bluuebunny/crossref_metadata_2025 huggingface dataset:
O07 Lower doses of retinol facilitate cell proliferation and epidermal thickening in photoaged skin
Authors: Mambwe Bezaleel , Bradley Eleanor , Bell Mike , Langton Abigail
Published: May 2024

Introduction and aims

Chronic exposure to solar ultraviolet radiation leads to cutaneous hypertrophic photoageing which clinically manifests as wrinkles, skin laxity and hyperpigmentation. This photoaged phenotype is underscored by a remodelled cutaneous microenvironment including epidermal thinning and rete ridge flattening. We have previously shown that cosmeceutical formulations of 0.3% and 1% retinol can effectively induce epidermal thickening and keratinocyte proliferation. However, these concentrations require careful usage to limit potential irritancy issues, highlighting a need to explore the benefits of lower dose retinol for daily skincare. Therefore, we compare the efficacy of lower doses of retinol in facilitating epidermal thickness and proliferation in photoaged skin, as this currently remains unknown.

Methods

Using the in vivo Manchester Patch Test Assay, test substances (vehicle and retinol at concentrations of 0.025%, 0.05%, 0.1% and 1%) were applied under occlusion to extensor forearms of healthy but photoaged volunteers (three men, three women; age range 66–86 years) for 12 days. Resultant skin biopsies were processed for histological assessment of epidermal thickness and keratinocyte proliferation.

Results

Epidermal thickness was significantly increased with 0.025% (P < 0.05), 0.05%, 0.1% and 1% (all P < 0.01) retinol treatment, compared with baseline or vehicle. Immunofluorescence staining of the proliferation marker Ki67 identified elevated keratinocyte proliferation following retinol treatment (P < 0.05 for 0.025%, 0.05% and 1%) compared with baseline. Although Ki67 expression in the 0.1% retinol treatment was elevated, significance was not achieved compared with baseline. However, compared with the vehicle, all retinol concentrations significantly increased Ki67 expression (P < 0.05). Clinically, 50% of volunteers showed an erythemal irritancy response to 1% retinol only.

Conclusions

We established that lower doses of retinol are capable of inducing keratinocyte proliferation and epidermal thickening without irritancy issues. Therefore, long-term effective treatment of photoaged skin with low-dose retinol products may be the preferred choice for individuals where retinol sensitivity has previously been an issue.
P24 Folliculin silencing in human hair follicles ex vivo upregulates intrafollicular mechanistic target of rapamycin complex 1 activity: a new model for studying Birt–Hogg–Dubé syndrome
Authors: Fostier William , Linowiecka Kinga , Chéret Jérémy , Paus Ralf , Rajan Neil
Published: May 2024

Introduction and aims

Birt–Hogg–Dubé (BHD) syndrome is a rare multisystem disorder caused by germline pathogenic variants in the FLCN gene. BHD skin tumours predominantly affect facial skin, confer a significant psychosocial burden, and there is a lack of nonsurgical therapies. Here we report a novel ex vivo human model to study the impact of FLCN loss in human hair follicles (HFs), the putative origin of BHD skin tumours.

Methods

Organ-cultured human anagen HFs and scalp skin were treated with small interfering RNA targeting FLCN (n = 2 donors) for 6 days ex vivo, followed by quantitative real-time polymerase chain reaction (qRT-PCR), and quantitative immunohistomorphometry (qIHM).

Results

Successful FLCN knockdown was confirmed at both the mRNA (34% reduction compared with nontargeting control levels measured by qRT-PCR) and protein level (12% reduction in FLCN expression measured by qIHM). In FLCN-silenced HFs (n = 14, two donors), our preliminary Results demonstrated an increase in p-S6 expression, a direct downstream kinase of mechanistic target of rapamycin complex (mTORC)1 signalling. This was spatially restricted to the hair bulb and proximal outer root sheath keratinocytes, and was significantly greater than quantified in nontargeting control HFs (P < 0.05).

Conclusions

FLCN silencing in ex vivo cultured, healthy human HFs and scalp skin provides a novel, instructive and accessible preclinical research model. We aim to delineate whether FLCN interacts with the key endogenous inhibitor of mTORC1 activity, TSC2, in future work, to gain insight into the role of FLCN in the pathobiology of BHD and the maintenance of healthy human HFs.
Preliminary Results from the International Registry on Liver Venous Deprivation (EuroLVD)
Authors: Joliat G R , Chevallier P , Wigmore S , Martin D , Labgaa I , Uldry E , Halkic N , Newhook T , Vauthey J N , Memeo R , Dasari B , Braunwarth E , Duran R , Denys A , Melloul E
Published: May 2024

Background

Liver venous deprivation (LVD) is a recently developed method to reach maximal liver hypertrophy before major hepatectomy. LVD combines simultaneous portal and ipsilateral hepatic vein embolization. An international registry was created in 2021.

Aims

This study aimed to describe the outcomes after LVD of patients included in the registry.

Methods

Since its creation, 7 international expert HPB centers participated to the registry. Preoperative characteristics, data on liver regeneration after LVD, and postoperative results after hepatectomy were collected. Future liver remnant (FLR) and standardized FLR ratios were defined as FLR/total functional liver volume and FLR/total estimated liver volume.

Results

A total of 191 patients were included (71 women). Median age was 63 (IQR 53-69) and body-mass index 24.8 kg/m2 (IQR 22.3-28.7). Fifty-three patients were ASA III/IV.

Main surgical indication was colorectal metastases (n=116). Median FLR and standardized FLR ratios before LVD were 33% (IQR 26-47) and 32% (IQR 23-39). Median time for the LVD procedure was 122 minutes (IQR 99-164). In one patient right hepatic vein embolization failed. Complications after LVD occurred in 14 patients (7%), including 7 hemorrhages/hematomas.

After LVD, median FLR and standardized FLR ratios significantly increased to 46% (IQR 39-59, p<0.001) and 44% (IQR 35-50, p<0.001), corresponding to a median kinetic growth rate of 3.2%/week (IQR 1.6-5.3). Hepatectomy was performed in 142 patients (69 extended hepatectomies), while 49 dropped out (7 for insufficient hypertrophy (4%), 27 for tumor progression (14%), and 15 for other reasons (8%)). Seventy-one patients had postoperative complications (50%), and only 2 developed postoperative liver failure (1%). Median Comprehensive Complication Index was 20.9 (IQR 0-30.8) and 10 patients were reoperated (7%).

Conclusion

The preliminary data of this international registry showed that LVD had a high technical success rate (190/191) with few post-procedural complications and significant kinetic growth. Major hepatectomy after LVD appeared to be safe.
Tolerance threshold of a pelagic species in China to total dissolved gas supersaturation: from the perspective of survival characteristics and swimming ability
Authors: Wang Hongtao , Wang Yuanming , Li Kefeng , Liang Ruifeng , Zhao Weiyang
Published: May 2024

Total dissolved gas (TDG) supersaturation downstream of dams can occur in the Yangtze River basin and is known to cause stress and even death in fish. Consequently, it is important to establish tolerance thresholds of endemic fish to protect local aquatic resources. We conducted experiments to assess survival characteristics and swimming ability of bighead carp, an important commercial fish dwelling in the Yangtze River, to evaluate its tolerance threshold to TDG supersaturation. The typical external symptoms of gas bubble trauma (GBT) were observed and the time when the fish lost equilibrium and died were recorded. The results showed that the mortality occurred when TDG level exceeded 125%, with obvious symptoms such as exophthalmos and bubbles on the head. The interval between loss of equilibrium and mortality decreased with an increase in TDG level. Neither exposure time nor TDG level significantly affected the critical swimming speed (Ucrit) of fish exposed to non-lethal exposure (110%, 120% and 125% TDG) over a 7 day period. Significant reductions in Ucrit were found under 130% and 135% TDG conditions when the exposure lasted 52.0 h and 42.9 h, respectively. The Ucrit also significantly decreased after exposure of 1.6 h under 140% TDG condition. Moreover, after exposure to 140% TDG for 39.2 h, 135% TDG for 56.5 h and 130% TDG for 95.9 h, bighead carp were transferred into air saturated water to recover for 24 h or 48 h; however, swimming performance remained impaired. The results of this study indicate that 125% TDG was the highest TDG level where limited mortality was observed and the swimming ability was not impaired, showing that 125% TDG can be set as the tolerance threshold of this species to guide the operation of dams in the Yangtze River Basin.
Conversation and pragmatics in children who are hard-of-hearing: a scoping review
Authors: Bongioletti Jenna , Doble Maree , Purcell Alison
Published: May 2024

Technological and therapeutic advances have allowed many children who are born hard-of-hearing (HoH) to start school with age-appropriate spoken language skills, yet many of these children continue to find everyday conversations challenging. This scoping review maps the evidence related to development of conversation and pragmatic skills in children who are HoH and learning spoken language. The review followed Arksey and O’Malley’s methodological framework and the PRISMA Extension for Scoping Reviews guidelines. Quality appraisal, data extraction, and thematic analysis were used to describe the data. Systematic searches identified 36 articles for inclusion. Sample sizes were small and heterogenous. Most studies focused on school-aged children with severe hearing loss or greater. Methodological rigor varied. Thematic analysis revealed two global themes. First, children who are HoH continue to find conversation and pragmatics difficult to master, and second, there are a set of audiological, communication, environmental, and demographic characteristics that are associated with better conversation and pragmatic outcomes, some of which are fixed, whereas others are malleable. Focused attention on designing valid and reliable assessments for conversation and pragmatic skills, and on developing therapeutic approaches targeting early conversation and pragmatic skill development, is needed to reduce the impact conversation and pragmatic differences across the lifespan.
DIASTOLIC DYSFUNCTION EVALUATION IN CARDIAC AMYLOIDOSIS: BEYOND TRADITIONAL PARAMETERS TO DISCRIMINATE BETWEEN TRUE HEART FAILURE WITH PRESERVED EJECTION FRACTION AND MIMICS
Authors: Sforna S , Zuchi C , Mengoni A , Lupi A , Belardinelli C , Massei F , Ambrosio G , Carluccio E
Published: May 2024

Background

Diastolic dysfunction in cardiac amyloidosis (CA), according to current guidelines, can be classified using mitral flow velocities, mitral annular e’ velocity, E/e’ ratio, tricuspid regurgitation jet and left atrial (LA) maximal volume. However, LA minimal volume and the ratio between LA and left ventricular (LV) volumes at end–diastole, known as left atrio–ventricular coupling index (LACI), have recently been proposed to refine prognosis and peak atrial longitudinal strain (PALS) has been demonstrated to better stratify diastolic dysfunction.

Aim of the Study

To evaluate, in patients with CA: 1) the role of LACI as marker of LV diastolic dysfunction; 2) whether LACI could discriminate cardiomyopathy from normal cardiac function; 3) whether LACI and/or PALS could help discriminate between true heart failure with preserved ejection fraction (HFpEF) and amyloidotic cardiomyopathy (HFpEF–mimic).

Methods

We retrospectively analyzed 63 patients with CA and compared them with 80 true HFpEF patients and 70 healthy people; echocardiography was performed at the time of the diagnosis and diastolic function was characterized according to current guidelines.

Results

In patients with CA, LACI significantly increased as diastolic dysfunction worsened (P for trend < 0.0001) and significantly correlated with LV filling pressures estimated by E/e’ ratio (beta = 0.65, P < 0.0001) and pulmonary artery systolic pressure (beta = 0.63, P < 0.0001). LACI, after adjustment for age, gender and body mass index (BMI), was significantly higher in CA [0.62 (95%CI 0.52–0.70)] and in HFpEF [0.61 (95%CI 0.55–0.68)] than in controls [0.29 (95%CI 0.19–0.39)], while the difference between the two diseased populations was not statistically significant; a cut–off value of 0.45 was able to discriminate between controls and diseased patients (sensitivity = 95%, specificity = 94%, area under ROC curve = 0.98). PALS, after adjustment for age, gender and BMI, was significantly lower in CA [11.1 (95%CI 8.4–13.8%) and 8.4 (95%CI 3.5–13.3%) respectively in ATTR and AL] than in HFpEF [17.4 (95%CI 15.6–19.3%)], and a cut–off value of 9.9% was able to discriminate between them (sensitivity = 89%, specificity = 73%, area under ROC curve = 0.86).

Conclusions

LACI is a novel index able to discriminate between normal and diseased patients. In CA, it shows good correlation with diastolic dysfunction and LV filling pressures. PALS can be used to discriminate between true HFpEF and CA.
LEFT ATRIAL STIFFNESS INDEX AS A NON–INVASIVE MEASURE TO PREDICT ATRIAL FIBRILLATION RECURRENCE AFTER CATHETER ABLATION
Authors: Di Simone V , Bonelli A , Guasti S , Grieco M , Inciardi R , Cersosimo A , Degiovanni A , Dell‘Era G , De Chiara B , Metra M , Patti G , Mazzone P , Moreo A
Published: May 2024

Background

Catheter ablation (CA) is an effective option for the management of patients with atrial fibrillation (AF), albeit burdened with a recurrence rate that needs to be taken into account. To date, strong echocardiographic parameters able to predict the maintenance of sinus rhythm after CA are lacking.

Objective

To investigate if left atrial stiffness index (LASI), as the ratio of E/e’ and peak atrial longitudinal strain (PALS) could be a predictor of AF recurrence after CA.

Methods and Results

This is a multicenter prospective study enrolling patients with paroxysmal or persistent AF referred for CA. A total of 118 patients were included in the study (mean age 65.8 ± 7.9 years, 28% female, mean left ventricular ejection fraction [LVEF] 57.1±7.9%). The median value of LASI was 0.4. The subgroup of patients with high LASI (≥0.4) did not show any difference in baseline clinical characteristics compared to those with low LASI, except for higher frequency of history of peripheral vascular disease and chronic heart failure (p= 0.043 and p= 0.018, respectively). Besides, the former group had significantly higher values of NTproBNP (686±707.0 pg/mL vs. 220.6±306.2 pg/mL, p<0.001), mean LA pressure (17.5±5.9 mmHg vs. 14.0±6.2 mmHg, p= 0.012), LA volume index [LAVi] (41.1±11.9 ml/m2 vs. 34.3±9.9 ml/m2, p 0.001), and lower value of LVGLS (14.7±4.0% vs 18.5±4.0%, p < 0.001) and RVGLS of the free wall (21.2 ± 5.1% vs. 24.9±5.6%, p < 0.001). During a follow–up period of 3 months, LASI showed a correlation with the probability of AF recurrence (for each increase of 0.1: OR 1.23; 95% CI [1.00, 1.50]; p = 0.045), also after adjustment for other variables. The ROC curve showed an area under the curve (AUC) of 0.69 for the prediction of AF recurrence. When compared with other LA parameters, LASI exhibited a slightly larger AUC (0.69 for LASI vs. 0.68 for LAVi, 0.33 for PALS and 0.45 for LA ejection fraction).

Conclusion

LASI is a novel non–invasive and useful parameter to predict AF recurrence after CA. It is potentially more accurate than other echocardiographic features routinely used in clinical practice.
ALTERNATIVE STRATEGIES FOR LEFT SUBCLAVIAN ARTERY REVASCULARIZATION DURING ZONE–2 AORTIC ARCH SURGERYEMENT
Authors: Totaro P , Kushta E , Aiello M , Pelenghi S
Published: May 2024

Objective

Anatomical extension of surgical treatment of thoracic aortic pathologies involving the aortic arch is still controversial. The adoption of distal anastomosis in aortic arch zone–2 (Z2–AAR), in order to facilitate bleeding control, has been widely recommended. In such case the revascularization of left subclavian artery (LSA) may add further concerns. Here we report our different strategy of LSA revascularization in 2 different scenario of Z2–AAR Clinical.

Cases

Case#1

17 yo male patient affected by Loeys–Dietz Syndrome and a previous David procedure at age of 11yo. He presented complaining chest pain and CT scan revealed a dilatation (5,8 cm) of ascending aorta and an intimal flap with preserved previous distal anastomosis. Surgical strategy #1 (Left subclavian artery in situ): Arch replacement (Zone 2 distal anastomosis) with Siena Graft 24mm and modified Elephant Trunk Tecnique (2cm distal endoluminal graft). Innominate artery and left carotid artery reimplantation. Distal Anastomosis Siena 24 (Z2).

Case #2

78 yo male with a previous (6 month before) Biological AVR (Trifecta 25) + ascending aorta replacement (Jotec 30). Presented complaining acute chest pain, CT Scan revealed a residual dilatation of distal ascending aorta, dissection/rupture of distal aortic arch at level of a complicated plaque. Surgical strategy #2 (Left subclavian artery reimplanted): Arch replacement (Zone 2 distal anastomosis) with Siena Graft 30mm and Elephant trunk Teccnique (10cm distal endoluminal graft). Closure of the extended ulcera. Total epiaortic vessels de–branching 10 mm Tube on LSA – Distal Anastomosis Siena 30 (Z2).

Conclusion

Surgical extension of aortic arch replacement is still matter of discussion. Zone–2 approach for aortic arch replacement seems a safe and effective option. In our mind strategy for left subclavian revascularization should be tailored according patient’s anatomy and potential future scenarios.
DECENNIAL ANALYSIS OF AVNRT ABLATION IN A SINGLE CENTRE
Authors: Ciliberti D , Zaccaria C , Perrotta L , Ricciardi G , Checchi L , Brogni F , Porcedda G , De Simone L , Michelucci A , Pieragnoli P
Published: May 2024

Background

Transcatheter ablation represents the first line therapy for atrio–ventricular nodal re–entrant tachycardia (AVNRT). Both radiofrequency (RF) and cryoablation (CRYO) have been shown to be effective, with a better safety profile for CRYO. Data on very long–term efficacy are scarces.

Purpose

To review our experience in AVNRT ablation performed in the last ten years and evaluate safety, efficacy and very long–term outcome of RF and CRYO.

Methods

We retrospectively analyzed all patients who underwent AVNRT ablation (RF or CRYO) between January 2013 and May 2023 at our centre. The majority of procedures were performed under electro–anatomical mapping (EAM) guidance to reduce radiation exposure. Acute efficacy endpoint was defined as slow pathway ablation, while long–term outcome was defined as the absence of AVNRT recurrence.

Results

A total of 387 consecutive patients (60,5% F; mean age 48 ± 19 years) were included; CRYO was performed in 241 patients (62%), RF in 131 patients (34%), hybrid approach (CRYO+RF) in 15 patients (4%). AVNRT induction was obtained during EPS in 295 cases (76%), in 25,4% after isoprotenerol administration. No significant differences for baseline characteristics were observed between the two groups except for age (CRYO: 42,2 ± 18 years vs RF 57,19 ± 16,5 years p <0.001). In pediatric population CRYO was performed in 93% of procedures. Figure 1 shows the distribution of RF/CRYO over 10 years at our centre, with a trend of significant increase in CRYO utilizations in the last years. Acute success was achieved in all 387 cases (100%; delta WP 28,5 ± 23,1 ms, delta AVN ERP 72,4 ± 44,7 ms). No permanent AV block or major periprocedural complications occurred, however transient AH prolongation was observed in 0.8% in CRYO pts vs 2,8% RF pts. The mean follow–up was 73±45 months, range 6–129 months. Overall long–term success rate was 93,3%, ranging from 91,3 % in CRYO and 96,6% in RF. Recurrence occurred in 26 cases (6,7%) after a median time of 20 months (4–40months). Recurrent AVNRT were treated with RF in the majority of cases, CRYO in 6 procedures, hybrid in only 1 case.

Conclusions

Transcatheter ablation is a safe and effective therapy for AVNRT. Our very long–term outcome data confirmed very high success rate even after 10 years follow–up. The increasing choice for CRYO may be due to the increasing number of pediatric and young patient referred to our centre.
A CAROTID GLOMUS TUMOR TREATED WITH SAPHENOUS BYPASS: A 15–YEAR FOLLOW–UP
Authors: Fazio G
Published: May 2024

Background

Carotid glomus is an exceptional extra–adrenal paraganglioma in childhood originating at the carotid body. Only 3% of paragangliomas occur in the head and the neck. Surgical resection of complex glomus tumors can be complicated by extensive blood loss and might require surgical sacrifice of an encased internal carotid artery. We report a 15 years follow up of a patient treated for a carotid glomus tumor.

Case Report

A 81 years old patient was admitted in our surgery division for a inguinal hernia. Before the surgery treatment a cardiological consult was performed. The patients reported a clinical history of carotid glomus tumor (Figure 1) detected for a transient ischemic attack. 15 years before a venous by–pass was performed, and till now the patients was asymptomatic. We investigated the saphenous vein bypass that presented a normal flow and was in good conditions. So the surgery for hernia was permitted.
LEFT BUNDLE BRANCH BLOCK AND ACUTE CORONARY SYNDROME: WHAT IS THE ROLE OF MODIFIED SGARBOSSA–SMITH CRITERIA AND THE WELLENS‘ PATTERN?
Authors: Pierfelice F , Ottaviani A , Zimarino M , Ricci F , Renda G , Gallina S
Published: May 2024

A 55–year–old man presented to the emergency room with intermittent chest pain that started the day before. His medical history included hypertension, and dyslipidemia. The initial electrocardiogram (ECG) showed sinus rhythm (75 bpm) with pre–existing left bundle branch block (LBBB), without modified Sgarbossa–Smith criteria, despite the hyperacute appearance of T waves in V2–V4 (Fig. 1). Additionally, there were alterations in ventricular repolarization in the lateral region, morphologically not fully justifiable by the mentioned conduction delay. Echocardiography revealed normal left and right ventricular systolic function and no valvular abnormalities. Laboratory tests showed a pathological release of myocardial necrosis enzymes, with a typical rise–and–fall curve (10 pg/mL, 100 pg/mL, 200 pg/mL; normal range: 1.7–34.2 pg/mL). Therefore, the patient was admitted to the intensive cardiac care unit (ICCU) with a working diagnosis of non–ST–segment elevation myocardial infarction (NSTEMI). There were no recurrent angina episodes or signs/symptoms of heart failure on physical examination. During hospitalization, ECG and echocardiography were repeated. The follow–up ECG (12 hours after admission) showed persistent LBBB with biphasic T waves in leads V2–V5 with slight negative deflection at the end. This T wave abnormality can be interpreted as Wellens’ ECG Type A (Fig. 3A). The echocardiogram remained unchanged. Consequently, the catheterization lab was activated for urgent coronary angiography. The examination revealed subocclusion of the mid–segment of the left anterior descending artery (LAD). A drug–eluting stent was deployed in the culprit lesion (Fig. 2), restoring coronary flow completely (TIMI Flow 3). The subsequent hospital stay proceeded without complications. The ECG performed before discharge showed a typical LBBB, with normalization of T waves in precordial leads (Fig 3B). The presented case is about ECGs containing a pre–existing LBBB pattern in a patient with chest pain. The modified Sgarbossa–Smith criteria were not met in either the first recorded ECG or the second, whereas Wellens’ signs were detectable. Wellens’ syndrome can be diagnosed in a case of LBBB and help detect a high–grade LAD stenosis even if modified Sgarbossa–Smith criteria are not met.
THE SIGN OF THE HORNS: A RARE CASE OF DOUBLE PERI–COMMISSURAL MITRAL FLAIL
Authors: Tofoni P , Capodaglio I , Lofiego C , Vagnarelli F , Patani F , Brugiatelli L , Maurizi K , Pietrucci F , Perna G , Dello Russo A , Di Eusanio M
Published: May 2024

A 80–year–old man with history of hypertension and dyslipidemia was admitted to our Cardiology Unit for exertional dyspnea (NYHA III) occurred during the last few days. The physical examination showed a systolic heart murmur (4/6 on Levine scale) and signs of pulmonary congestion. Transthoracic echocardiography revealed a massive mitral regurgitation (Fig.1) together with severe dilation of the left atrium, mild–to–moderate aortic regurgitation, high probability of pulmonary hypertension and normal biventricular systolic function. A transesophageal echocardiography (TEE) was performed to clarify mitral valve anatomy. A double flail of the posterior leaflet was present involving the peri–commissural portions due to a single chordal rupture on P1 scallop and a double chordal rupture on P3 scallop (Fig.2). P2 scallop was prolapsing and there was a billowing of the anterior leaflet. In addiction mitral annulus was dilated (antero–posterior diameter of 43 mm and intercommissural diameter of 45 mm). We named this finding “sign of the horns” for his 3D echocardiographic appearance (Fig.3) given the double flail resembling two fingers. A surgical correction was performed with 3 GoreTex neochords implantation on the posterior leaflet and an annuloplasty ring (Physio II n. 34) implantation during extracorporeal circulation through right anterior minithoracotomy. Surgical and echocardiographic results were optimal. The patient was discharged after 7 days of hospitalization.

Conclusion

Coexistence of a double peri–commissural flail in the same leaflet is a very rare echocardiographic finding and we named it “double horn sign”. TEE is an essential examination in this scenario in order to understand the exact mechanism of the regurgitation for an optimal preoperative planning.
Causal relationship between primary biliary cholangitis and inflammatory bowel disease: a Mendelian randomization study
Authors: Zhu Qi , Fu Yunfeng , Qiu Jianhao , Guan Langyi , Liao Foqiang , Xing Yawei , Zhou Xiaodong
Published: May 2024

Background

Several studies indicated that inflammatory bowel disease (IBD) may contribute to increased susceptibility to primary biliary cholangitis (PBC). However, the causal relationship between IBD and PBC remains unclear.

Methods

The genetic variant data of patients with IBD and PBC were obtained from published genome-wide association studies (GWASs). The IBD data were further divided into a discovery dataset and a validation dataset depending on the data source. We conducted a two-sample Mendelian randomization (MR) analysis using the inverse variance weighting (IVW), MR-Egger, weighted median (WM), MR robust adjusted profile score (MR-RAPS), and maximum likelihood (ML) methods, with IVW being the main focus, to verify the causal relationship between IBD and PBC. Additionally, a series of sensitivity analyses were performed to ensure the reliability of the results.

Results

In the discovery cohort, the IVW analysis results (OR = 1.114, P = 0.011) indicated a significant association between IBD and PBC. The MR-RAPS (OR = 1.130, P = 0.007) and ML (OR = 1.115, P = 0.011) analyses yielded results consistent with those of IVW in confirming IBD as a risk factor for PBC. In the validation cohort, consistent findings were observed regarding the causal relationship between IBD and PBC using IVW, MR-RAPS, and ML analyses; all three methods identified IBD as a risk factor for developing PBC. By the IVW analysis, Crohn's disease (CD) emerged as the most prominent subtype of IBD associated with an increased risk of developing PBC in both the discovery cohort (OR = 1.068, P = 0.049) and the validation cohort (OR = 1.082, P = 0.019).

Conclusion

The results of the MR analysis suggest a causal relationship between IBD and PBC, highlighting the necessity for proactive PBC prevention in patients with IBD, particularly those with CD.
Comparison of different promoters to improve AAV vector-mediated gene therapy for neuronopathic Gaucher disease
Authors: Massaro Giulia , Geard Amy F , Nelvagal Hemanth R , Gore Katrina , Clemo Nadine K , Waddington Simon N , Rahim Ahad A
Published: May 2024

Gaucher Disease (GD) is an inherited metabolic disorder caused by mutations in the GBA1 gene. It can manifest with severe neurodegeneration and visceral pathology. The most acute neuronopathic form (nGD), for which there are no curative therapeutic options, is characterised by devastating neuropathology and death during infancy. In this study, we investigated the therapeutic benefit of systemically delivered AAV9 vectors expressing the human GBA1 gene at two different doses comparing a neuronal-selective promoter with ubiquitous promoters. Our results highlight the importance of a careful evaluation of the promoter sequence used in gene delivery vectors, suggesting a neuron-targeted therapy leading to high levels of enzymatic activity in the brain but lower GCase expression in the viscera, might be the optimal therapeutic strategy for nGD.
Variable effects of captivity on microbiomes in populations of IUCN-endangered Blanding’s turtles (Emydoidea blandingii)
Authors: Jenkins Lauren , McKnight Donald T , Parks Matthew , Byer Nathan W , Oliaro Francis J , Thompson Dan , Scott Rodney
Published: May 2024

Aims

Microbiome composition is increasingly considered in species reintroduction efforts and may influence survival and reproductive success. Many turtle species are threatened by anthropogenic pressures and are frequently raised in captivity for reintroduction efforts, yet little is known about turtle microbiome composition in either wild or captive settings. Here, we investigated trends in microbiome composition of captive and wild IUCN-endangered Blanding’s turtles (Emydoidea blandingii).

Methods and results

We amplified and sequenced the V4 region of the 16S rDNA locus from plastron, cloaca, and water samples of wild E. blandingii adults and two populations of captive E. blandingii juveniles being raised for headstarting. Plastron, cloaca, and water-associated microbiomes differed strongly from each other and were highly variable among captive sites and between captive and wild sites. Across plastron, cloaca, and water-associated microbial communities, microbial diversity changed over time, but not in a predictable direction between captive sites. Plastron beta diversity correlated with growth rate in captive samples, indicating that external microbiomes may correlate with individual fitness.

Conclusions

Our results indicate that external and internal microbiomes vary between captive and wild turtles and may reflect differences in fitness of captive-raised individuals.
Toward a unified understanding of drug-drug interactions: mapping Japanese drug codes to RxNorm concepts
Authors: Kawakami Yukinobu , Matsuda Takuya , Hidaka Noriaki , Tanaka Mamoru , Kimura Eizen
Published: May 2024

Objectives

Linking information on Japanese pharmaceutical products to global knowledge bases (KBs) would enhance international collaborative research and yield valuable insights. However, public access to mappings of Japanese pharmaceutical products that use international controlled vocabularies remains limited. This study mapped YJ codes to RxNorm ingredient classes, providing new insights by comparing Japanese and international drug-drug interaction (DDI) information using a case study methodology.

Materials and Methods

Tables linking YJ codes to RxNorm concepts were created using the application programming interfaces of the Kyoto Encyclopedia of Genes and Genomes and the National Library of Medicine. A comparative analysis of Japanese and international DDI information was thus performed by linking to an international DDI KB.

Results

There was limited agreement between the Japanese and international DDI severity classifications. Cross-tabulation of Japanese and international DDIs by severity showed that 213 combinations classified as serious DDIs by an international KB were missing from the Japanese DDI information.

Discussion

It is desirable that efforts be undertaken to standardize international criteria for DDIs to ensure consistency in the classification of their severity.

Conclusion

The classification of DDI severity remains highly variable. It is imperative to augment the repository of critical DDI information, which would revalidate the utility of fostering collaborations with global KBs.
Validation and clinical discovery demonstration of breast cancer data from a real-world data extraction platform
Authors: Nottke Amanda , Alan Sophia , Brimble Elise , Cardillo Anthony B , Henderson Lura , Littleford Hana E , Rojahn Susan , Sage Heather , Taylor Jessica , West-Odell Lisandra , Berk Alexandra
Published: May 2024

Objective

To validate and demonstrate the clinical discovery utility of a novel patient-mediated, medical record collection and data extraction platform developed to improve access and utilization of real-world clinical data.

Materials and Methods

Clinical variables were extracted from the medical records of 1011 consented patients with breast cancer. To validate the extracted data, case report forms completed using the structured data output of the platform were compared to manual chart review for 50 randomly-selected patients with metastatic breast cancer. To demonstrate the platform’s clinical discovery utility, we identified 194 patients with early-stage clinical data who went on to develop distant metastases and utilized the platform-extracted data to assess associations between time to distant metastasis (TDM) and early-stage tumor histology, molecular type, and germline BRCA status.

Results

The platform-extracted data for the validation cohort had 97.6% precision (91.98%-100% by variable type) and 81.48% recall (58.15%-95.00% by variable type) compared to manual chart review. In our discovery cohort, the shortest TDM was significantly associated with metaplastic (739.0 days) and inflammatory histologies (1005.8 days), HR−/HER2− molecular types (1187.4 days), and positive BRCA status (1042.5 days) as compared to other histologies, molecular types, and negative BRCA status, respectively. Multivariable analyses did not produce statistically significant results.

Discussion

The precision and recall of platform-extracted clinical data are reported, although specificity could not be assessed. The data can generate clinically-relevant insights.

Conclusion

The structured real-world data produced by a novel patient-mediated, medical record-extraction platform are reliable and can power clinical discovery.
Functional response and predation rate of Cryptolaemus montrouzieri (Coleoptera: Coccinellidae) to Paracoccus marginatus (Hemiptera: Pseudococcidae) at different temperatures
Authors: Rostami Elahe , Huang Dao-Ling , Shi Meng-Zhu , Zheng Li-Zhen , Li Jian-Yu , Madadi Hossein , Fu Jian-Wei
Published: May 2024

The ladybug, Cryptolaemus montrouzieri (Mulsant) (Coleoptera: Cocccinellidae)(Mulsant)(Coleoptera: Cocccinellidae), is a highly efficient predator in controlling mealybug populations and is considered an effective agent for controlling the papaya mealybugs (Paracoccus marginatus) (Williams & Granara de Willink) (Hemiptera: Pseudococcidae). Various criteria have been proposed for evaluating predator effectiveness, with the consumption rate of prey by individual predators, specifically the functional response, emerging as a common and crucial metric. This study evaluated the functional responses of third- and fourth-instar larvae, as well as male and female adults (<48 h old) of C. montrouzieri to adult females of P. marginatus at 3 different temperatures (22 °C, 28 °C, and 35 °C) with 70% ± 5% RH and a 12L:12D h photoperiod. Prey densities were 2, 4, 8, 16, 32, 45, or 60 papaya mealybugs per predator for all tests. The response to prey density by third- and fourth-instar larvae or both sexes of adult C. montrouzieri was a type II at all temperatures. The highest attack rate and lowest handling time were estimated at 28 °C in males and 35 °C in females, respectively. The highest daily prey consumption rate occurred at 35 °C in both the immature and adult stages of C. montrouzieri. These findings support the potential of C. montrouzieri in controlling the papaya mealybug, especially in tropical and subtropical regions, given its search efficiency at high temperatures tested in this study. However, additional field investigations are needed to ascertain the control efficacy of C. montrouzieri for this mealybug in biocontrol programs.
Eschewing the discretionary court-based approach to child maintenance in Singapore: towards a consistent and predictable legal framework
Authors: Tan Ming Ren
Published: May 2024

Divorcing parents generally agree that they should maintain their children. What they often disagree on, however, is the quantification and apportionment of child maintenance. Put simply, how should child maintenance be quantified? After quantifying child maintenance, how should child maintenance be apportioned between the parents? Should the apportionment be numerically equal? Or should the apportionment be numerically different, and if so, how? Although these are deceptively simple questions, they have no easy answers. Unlike jurisdictions such as the UK and Australia, which rely on administrative agencies for the determination of child maintenance, Singapore serves as an interesting case study in that it adopts a discretionary court-based approach to child maintenance against the backdrop of an absence of child maintenance guidelines that could potentially guide the courts in their exercise of discretion. In this regard, this article critiques Singapore’s discretionary court-based approach to child maintenance and advances a consistent and predictable legal framework that the courts can apply when dealing with child maintenance disputes in the interests of promoting certainty and reducing acrimony between divorcing parents.
Ultrasound-Guided Lidocaine Injection as a Novel Predictor of Response to Botulinum for Patients With Myofascial Pain Syndrome: A Case Report
Authors: Agee Olivia A , Leggit Jeffery C
Published: May 2024

Botulinum injection is a well-known non-surgical intervention utilized in the management of myofascial pain syndrome (MPS). However, sparse evidence exists regarding the utility of ultrasound guidance of injectate or lidocaine as a predictive marker of patient response to botulinum toxin A (BTX-A). A 39-year-old male active duty service member demonstrated typical signs and symptoms of MPS. He reported a 10-year history of neck and back spasms that were triggered by exertion but also could occur spontaneously. Based on the characteristic regional motor-sensory defects, treatment options were discussed. With shared decision-making, the patient opted to try ultrasound-guided injection of lidocaine followed by xenomin brand BotoxA. Immediately following lidocaine injection, the patient reported complete relief of symptoms. Both injections were uncomplicated, and the patient reported great reduction in symptoms during the subsequent visit 2 months later. Relief of pain following ultrasound-guided injection of lidocaine may serve as an indicator of successful patient response to BTX-A in patients with MPS.
Disability Claims for Female Veterans Exposed to Contaminated Water at Marine Base Camp Lejeune
Authors: Weaver Frances M , Cao Lishan , Stroupe Kevin T , Pratt Alessandra , Tanner Caroline M , Goldman Samuel M
Published: May 2024

Introduction

Between 1953 and 1987, over one million Veterans were exposed to contaminated water at Marine Corps Base Camp Lejeune, North Carolina. We examined the relationship between toxicant exposure and subsequent disability ratings in female veterans.

Materials and Methods

Comparisons were made between females stationed at Camp Lejeune and from Marine Corps Base Camp Pendleton, California who were not known to have been exposed to these toxicants, between 1975 and 1985, using data from the Agency for Toxic Substances and Diseases Registry and VA data.

Results

A total of 4,491 (52%) females from Camp Lejeune and 2,811 (47%) from Camp Pendleton used VA health care between October 1, 1999 and February 17, 2021. Approximately 51% of Camp Lejeune females were exposed to toxicants. More than half (50.6% and 53.9% from Lejeune and Pendleton, respectively) had a disability rating ≥10%. Females who were Black, Hispanic, officers, or had longer duration in camp were more likely to have a disability rating, whereas females exposed to toxicants were less likely to have a disability rating. When the regression was redone examining the predictors of disability due to any of 8 presumptive conditions associated with toxicant exposure, the only significant variable was having been at Camp Lejeune (odds ratio [OR], 2.5, 95% CI, 1.3–4.7). Toxicant exposure was not significant when only Camp Lejeune females were included in the model.

Conclusion

Little attention has been given to female veterans exposed to toxicants at Camp Lejeune. Although we did not find an association between exposure and disability ratings, reliance on service-connected disability codes and small numbers were limitations. Further examination using international code of diseases diagnostic codes may be warranted.
The disparity in pediatric spinal cord tumor clinical trials: A scoping review of registered clinical trials from 1989 to 2023
Authors: Villanueva Obed Posada , Papadakis Joanna E , Mosher Amanda M , Cooney Tabitha , Fehnel Katie P
Published: May 2024

Background

Spinal cord tumors (SCTs) comprise 10% of all central nervous system (CNS) tumors. Pediatric SCTs are often excluded and underrepresented in clinical trials though exclusion rates haven’t been reported.

Methods

We reviewed all interventional clinical trials recruiting patients <21 years with SCTs on ClinicalTrials.gov between 1989 and 2023.

Results

Five hundred and two CNS tumor trials were identified, of which 255 included SCTs and/or spincal metastases. Among these, 96.5% were open to all CNS tumors (brain or spine); however, only 3.5% were exclusive to spine tumors. One trial was specific to pediatric spine tumors (inclusive of bone, soft tissue, and neural tumors); no trial was specific to primary pediatric SCTs. Most trials were located in North America, with multisite investigations being more common than single-institution designs. Trials frequently evaluated interventions/treatments (89%), supportive care/quality of life measures (7.1%), or diagnostic protocols (3.1%). Among included treatment paradigms, systemic therapies using cytotoxic chemotherapies, targeted therapies, and/or immunotherapies were more common among brain/spine trials, while radiotherapy, surgical adjuncts, and/or local drug delivery more frequently occurred in spinal tumor trials.

Conclusions

Though SCTs comprise 10% of pediatric CNS tumors, they remain underrepresented in clinical trials. This lack of trials specific to advancing pediatric SCTs management highlights an area of clinical and research need.
Severe Mpox Among People With Advanced Human Immunodeficiency Virus Receiving Prolonged Tecovirimat in New York City
Authors: Garcia Elizabeth A , Foote Mary M K , McPherson Tristan D , Lash Maura K , Bosompem Amma N , Bouscaren Alyssa , Chan Justin , DiLorenzo Madeline A , Feihel Dennis , Fowler Randal C , Gandhi Vani , Jenny-Avital Elizabeth R , Kopping Erik J , Mazo Dana , McLean Jacob , Mgbako Ofole , Sayegh Mark N , Shaw Raphael N , Su Michelle , Meissner Jeanne Sullivan , Wang Jade C , Wen Wendy , Winters John C , Zeana Cosmina B , Zucker Jason , Wong Marcia
Published: May 2024

Severe mpox has been observed in people with advanced human immunodeficiency virus (HIV). We describe clinical outcomes of 13 patients with advanced HIV (CD4 <200 cells/μL), severe mpox, and multiorgan involvement. Despite extended tecovirimat courses and additional agents, including vaccinia immune globulin, cidofovir, and brincidofovir, this group experienced prolonged hospitalizations and high mortality.
ALMA 2D super-resolution imaging of Taurus–Auriga protoplanetary disks: Probing statistical properties of disk substructures
Authors: Yamaguchi Masayuki , Muto Takayuki , Tsukagoshi Takashi , Nomura Hideko , Hirano Naomi , Nakazato Takeshi , Ikeda Shiro , Tamura Motohide , Kawabe Ryohei
Published: May 2024

In the past decade, ALMA observations of protoplanetary disks revealed various substructures including gaps and rings. Their origin of substructures may be probed through statistical studies of their physical properties. We present the analyses of archival ALMA Band 6 continuum data of 43 disks (39 Class II and four Herbig Ae) in the Taurus–Auriga region. We employ a novel 2D super-resolution imaging technique based on sparse modeling to obtain images with high fidelity and spatial resolution. As a result, we have obtained images with spatial resolutions comparable to a few au (${0_{.}^{\prime\prime}02}$–${0_{.}^{\prime\prime}1}$), which is two to three times better than conventional CLEAN methods. All dust disks are spatially resolved, with the radii ranging from 8 to 238 au with a median radius of 45 au. Half of the disks harbor clear gap structures, the radial locations of which show a bimodal distribution with peaks at ≲20 au and ≳30 au. We also see structures indicating weak gaps at all the radii in the disk. We find that the widths of these gaps increase with their depths, which is consistent with the model of planet–disk interactions. The inferred planet mass–orbital radius distribution indicates that the planet distribution is analogous to our solar system. However, planets with Neptune mass or lower may exist in all the radii.
The Beliefs of Nonbelievers: Exclusive Empiricism and Mortal Finitude Among Atheists and Agnostics
Authors: Blankholm Joseph , Cragun Ryan , Hawley Suárez Abraham , Stephen Shakir
Published: May 2024

This essay argues that “atheist” and “agnostic” are not merely negative labels that indicate a person lacks belief in God or is not religious. Relying on a new survey of very secular Americans and the General Social Survey, we demonstrate a statistically significant and substantively meaningful relationship, in both predictive directions, between identifying as atheist or agnostic and holding certain beliefs about how best to know the world and what happens when we die. We can reliably predict that most people in the United States who trust science, reason, and evidence and do not trust religious sources will identify as atheist or agnostic—and vice-versa. We find the same bi-directional relationship with belief in mortal finitude, i.e., that death is the final end. Our findings suggest that exclusive empiricism and mortal finitude are positive tenets of belief systems that those who identify as atheist or agnostic are likely to hold.
Religion Lived In-Between. Time, Space, and Religious Practices of Roman Catholic Women in Poland
Authors: Szwed Anna
Published: May 2024

The article focuses on the role of time and space in the religious practices of Roman Catholic women. It aims to demonstrate not only how the spatial-temporal conditions of everyday life shape religious practices, but also how the space and time for practicing religion are produced as a result of practices. The article also shows how religious and other practices compete for limited spatial-temporal resources, contributing to the transformation of religious practices by incorporating new materials, technologies, and meanings. Based on the results of qualitative research among Roman Catholic women in Poland and using the praxeological lived religion approach, the analysis shows that religion is lived by women in-between—interwoven in temporal and spatial terms between other practices, either dominated by them or sometimes gaining a monopoly. The shape of religion in everyday life, therefore, does not only depend solely on the dynamics of religious practices, but also results from tensions between various social practices.