bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial
Authors: Garcia-Prats Anthony J , Svensson Elin M , Winckler Jana , Draper Heather R , Fairlie Lee , van der Laan Louvina E , Masenya Masebole , Schaaf H Simon , Wiesner Lubbe , Norman Jennifer , Aarnoutse Rob E , Karlsson Mats O , Denti Paolo , Hesseling Anneke C
Published: September 2021

Background

Rifampicin doses of 40 mg/kg in adults are safe and well tolerated, may shorten anti-TB treatment and improve outcomes, but have not been evaluated in children.

Objectives

To characterize the pharmacokinetics and safety of high rifampicin doses in children with drug-susceptible TB.

Patients and methods

The Opti-Rif trial enrolled dosing cohorts of 20 children aged 0–12 years, with incremental dose escalation with each subsequent cohort, until achievement of target exposures or safety concerns. Cohort 1 opened with a rifampicin dose of 15 mg/kg for 14 days, with a single higher dose (35 mg/kg) on day 15. Pharmacokinetic data from days 14 and 15 were analysed using population modelling and safety data reviewed. Incrementally increased rifampicin doses for the next cohort (days 1–14 and day 15) were simulated from the updated model, up to the dose expected to achieve the target exposure [235 mg/L·h, the geometric mean area under the concentration–time curve from 0 to 24 h (AUC0–24) among adults receiving a 35 mg/kg dose].

Results

Sixty-two children were enrolled in three cohorts. The median age overall was 2.1 years (range = 0.4–11.7). Evaluated doses were ∼35 mg/kg (days 1–14) and ∼50 mg/kg (day 15) for cohort 2 and ∼60 mg/kg (days 1–14) and ∼75 mg/kg (day 15) for cohort 3. Approximately half of participants had an adverse event related to study rifampicin; none was grade 3 or higher. A 65–70 mg/kg rifampicin dose was needed in children to reach the target exposure.

Conclusions

High rifampicin doses in children achieved target exposures and the doses evaluated were safe over 2 weeks.
Population pharmacokinetics of the rilpivirine long-acting formulation after intramuscular dosing in healthy subjects and people living with HIV
Authors: Neyens M , Crauwels H M , Perez-Ruixo J J , Rossenu S
Published: September 2021

Objectives

To characterize the population pharmacokinetics of the rilpivirine long-acting (LA) formulation after intramuscular administration.

Methods

Rich and sparse rilpivirine plasma concentration data were obtained from seven clinical studies. In total, 18 261 rilpivirine samples were collected from 986 subjects (131 healthy subjects from Phase I studies and 855 people living with HIV from Phase IIb/III studies). Doses ranged from 300 to 1200 mg, as single-dose or multiple-dose regimens (every 4 or 8 weeks). In Phase III studies, an initiation injection of 900 mg followed by continuation injections of 600 mg every 4 weeks was used. Non-linear mixed-effects modelling was performed using NONMEM® software.

Results

A one-compartment model with linear elimination and two parallel absorption pathways (fast and slow) with sequential zero-first-order processes adequately captured rilpivirine flip-flop pharmacokinetics after intramuscular administration of the LA formulation. The estimated apparent elimination half-life of rilpivirine LA was 200 days. None of the evaluated covariates (age, body weight, BMI, sex, race, health status and needle length) had a clinically relevant impact on rilpivirine pharmacokinetics.

Conclusions

The population pharmacokinetic model suitably describes the time course and associated variability of rilpivirine plasma concentrations after rilpivirine LA intramuscular administration. The monthly regimen consists of an oral lead-in period (rilpivirine 25 mg tablets once daily for 4 weeks), followed by an initiation injection of 900 mg rilpivirine LA, then 600 mg rilpivirine LA continuation injections monthly. The absence of a clinically relevant effect of covariates on rilpivirine pharmacokinetics suggests that rilpivirine LA dose adjustments for specific subgroups are not warranted.
Molecular analysis of an increase in trimethoprim/sulfamethoxazole-resistant MRSA reveals multiple introductions into a tertiary care hospital, Germany 2012–19
Authors: Nurjadi Dennis , Klein Sabrina , Hannesen Julius , Heeg Klaus , Boutin Sébastien , Zanger Philipp
Published: September 2021

Objectives

Increasing spread of resistance could jeopardize the use of antifolates against MRSA infections.

Methods

We compared the prevalence of phenotypic trimethoprim/sulfamethoxazole resistance in 20 534 clinical Staphylococcus aureus isolates (19 096 MSSA and 1438 MRSA) of non-redundant patients at Heidelberg University Hospital over 8 years and performed WGS on trimethoprim/sulfamethoxazole-resistant MRSA.

Results

From 2012 to 2019, trimethoprim/sulfamethoxazole resistance in MSSA (674/19 096; 3.5%) ranged between 1.5% and 7.2% and in MRSA (135/1438; 9.4%) between 0.5% and 20.2%, reaching a peak in 2016 and 2018, respectively (Ptrend < 0.001). Trimethoprim/sulfamethoxazole resistance was more likely in outpatients than inpatients (P = 0.005), younger patients (P < 0.001), skin and soft tissue infections (SSTIs) (MRSA only, P = 0.05), submissions from pulmonology (MRSA only, P = 0.001), the upper respiratory tract (MSSA only, P < 0.001) and general surgery (MSSA only, P = 0.001). WGS of 76 trimethoprim/sulfamethoxazole-resistant MRSA revealed that 59% belonged to major pandemic CA-MRSA clones (ST22, ST8, ST398, ST772, ST30), 47% harboured Panton–Valentine leucocidin (PVL), 97% SCCmec IV/V, 71% dfrG and 28% dfrA. SNP-based phylogeny of trimethoprim/sulfamethoxazole-resistant MRSA core genomes favoured independent introduction over clonal expansion as the source, most prominently of dfrA+ trimethoprim/sulfamethoxazole-resistant ST22 MRSA from the Gaza Strip.

Conclusions

The presented results support that trimethoprim/sulfamethoxazole-resistant S. aureus, formerly associated with SSTI from outpatients and S. aureus in the (sub)tropics, is on the rise in the temperate zone, potentially due to migration. Closer monitoring of trimethoprim/sulfamethoxazole resistance in S. aureus is recommended to safeguard the effectiveness of antifolate compounds.
The use of first-generation cephalosporin antibiotics, cefalexin and cefradine, is not associated with induction of simulated Clostridioides difficile infection
Authors: Buckley Anthony M , Moura Ines B , Altringham James , Ewin Duncan , Clark Emma , Bentley Karen , Wilkinson Vikki , Spittal William , Davis Georgina , Wilcox Mark H
Published: September 2021

Objectives

The use of broad-spectrum cephalosporins is associated with induction of Clostridioides difficile infection (CDI). Recent knowledge on the importance of the healthy microbiota in preventing pathogen colonization/outgrowth highlights the caution needed when prescribing broad-spectrum antibiotics. The use of historical narrow-spectrum antibiotics, such as first-generation cephalosporins, is gaining increased attention once more as they have a reduced impact on the microbiota whilst treating infections. Here, the effects of two first-generation cephalosporins, compared with a third-generation cephalosporin, on the human microbiota were investigated and their propensity to induce simulated CDI.

Methods

Three in vitro chemostat models, which simulate the physiochemical conditions of the human colon, were seeded with a human faecal slurry and instilled with either narrow-spectrum cephalosporins, cefalexin and cefradine, or a broad-spectrum cephalosporin, ceftriaxone, at concentrations reflective of colonic levels.

Results

Instillation of cefalexin was associated with reduced recoveries of Bifidobacterium and Enterobacteriaceae; however, Clostridium spp. recoveries remained unaffected. Cefradine exposure was associated with decreased recoveries of Bifidobacterium spp., Bacteroides spp. and Enterobacteriaceae. These changes were not associated with induction of CDI, as we observed a lack of C. difficile spore germination/proliferation, thus no toxin was detected. This is in contrast to a model exposed to ceftriaxone, where CDI was observed.

Conclusions

These model data suggest that the minimal impact of first-generation cephalosporins, namely cefalexin and cefradine, on the intestinal microbiota results in a low propensity to induce CDI.
Child Labour and the Arrival of Refugees: Evidence from Tanzania
Authors: Kofol Chiara , Naghsh Nejad Maryam
Published: September 2021

Despite efforts to reduce the incidence of child labour, about one in three children in Sub-Saharan Africa works. Using data for the Kagera region of Tanzania, we estimate how rates of child labour were impacted by a large influx of refugees fleeing from genocide in both Rwanda and Burundi. We find that the areas most affected by this population shock initially had a lower incidence of child labour. However, 10 years later, children in these areas were more likely to work on a farm and participate in domestic chores as the demand for agricultural labour increased.
From Divergence to Convergence: The Role of Intermediaries in Developing Competition Laws in ASEAN
Authors: Ng Wendy
Published: September 2021

Despite the diversity of contexts and circumstances in which competition laws are developed and exist, many countries have enacted competition laws that are broadly similar. To learn more about the dynamics shaping the development of competition law at the national, regional, and international levels, this article investigates the development of competition law in the Association of Southeast Asian Nations (ASEAN) region, a region whose competition laws remain underexplored. This article undertakes a case study on the drafting of competition law in the ASEAN member states with the most recently drafted and/or enacted new comprehensive competition laws, that being Brunei Darussalam, Cambodia, Lao PDR, Myanmar, and the Philippines. It finds that, while there were differences in the processes of drafting and enacting competition law in these countries as well as in their local contexts, their competition laws are similar in many respects. The case study also finds that intermediaries facilitated the processes of translation and adaptation that occurred in developing competition law in these ASEAN member states. This article argues that the important role that intermediaries played in developing competition laws was a key reason for the broad convergence of these competition laws across their diverse local settings.
Overcome Isomer Interference in 1α,25-Dihydroxyvitamin D Quantitation by Liquid Chromatography-Tandem Mass Spectrometry
Authors: Jin Zhicheng , Bertholf Roger L , Yi Xin
Published: September 2021

Background

The circulating concentration of 1α,25-dihydroxyvitamin D [1α,25(OH)2D] is very low, and the presence of multiple isomers may lead to inaccurate quantitation if not separated prior to analysis. Antibody-based immunoextraction procedures are sometimes used to remove structurally related isomers of 1α,25(OH)2D prior to an LC-MS/MS analysis. However, immunoextraction increases sample preparation time and cost. In addition, some dihydroxyvitamin D metabolites are not completely removed by immunoextraction.

Method

We developed an HPLC method using a phenyl-hexyl column to investigate interfering isomers of 1α,25(OH)2D.

Result

Using this method, 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) derivatization product of 1α,25(OH)2D was found to be present as 2 epimers, which were separated chromatographically with an area ratio of 2:1. PTAD derivatized metabolite of 25-hydroxyvitamin D3 [i.e., 4β,25-dihydroxyvitamin D3 (4β,25(OH)2D3)] eluted out between 6R and 6S epimers of derivatized 1α,25(OH)2D3. If not chromatographically resolved, 4β,25(OH)2D can affect 1α,25(OH)2D quantitation. In a method comparison study, it was found that the presence of 4β,25(OH)2D produced positive bias up to 127% on 1α,25(OH)2D3 quantitation.

Conclusion

The LC-MS/MS method we developed without an immunoextraction procedure was able to resolve the major interference peak from 1α,25(OH)2D and achieved reliable quantitation of 1α,25(OH)2D.
Practical Clinical Applications of Islet Autoantibody Testing in Type 1 Diabetes
Authors: Winter William E , Pittman David L , Jialal Ishwarlal
Published: September 2021

Background

The distinction between type 1 diabetes (T1D) and type 2 diabetes (T2D) is extremely important for the choice of therapy, body weight and dietary management, screening for coexistent autoimmune diseases and comorbidities, anticipated prognosis, and risk assessment in relatives. Not uncommonly, the presentation of the patient may not allow an unambiguous discrimination between T1D and T2D. To help resolve this challenge, the detection of islet autoantibodies can support the diagnosis of T1D.

Content

The presence of islet autoantibodies in a person with diabetes indicates an autoimmune etiology therefore establishing the diagnosis of T1D. Presently 5 islet autoantibodies are available for routine clinical use: islet cell cytoplasmic autoantibodies (ICA), insulin autoantibodies (IAA), glutamic acid decarboxylase autoantibodies (GADA), insulinoma associated-2 autoantibodies (IA-2A), and zinc transporter-8 autoantibodies (ZnT8A). There are caveats to the selection of which islet autoantibodies should be measured. Islet autoantibodies can also predict the development of T1D. Therefore, once safe and effective therapies are available to prevent T1D, islet autoantibody testing is expected to become a routine part of medical practice. A very rare cause of autoimmune diabetes is the type B insulin resistance syndrome resulting from antagonistic autoantibodies to the insulin receptor. Rarely hypoglycemia can result from agonistic insulin receptor autoantibodies, or high-titer IAA causing the autoimmune insulin syndrome (i.e., Hirata disease).

In summary, autoimmune causes of dysglycemia are increasing in clinical importance requiring the scrutiny of laboratorians. The determination of islet autoantibodies can greatly aid in the diagnosis and the prediction of T1D.
Digital health needs for implementing high-quality primary care: recommendations from the National Academies of Sciences, Engineering, and Medicine
Authors: Krist Alex H , Phillips Robert , Leykum Luci , Olmedo Benjamin
Published: September 2021

A National Academies of Sciences, Engineering, and Medicine committee developed a plan to implement high-quality primary care. One of the 5 key objectives was designing information technology that serves the patient, family, and interprofessional care team. The committee defined high-quality primary care as the provision of whole person, integrated, accessible, and equitable healthcare by interprofessional teams who are accountable for addressing most of an individual’s health across settings and through sustained relationships. The committee recommended 2 essential actions for digital health. The first action is developing the next phase of digital health certification standards that support relationship-based, continuous, person-centered care; simplify user experience; ensure equitable access; and hold vendors accountable. Second, the committee recommended adopting a comprehensive aggregate patient data system usable by any certified digital health tool. This article reviews primary care’s digital health needs and describes successful digital health for primary care.
Revealing Unknown Controlled Substances and New Psychoactive Substances Using High-Resolution LC–MS-MS Machine Learning Models and the Hybrid Similarity Search Algorithm
Authors: Lee So Yeon , Lee Sang Tak , Suh Sungill , Ko Bum Jun , Oh Han Bin
Published: September 2021

High-resolution liquid chromatography–tandem mass spectrometry (LC--MS-MS)-based machine learning models are constructed to address the analytical challenge of identifying unknown controlled substances and new psychoactive substances (NPSs). Using a training set composed of 770 LC–MS-MS barcode spectra (with binary entries 0 or 1) obtained generally by high-resolution mass spectrometers, three classification machine learning models were generated and evaluated. The three models are artificial neural network (ANN), support vector machine (SVM) and k-nearest neighbor (k-NN) models. In these models, controlled substances and NPSs were classified into 13 subgroups (benzylpiperazine, opiate, benzodiazepine, amphetamine, cocaine, methcathinone, classical cannabinoid, fentanyl, 2C series, indazole carbonyl compound, indole carbonyl compound, phencyclidine and others). Using 193 LC–MS-MS barcode spectra as an external test set, accuracy of the ANN, SVM and k-NN models were evaluated as 72.5%, 90.0% and 94.3%, respectively. Also, the hybrid similarity search (HSS) algorithm was evaluated to examine whether this algorithm can successfully identify unknown controlled substances and NPSs whose data are unavailable in the database. When only 24 representative LC–MS-MS spectra of controlled substances and NPSs were selectively included in the database, it was found that HSS can successfully identify compounds with high reliability. The machine learning models and HSS algorithms are incorporated into our home-coded artificial intelligence screener for narcotic drugs and psychotropic substances standalone software that is equipped with a graphic user interface. The use of this software allows unknown controlled substances and NPSs to be identified in a convenient manner.
Effects of cryptochrome-modulating compounds on circadian behavioural rhythms in zebrafish
Authors: Iida Mui , Nakane Yusuke , Yoshimura Takashi , Hirota Tsuyoshi
Published: September 2021

The circadian clock controls daily rhythms of various physiological processes, and impairment of its function causes many diseases including sleep disorders. Chemical compounds that regulate clock function are expected to be applied for treatment of circadian clock-related diseases. We previously identified small-molecule compounds KL001, KL101 and TH301 that lengthen the period of cellular circadian clock by directly targeting clock proteins cryptochromes (CRYs) in mammals. KL001 targets both CRY1 and CRY2 isoforms, while KL101 and TH301 are isoform-selective compounds and require CRY C-terminal region for their effects. For further application of these compounds, the effects on locomotor activity rhythms at the organismal level need to be investigated. Here we used zebrafish larvae as an in vivo model system and found that KL001 lengthened the period of locomotor activity rhythms in a dose-dependent manner. In contrast, KL101 and TH301 showed no effect on the period. The amino acid sequences of CRY C-terminal regions are diverged in zebrafish and mammals, supporting the importance of this region for the effects of KL101 and TH301. This study demonstrated efficacy of CRY modulation for controlling circadian behavioural rhythms in organisms and suggested species-dependent differences in the effects of isoform-selective CRY-modulating compounds.
Selling Time: Multiple Temporalities in the Promotion of Danish Design Classics
Authors: Munch Anders V , Jensen Hans-Christian
Published: September 2021

The promotion of design classics was established in Denmark in the 1960s, turning Danish Modern into a tradition, and today it is carried out through institutionalized discourses and multiple temporalities, as we show in the cases of the Wishbone Chair and the Vipp brand. There has been much critique of the canonization of design classics, but little research literature on the concept itself, compared to related concepts such as icons or retro. Drawing on theories from design historiography, sociology, material culture studies and the hermeneutic philosophy of history to examine ageing objects, temporal values and non-synchronicity, these cases sketch multiple layers of temporality, offering very different experiences and values depending on how much engagement, knowledge and time the consumer might be able to invest. That classics are mainly praised as timeless objects stands against a promotion loaded with temporal layers of age, memory and history.
Renegotiating Sectarian Space through the Realia and Monasteries of Early Medieval Bengal
Authors: Fleming Benjamin J.
Published: September 2021

This article considers the practices about ‘the special dead’ related to the monastery at Pāhāṛpur (‘Hill--town’) in the Rājshāhī region of North--Western Bangladesh. This Early Medieval community was rich in religious diversity from the Gupta to Pāla periods—dense with evidence of Jain, Hindu, and Buddhist activity. There are a number of stūpa structures throughout the grounds for the burial of revered teachers and leaders such that the living comingled with the dead in an academic and religious setting. The Pāla era monastery was dedicated to advanced learning, meditation, worship, student housing, and burial. At the centre of the monastery is a large stūpa that has been celebrated widely for its diverse imagery in the form of terracotta plaques and relief sculptures with Hindu, Buddhist, and Jain themes. This article focuses on the reception history of this site and especially on its unique role as a mediator of religious voices from the region’s past. Under Dharmapāla, the site became branded as Buddhist as part of a broader imperial effort to promote Buddhist networks. Locally, however, the site maintained and promoted relationships to Hindu and Jain communities as well as Buddhist ones. Its endurance as a sacred site through complex interreligious permutations is intriguing though not surprising. Death and learning were not separated. Evidence from Pāhāṛpur raises questions about the communities who lived there as well as our understanding of their approach to death in practice in the Bengal region.
The Professional Market of International Criminal Justice
Authors: Christensen Mikkel Jarle
Published: September 2021

This article analyses the division of labour and patterns of elite reproduction that characterize international criminal justice as a market of services. Using a sociological framework and building on empirical data on 996 professional agents, the analysis outlines how the market in and around the international criminal courts is structured by three different social groups that dominate the formal roles of judges, prosecutors and defence counsel. The article investigates the relative positionality of these groups highlighting the low degree of mobility between them. It also demonstrates the reproduction of male, global north professionals at the top of these groups, pointing towards intersectional dynamics of inclusion and exclusion in this market. To deepen the analysis of divisions of labour and reproduction of status, the article turns to a closer analysis of the patterns of expertise upon which elite status is built and how it links the three groups to the wider market of international criminal justice. The relations between the identified social groups, the elite of which have very particular characteristics dominated by global north professionals, educations and networks, structure a core part of the market of international criminal justice and formats the social fault lines behind its normative debates.
Higher serum alkaline phosphatase value indicates the need for bone mineral density testing in non-metastatic prostate cancer patients undergoing androgen deprivation therapy
Authors: Hagiwara Kanade , Sakamoto Akihiko , Sasaki Kenichi , Kanatani Atsushi , Kimura Masaki , Kaneko Tomoyuki , Takahashi Sayuri , Yamada Yukio , Nakagawa Tohru
Published: September 2021

Purpose

Osteoporosis is a well-known adverse effect of androgen deprivation therapy for prostate cancer. This study aimed to reveal the factors associated with the diagnosis of osteoporosis in prostate cancer patients undergoing androgen deprivation therapy.

Methods

This retrospective cross-sectional study included 106 prostate cancer patients treated with androgen deprivation therapy. Patients with bone metastasis at the initiation of androgen deprivation therapy and those with castration-resistant prostate cancer were excluded. Bone mineral density was measured at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Osteoporosis was defined as bone mineral density equal to or below either −2.5 SD or 70% of the mean in young adults. The association between clinicopathological variables and bone mineral density or diagnosis of osteoporosis was investigated.

Results

Thirty-six (34%) patients were found to have osteoporosis. The incidence of osteoporosis increased in a stepwise manner depending on the duration of androgen deprivation therapy. Multivariate logistic regression analysis identified a longer duration of androgen deprivation therapy (months, odd’s ratio = 1.017, P = 0.006), lower body mass index (kg/m2, odd’s ratio = 0.801, P = 0.005) and higher serum alkaline phosphatase value (U/l, odd’s ratio 1.007, P = 0.014) as the factors independently associated with the diagnosis of osteoporosis. Eleven out of 50 (22%), 14 out of 35 (40%) and 11 out of 20 patients (55%) were osteoporotic in the patients with serum alkaline phosphatase values <238 U/l, 238–322 U/l and >322 U/l, respectively (P = 0.022).

Conclusions

Osteoporosis is common in prostate cancer patients undergoing androgen deprivation therapy; furthermore, its incidence increases depending on the duration of androgen deprivation therapy. Bone mineral density testing should be considered for all patients on androgen deprivation therapy, especially for those with a lower body mass index and higher serum alkaline phosphatase value.
Reevaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials
Authors: Yin Jun , Salem Mohamed E , Dixon Jesse G , Jin Zhaohui , Cohen Romain , DeGramont Aimery , Van Cutsem Eric , Taieb Julien , Alberts Steven R , Wolmark Norman , Schmoll Hans-Joachim , Saltz Leonard B , George Thomas J , Goldberg Richard R M , Kerr Rachel , Lonardi Sara , Yoshino Takayuki , Yothers Greg , Grothey Axel , Andre Thierry , Shi Qian
Published: September 2021

Background

Disease-free survival (DFS) with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival (OS) with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence in patients who received adjuvant FOLFOX. Hence, reevaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed.

Methods

Individual patient data from 9 randomized studies conducted between 1998 and 2009 were included; 3 trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (RWLS2) and Copula bivariate (RCopula2) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation.

Results

Data from a total of 18 396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (T1-3 and N1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high or deficient mismatch repair tumors. Trial-level correlation between 3-year DFS and 5-year OS remained strong (RWLS2 = 0.82, 95% CI = 0.67 to 0.98; RCopula2 = 0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results.

Conclusions

Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.
Cannabis and the Cancer Patient
Authors: Braun Ilana M , Abrams Donald I , Blansky Stacey E , Pergam Steven A
Published: September 2021

Session 2 of the National Cancer Institute’s Cannabis, Cannabinoids, and Cancer Research Workshop opened with testimony from a lymphoma survivor who detailed medicinal cannabis-related improvements in nausea, low appetite, insomnia, and mental health and the limited clinical counsel she received regarding cannabis use. Discussion next turned to the evolution of the legal landscape of cannabis in the United States, one in which state and federal laws frequently conflict and the Controlled Substance Act renders cannabis Schedule I. This legal climate creates conundrums for US medicinal cannabis researchers who contend with limited funding opportunities, avenues to source trial drug, and procedural red tape and for oncology clinicians who recommend medicinal cannabis to patients with some frequency while perceiving themselves as ill equipped to make such clinical recommendations. Ultimately, it creates challenges for cancer patients who find themselves turning to nonmedical and anecdotal information sources. The risks of cannabis use by the cancer patient were discussed next. These include infection, pharmacodynamic and pharmacokinetic drug-botanical interactions, cyclic nausea and vomiting, e-cigarette or vaping product use–associated illness, legal issues, and high cost. The session concluded with a broad survey of the research supporting oncologic cannabinoid use, conclusive evidence for chemotherapy-induced nausea and vomiting, and suggestive evidence for cancer-related pain.
Repair pathways for radiation DNA damage under normoxic and hypoxic conditions: Assessment with a panel of repair-deficient human TK6 cells
Authors: Tsuda Masataka , Shimizu Naoto , Tomikawa Hinako , Morozumi Ryosuke , Ide Hiroshi
Published: September 2021

Various types of DNA lesions are produced when cells are exposed to ionizing radiation (IR). The type and yield of IR-induced DNA damage is influenced by the oxygen concentration. Thus, different DNA repair mechanisms may be involved in the response of normoxic and hypoxic cells to irradiation with IR. However, differences between the repair mechanisms of IR-induced DNA damage under normoxic versus hypoxic conditions have not been clarified. Elucidating the relative contribution of individual repair factors to cell survival would give insight into the repair mechanisms operating in irradiated normoxic and hypoxic cells. In the present study, we used a panel of repair-deficient human TK6 cell lines that covered seven repair pathways. Cells were irradiated with X-rays under normoxic and hypoxic conditions, and the sensitivities of each mutant relative to the wild-type (i.e. relative sensitivity) were determined for normoxic and hypoxic conditions. The sensitivity of cells varied depending on the type of repair defects. However, for each repair mutant, the relative sensitivity under normoxic conditions was comparable to that under hypoxic conditions. This result indicates that the relative contribution of individual repair pathways to cell survival is comparable in normoxic and hypoxic cells, although the spectrum of IR-induced DNA damage in hypoxic cells differs from that of normoxic cells.
Study of feasible and safe condition for total body irradiation using cardiac implantable electronic devices
Authors: Matsubara Hiroaki , Ezura Takatomo , Hashimoto Yaichiro , Karasawa Kumiko , Nishio Teiji , Tsuneda Masato
Published: September 2021

Cardiac implantable electronic devices (CIEDs) were believed to have a tolerance dose and that direct irradiation has to be avoided. Thus, no clinical guidelines have mentioned the feasibility of total body irradiation (TBI) with a CIED directly. The purpose of this work was to study a feasible and safe condition for TBI using a CIED. Eighteen CIEDs were directly irradiated by a 6-MV X-ray beam, where a non-neutron producible beam was employed for the removal of any neutron contribution to CIED malfunction. Irradiation up to 10 Gy in accumulated dose was conducted with a 100-cGy/min dose rate, followed by up to 20 Gy at 200 cGy/min. An irradiation test of whether inappropriate ventricular shock therapy was triggered or not was also performed by using a 6-MV beam of 5, 10, 20 and 40 cGy/min to two CIEDs. No malfunction was observed during irradiation up to 20 Gy at 100 and 200 cGy/min without activation of shock therapy. These results were compared with typical TBI, suggesting that a CIED in TBI will not encounter malfunction because the prescribed dose and the dose rate required for TBI are much safer than those used in this experiment. Several inappropriate shock therapies were, however, observed even at 10 cGy/min if activated. The present result suggested that TBI was feasible and safe if a non-neutron producible beam was employed at low dose-rate without activation of shock therapy, where it was not inconsistent with clinical and non-clinical data in the literature. The feasibility of TBI while using a CIED was discussed for the first time.
Lumbar radiculopathy due to foraminal stenosis with ossification of the ligamentum flavum: a case report
Authors: Ushio Shuta
Published: September 2021

The patient was an 82-year-old woman with a diagnosis of lumbar radiculopathy due to foraminal stenosis accompanied by ossification of the ligamentum flavum (OLF). Computed tomography scans of the lumbar spine revealed ossification in the capsular portion of the ligamentum flavum around the L2–L3 facet joint. In addition, computed tomography images acquired a few months before the onset of radiculopathy had shown that the ossification site had gradually expanded to include the superior articular process. The patient’s symptoms disappeared immediately after excision of the OLF. Histopathological examination of the resected specimen indicated replacement of degenerated ligamentum flavum with ossified tissue via a gradual endochondral ossification process. It is important to be aware that foraminal stenosis can in rare cases occur due to OLF, even in the lumbar spine.
Hepatectomy using a combination of extrafascial extrahepatic (Takasaki approach) and extrafascial intrahepatic pedicle approaches (Ton That Tung approach)
Authors: Van Ha Quyet , Nguyen Toan Huy , Van Nguyen Huong , Le Xuan Anh , Tran Kinh Huy
Published: September 2021

Selective pedicle control and anatomical liver resection are considered standard techniques in hepatectomy for hepatocellular carcinoma. In 1963, Ton That Tung made significant improvements in hepatectomy techniques with the principle of locating and ligation of Glissonean pedicle in the liver parenchyma based on precise knowledge of vascular and biliary anatomy (Tung TT, Quang ND. A new technique for operating on the liver. Lancet 1963;281:192–3). In 1986, the extrafascial Glissonean dissection was first introduced by Takasaki in 1986. This is a simple and safe technique that helps to identify the exact borders between liver sections for anatomic liver resection (Takasaki K. Glissonean pedicle transection method for hepatic resection: a new concept of liver segmentation. J Hepatobiliary Pancreat Surg 1998;5:286–91). The combination of two techniques helps minimize complications, reduce ischemic time of future liver remnant, intraoperative blood loss and avoid migration of cancer cells into other segments.
Litrre’s hernia: partially reduced inguinal hernia in a 3-year-old boy
Authors: Gawrieh Bardisan , Shater Waseem , Deeb Mohammad Ali , Ghuzlan Alaa , Kassab Hanna , Salhab Nabila
Published: September 2021

This report examines the case of a 3-year-old child presenting with a 1-month history of swelling in the right groin. The boy had no associated nausea or vomiting, was afebrile and had had normal bowel movements. Attempts to reduce the swelling were only partially successful. Ultrasonography indicated the presence of turbid hydrocele and a hernia sac containing an intestinal loop. Accordingly, the patient underwent an urgent herniotomy. Exposing the hernia sac revealed 5 cm Meckel’s diverticulum, and the base of the diverticulum was resected from the inside of the hernia sac. The boy was discharged 4 days after the operation in good clinical condition. The presented case highlights the need to consider Littre’s hernia when dealing with partially reduced inguinal hernias in children with no general signs or evidence of intestinal obstruction.
Posterior classical caesarean section in a myomatous gravid uterus at term: a case report
Authors: Makwe Christian C , Ugwu Aloy O , Osuji Gabriel N , Anumni Chinedu , Ekor Oluwayemisi E , Asiyanbi Gabriel K
Published: September 2021

We present a case of a 30-year-old primigravida, at 38-week gestation, who had a posterior classical uterine incision due to a huge anterior wall leiomyoma associated with uterine torsion and breech presentation. The rarity of this type of uterine incision, the size of the uterine myoma and the uterine torsion prompted this case report.

During caesarean section, the diagnoses of uterine torsion and a huge anterior wall leiomyoma were made. She had safe delivery of the fetus through a posterior classical caesarean section. The patient had an uneventful post-operative period and was discharged home with her baby on the fourth post-operative day.
Surgical repair of severely incompetent quadricuspid truncal valve
Authors: Sandoval Boburg Rodrigo , Mustafi Migdat , Hofbeck Michael , Schlensak Christian
Published: September 2021

The surgical management of truncus arteriosus poses a constant challenge for the cardiac team treating the patient. A correct diagnosis, surgical therapy and post-operative management are crucial for the survival of the patient. Almost 30% of the patients show an abnormal number of leaflets in the truncal valve (TV), the majority being quadricuspid valves. Additionally, around 25% of the patients show some degree of TV incompetence. We demonstrate an effective way to reconstruct incompetent, quadricuspid valves with good post-operative outcome.
Duplication of the urethra in an adult male presenting with scrotal fistula: a rare case report
Authors: Tlili Ghassen , Ahmed Khaled ben , Acacha Emir , Taghrid Tlili , Ktari Kamel , Wiem Majdoub , Jaidane Mehdi , Saad Hamadi
Published: September 2021

Urethral duplication is a rare congenital abnormality with varied clinical manifestations; to this day, <300 cases were reported in the literature. It is affecting mainly males and is nearly always diagnosed in childhood or adolescence. It may be complete or incomplete, and the most widely accepted classification of the different types of urethral duplication was developed by Effman et al. Herein, we present a rare case of urethral duplication revealed by scrotal fistula in an adult man. A duplication is an unusual form of Y-type duplication: it is an incomplete urethral duplication urethra opening on the scrotum without communication with the urethra or bladder.
Challenges of Virtual RDS for Recruitment of Sexual Minority Women for a Behavioral Health Study
Authors: Middleton Deirdre , Drabble Laurie A , Krug Deborah , Karriker-Jaffe Katherine J , Mericle Amy A , Hughes Tonda L , Iachan Ronaldo , Trocki Karen F
Published: September 2021

Respondent-driven sampling (RDS) is an approach commonly used to recruit nonprobability samples of rare and hard-to-find populations. The purpose of this study was to explore the utility of phone- and web-based RDS methodology to sample sexual minority women (SMW) for participation in a telephone survey. Key features included (i) utilizing a national probability survey sample to select seeds; (ii) web-based recruitment with emailed coupons; and (iii) virtual processes for orienting, screening, and scheduling potential participants for computer-assisted telephone interviews. Rather than resulting in a large diverse sample of SMW, only a small group of randomly selected women completed the survey and agreed to recruit their peers, and very few women recruited even one participant. Only seeds from the most recent of two waves of the probability study generated new SMW recruits. Three RDS attempts to recruit SMW over several years and findings from brief qualitative interviews revealed four key challenges to successful phone- and web-based RDS with this population. First, population-based sampling precludes sampling based on participant characteristics that are often used in RDS. Second, methods that distance prospective participants from the research team may impede development of relationships, investment in the study, and motivation to participate. Third, recruitment for telephone surveys may be impeded by multiple burdens on seeds and recruits (e.g., survey length, understanding the study and RDS process). Finally, many seeds from a population-based sample may be needed, which is not generally feasible when working with a limited pool of potential seeds. This method may yield short recruitment chains, which would not meet key RDS assumptions for approximation of a probability sample. In conclusion, potential challenges to using RDS in studies with SMW, particularly those using virtual approaches, should be considered.
Interviewer Effects in Live Video and Prerecorded Video Interviewing
Authors: West Brady T , Ong Ai Rene , Conrad Frederick G , Schober Michael F , Larsen Kallan M , Hupp Andrew L
Published: September 2021

Live video (LV) communication tools (e.g., Zoom) have the potential to provide survey researchers with many of the benefits of in-person interviewing, while also greatly reducing data collection costs, given that interviewers do not need to travel and make in-person visits to sampled households. The COVID-19 pandemic has exposed the vulnerability of in-person data collection to public health crises, forcing survey researchers to explore remote data collection modes—such as LV interviewing—that seem likely to yield high-quality data without in-person interaction. Given the potential benefits of these technologies, the operational and methodological aspects of video interviewing have started to receive research attention from survey methodologists. Although it is remote, video interviewing still involves respondent–interviewer interaction that introduces the possibility of interviewer effects. No research to date has evaluated this potential threat to the quality of the data collected in video interviews. This research note presents an evaluation of interviewer effects in a recent experimental study of alternative approaches to video interviewing including both LV interviewing and the use of prerecorded videos of the same interviewers asking questions embedded in a web survey (“prerecorded video” interviewing). We find little evidence of significant interviewer effects when using these two approaches, which is a promising result. We also find that when interviewer effects were present, they tended to be slightly larger in the LV approach as would be expected in light of its being an interactive approach. We conclude with a discussion of the implications of these findings for future research using video interviewing.
The advent of social media influencer tourism: travel health risks and opportunities
Authors: Mangan Ryan M , Flaherty Gerard T
Published: September 2021

The authors assert that social media influencer tourism should be recognized as a novel entity in travel medicine, in order to protect this vulnerable group of travellers from harm to themselves and their host destinations, and to harness their potential as communicators of positive public health messages.
Karl Barth and Nostra Aetate: New Evidence from the Second Vatican Council
Authors: Herskowitz Daniel M
Published: September 2021

This essay exposes and discusses Karl Barth’s previously unknown involvement in the Second Vatican Council debates over the document on the Jews, which would soon be commonly known as Chapter IV of Nostra Aetate, and argues for its importance for our understanding of Barth’s personal and theological attitude towards Jews and Judaism. Drawing on unknown archival material, it demonstrates Barth’s deep familiarity with all of the main drafts of the document and his awareness of the various forces, both internal and external to the Catholic Church, trying to influence its theological message. It also reveals and analyses a three-page interpretation of the textual history of the document on the Jews written by Barth himself, in which he assesses its various drafts and considers a request from the Jewish committee involved with the Council to approach the Pope personally on their behalf. Lastly, it argues that this episode sheds important light on Barth’s understanding of the accusation of Jewish ‘deicide’ and his doctrine of Israel more generally, both complementing and furthering what is presented in Church Dogmatics, Ad Limina Apostolorum, and elsewhere.
The quiescent centre and root apical meristem: organization and function
Authors: Dubrovsky Joseph G , Vissenberg Kris
Published: September 2021

This special issue is dedicated to the 100th anniversary of the birth of Frederick Albert Lionel Clowes, who discovered the quiescent centre (QC) of the root apical meristem (RAM). His discovery was a foundation for contemporary studies of the QC and RAM function, maintenance, and organization. RAM function is fundamental for cell production and root growth. This special issue bundles reviews on the main tendencies, hypotheses, and future directions, and identifies unknowns in the field.
Exploring Spanish contemporary song lyrics through Digital Humanities methods: Some thematic and structural properties
Authors: Hernández-Lorenzo Laura , Diaz Aitor , Perez Alvaro , Ros Salvador , González-Blanco Elena
Published: September 2021

In this article, we present a quantitative study with Digital Humanities methods on an extensive corpus of Spanish contemporary song lyrics, a type of text related to poetry. On the one hand, poetry and songs not only have been connected since their origins, but they share some characteristics, such as the division in lines or the use of rhymes. On the other hand, Digital Humanities quantitative approaches have already been applied to poetry, but we still lack a study in the same fashion for lyrics. Taking advantage of the advances in automatic scansion and syllabification, rhyme detection, or Topic Modeling technologies, the present study analyzes Spanish contemporary song lyrics’ main thematic and structural properties, comparing them with those used in poetic texts. Our results offered new insights into the characteristics of the analyzed texts and their connections to poetic ones.
On probabilistic argumentation and subargument-completeness
Authors: Riveret Régis , Oren Nir
Published: September 2021

Probabilistic argumentation combines probability theory and formal models of argumentation. Given an argumentation graph where vertices are arguments and edges are attacks or supports between arguments, the approach of probabilistic labellings relies on a probability space where the sample space is any specific set of argument labellings of the graph, so that any labelling outcome can be associated with a probability value. Argument labellings can feature a label indicating that an argument is not expressed, and in previous work these labellings were constructed by exploiting the subargument-completeness postulate according to which if an argument is expressed then its subarguments are expressed and through the use of the concept of ‘subargument-complete subgraphs’. While the use of such subgraphs is interesting to compare probabilistic labellings with other works in the literature, it may also hinder the comprehension of a relatively simple framework. In this short communication, we revisit the construction of probabilistic labellings and demonstrate how labellings can be specified without reference to the concept of subargument-complete subgraphs. By doing so, the framework is simplified and yields a more natural model of argumentation.
Maximality of bi-intuitionistic propositional logic
Authors: Olkhovikov Grigory , Badia Guillermo
Published: September 2021

In the style of Lindström’s theorem for classical first-order logic, this article characterizes propositional bi-intuitionistic logic as the maximal (with respect to expressive power) abstract logic satisfying a certain form of compactness, the Tarski union property and preservation under bi-asimulations. Since bi-intuitionistic logic introduces new complexities in the intuitionistic setting by adding the analogue of a backwards looking modality, the present paper constitutes a non-trivial modification of the previous work done by the authors for intuitionistic logic (Badia and Olkhovikov, 2020, Notre Dame Journal of Formal Logic, 61, 11–30).