhtiyor , Choi Yongki , Yang Zhongyu , Mallik Sanku , Quadir Mohiuddin
Published: March 2024

Self-assembled materials capable of modulating their assembly properties in response to specific enzymes play a pivotal role in advancing ‘intelligent’ encapsulation platforms for biotechnological applications. Here, we introduce a previously unreported class of synthetic nanomaterials that programmatically interact with histone deacetylase (HDAC) as the triggering stimulus for disassembly. These nanomaterials consist of co-polypeptides comprising poly (acetyl L-lysine) and poly(ethylene glycol) blocks. Under neutral pH conditions, they self-assemble into particles. However, their stability is compromised upon exposure to HDACs, depending on enzyme concentration and exposure time. Our investigation, utilizing HDAC8 as the model enzyme, revealed that the primary mechanism behind disassembly involves a decrease in amphiphilicity within the block copolymer due to the deacetylation of lysine residues within the particles’ hydrophobic domains. To elucidate the response mechanism, we encapsulated a fluorescent dye within these nanoparticles. Upon incubation with HDAC, the nanoparticle structure collapsed, leading to controlled release of the dye over time. Notably, this release was not triggered by denatured HDAC8, other proteolytic enzymes like trypsin, or the co-presence of HDAC8 and its inhibitor. We further demonstrated the biocompatibility and cellular effects of these materials and conducted a comprehensive computational study to unveil the possible interaction mechanism between enzymes and particles. By drawing parallels to the mechanism of naturally occurring histone proteins, this research represents a pioneering step toward developing functional materials capable of harnessing the activity of epigenetic enzymes such as HDACs.
Neural substrates and behavioral relevance of speech envelope tracking: evidence from post-stroke aphasia
Authors: De Clercq Pieter , Kries Jill , Vanthornhout Jonas , Gerrits Robin , Francart Tom , Vandermosten Maaike
Published: March 2024

Neural tracking of the low-frequency temporal envelope of speech has emerged as a prominent tool to investigate the neural mechanisms of natural speech processing in the brain. However, there is ongoing debate regarding the functional role of neural envelope tracking. In this context, our study aims to offer a novel perspective by investigating the critical brain areas and behavioral skills required for neural envelope tracking in aphasia, a language disorder characterized by impaired neural envelope tracking.

We analyzed an EEG dataset of 39 individuals with post-stroke aphasia suffering a left-hemispheric stroke who listened to natural speech. Our analysis involved lesion mapping, where left lesioned brain voxels served as binary features to predict neural envelope tracking measures. We also examined the behavioral correlates of receptive language, naming, and auditory processing (via rise time discrimination task) skills.

The lesion mapping analysis revealed that lesions in language areas, such as the middle temporal gyrus, supramarginal gyrus and angular gyrus, were associated with poorer neural envelope tracking. Additionally, neural tracking was related to auditory processing skills and language (receptive and naming) skills. However, the effects on language skills were less robust, possibly due to ceiling effects in the language scores.

Our ﬁndings highlight the importance of central brain areas implicated in language understanding, extending beyond the primary auditory cortex, and emphasize the role of intact auditory processing and language abilities in effectively processing the temporal envelope of speech. Collectively, these ﬁndings underscore the signiﬁcance of neural envelope tracking beyond mere audibility and acoustic processes.

Signiﬁcance statement

While some studies have proposed that neural envelope tracking primarily relates to audibility and acoustic speech processes, others have suggested its involvement in actual speech and language comprehension. By investigating the critical brain areas and behavioral skills essential in aphasia, we argue for a broader signiﬁcance of neural envelope tracking in language processing. Furthermore, our ﬁndings highlight a speciﬁcity among individuals with aphasia, indicating its correlation with lesions in temporal brain regions associated with receptive language functions. This addresses the signiﬁcant heterogeneity in lesion characteristics present among individuals with aphasia and suggests the potential of neural tracking as an EEG-based tool for speciﬁcally assessing receptive language abilities in this population.
Transport-based transfer learning on Electronic Health Records: Application to detection of treatment disparities
Authors: Li Wanxin , Park Yongjin P. , Duc Khanh Dao
Published: March 2024

Abstract

Many healthcare systems increasingly recognize the opportunities Electronic Health Records (EHRs) promise. However, EHR data sampled from different population groups can easily introduce unwanted biases, rarely permit individual-level data sharing, and make the data and fitted model hardly transferable across different population groups. In this paper, we propose a novel framework that leverages unbalanced optimal transport to facilitate the unsupervised transfer learning of EHRs between different population groups using a model trained in an embedded feature space. Upon deriving a theoretical bound, we find that the generalization error of our method is governed by the Wasserstein distance and unbalancedness between the source and target domains, as well as their labeling divergence, which can be used as a guide for binary classification and regression tasks. Our experiments, conducted on experimental datasets from MIMIC-III database, show that our transfer learning strategy significantly outperforms standard and machine learning transfer learning methods, with respect to accuracy and computational efficiency. Upon applying our framework to predict hospital duration for populations with different insurance plans, we finally find significant disparities across groups, suggesting our method as a potential tool to assess fairness in healthcare treatment.
Frailty is associated with low physical activity and poor sleep quality in patients undergoing myeloablative allogeneic hematopoietic cell transplantation: A Fitbit® Pilot Study
Authors: Libbert Caryn R. , He Fiona , El Jurdi Najla , Fagrelius Helen , Juckett Mark , Maakaron Joseph , Juckett William , Evanoff Nicholas , Dengel Donald R. , Holtan Shernan G.
Published: March 2024

Allogeneic hematopoietic cell transplantation (alloHCT) is a vital therapy for various hematologic diseases, though it demands high physiological resilience. Frailty, a syndrome impacting the body’s ability to withstand stress, affects outcomes of alloHCT across all ages.This study examines the relationship between frailty and peri-transplant activity and sleep patterns using Fitbit® devices. In this pilot study, adults scheduled for their first myeloablative alloHCT at the University of Minnesota from June 2022 to January 2023 were included if they had a compatible device for the Fitbit® app. Participants were monitored for activity and sleep from admission to day +30 post-transplant. Frailty was assessed pre-transplant using Fried Phenotype criteria. Data were analyzed for activity and sleep patterns differences among not frail, pre-frail, and frail groups. Nine patients provided sufficient data for analysis, showing significant variances in activity levels and sleep patterns across frailty categories. Not frail patients exhibited significantly higher daily steps and active minutes than pre-frail and frail patients. Not frail patients also had the highest amount of restorative deep and rapid eye movement sleep. Due to Fitbit methodology and likely frequent interruptions, 28% of the days in the first month post-transplant had a recorded sleep time of 0 minutes. Although our sample size was small, our findings underscore the importance of frailty in influencing activity and sleep patterns among alloHCT recipients.
Rapid Biphasic Decay of Intact and Defective HIV DNA Reservoir During Acute Treated HIV Disease
Authors: Barbehenn Alton , Shi Lei , Shao Junzhe , Hoh Rebecca , Hartig Heather M. , Pae Vivian , Sarvadhavabhatla Sannidhi , Donaire Sophia , Sheikhzadeh Caroline , Milush Jeffrey , Laird Gregory M. , Mathias Mignot , Ritter Kristen , Peluso Michael J. , Martin Jeffrey , Hecht Frederick , Pilcher Christopher , Cohen Stephanie E. , Buchbinder Susan , Havlir Diane , Gandhi Monica , Henrich Timothy J. , Hatano Hiroyu , Wang Jingshen , Deeks Steven G. , Lee Sulggi A.
Published: March 2024

Despite antiretroviral therapy (ART), HIV persists in latently-infected cells (“the reservoir”) which decay slowly over time. Here, leveraging >500 longitudinal samples from 67 people with HIV (PWH) treated during acute infection, we developed a novel mathematical model to predict reservoir decay from peripheral CD4+ T cells. Nonlinear generalized additive models demonstrated rapid biphasic decay of intact DNA (week 0-5: t1/2∼2.83 weeks; week 5-24: t1/2∼15.4 weeks) that extended out to 1 year. These estimates were ∼5-fold faster than prior decay estimates among chronic treated PWH. Defective DNA had a similar biphasic pattern, but data were more variable. Predicted intact and defective decay rates were faster for PWH with earlier timing of ART initiation, higher initial CD4+ T cell count, and lower pre-ART viral load. These data add to our limited understanding of HIV reservoir decay at the time of ART initiation, informing future curative strategies targeting this critical time.
Home-based transcranial direct current stimulation in bipolar depression: an open-label treatment study of clinical outcomes, acceptability and adverse events
Authors: Ghazi-Noori Ali-Reza , Woodham Rachel D. , Rezaei Hakimeh , Sharif Mhd Saeed , Bramon Elvira , Ritter Philipp , Bauer Michael , Young Allan H. , Fu Cynthia H.Y.
Published: March 2024

Current treatments for bipolar depression have limited effectiveness, tolerability and acceptability. Transcranial direct current stimulation (tDCS) is a novel non-invasive brain stimulation method that has demonstrated treatment efficacy for major depressive episodes. tDCS is portable, safe, and individuals like having sessions at home. We developed a home-based protocol with real-time remote supervision. In the present study, we have examined the clinical outcomes, acceptability and feasibility of home-based tDCS treatment in bipolar depression. Participants were 44 individuals with bipolar disorder (31 women), mean age 47.27+12.89 years, in current depressive episode of moderate to severe severity (mean Montgomery-Åsberg Depression Rating Scale (MADRS) score 24.59+2.64). tDCS was provided in a bilateral frontal montage, F3 anode, F4 cathode, 2mA, for 30 minutes, in a 6-week trial, for a total 21 sessions. Participants maintained their current treatment (psychotherapy, antidepressant or mood stabilising medication) or maintained being medication-free. A researcher was present by video call at each session. 93.2% participants (n=41) completed the 6-week treatment. There was a significant improvement in depressive symptoms following treatment (mean MADRS 8.77+5.37), the rate of clinical response was 77.3% (MADRS improvement of <=50% from baseline), and the rate of clinical remission was 47.7% (MADRS rating of <=9). Acceptability was endorsed as “very acceptable” or “quite acceptable” by all participants. No participants developed mania or hypomania. Due to the open-label design, efficacy findings are preliminary. In summary, home-based tDCS with real-time supervision was associated with significant clinical improvements and high acceptability in bipolar depression.
A nationwide Guillain-Barré syndrome epidemiological study in Spain during the COVID-19 years
Authors: Blanco-Ruiz Marina , Martín-Aguilar Lorena , Caballero-Ávila Marta , Lleixà Cinta , Pascual-Goñi Elba , Collet-Vidiella Roger , Tejada-Illa Clara , Turon-Sans Janina , Álvaro-Carbayo  , Llansó Laura , Cortés Elena , Pascasio Laura Amaya , Querol Luis
Published: March 2024

OBJECTIVE

To perform a nationwide epidemiological study of Guillain-Barré syndrome (GBS) in Spain, analysing background incidences and seasonal variation and trying to identify incidence changes during the COVID-19 years.

METHODS

Observational study collecting all GBS diagnoses from National Epidemiological Surveillance Network (RENAVE) collected by the Ministry of Health. Patients discharged with GBS as main diagnosis and admitted during 2018-2021 were included. Data on the incidence of SARS-CoV-2 infections and vaccinations were obtained from the National Epidemiology Centre.

RESULTS

In total, 3147 cases were included, 832 in 2018, 861 in 2019, 670 in 2020 and 784 in 2021. Nationwide hospital incidence was 1.78 in 2018, 1.71 in 2019, 1.41 in 2020 and 1.66 in 2021, with an increased frequency in males, elderly population, and in the winter season. Eleven percent of GBS patients needed ventilatory support. GBS and SARS-CoV-2 incidences did not correlate with one another (r=-0.29, p=0.36). GBS incidence decreased during 2020 and during COVID-19 lockdown period in comparison to the same months of 2018-2019. No relationship was found between vaccines and GBS cases during vaccination roll-out in 2021.

INTERPRETATION

Incidence of GBS in Spain is similar to that of other countries. Despite prior reports describing a significant increase in COVID-19-associated GBS in Spain, we detected a significant drop of GBS incidence during the SARS-CoV-2 pandemic, probably due to prevention measures. No relationship was found between SARS-CoV-2 or vaccinations and GBS incidences at the population level but data on relationship of vaccinations and GBS at the individual level were not available.