bluuebunny/crossref_metadata_2025 huggingface dataset:
Unravelling the limb regeneration mechanisms of Polypedates maculatus, a sub-tropical frog, by transcriptomics
Authors: Mahapatra Cuckoo , Naik Pranati , Swain Sumanta Kumar , Mohapatra Pratyush Paradarsita
Published: March 2023

Background

Regeneration studies help to understand the strategies that replace a lost or damaged organ and provide insights into approaches followed in regenerative medicine and engineering. Amphibians regenerate their limbs effortlessly and are indispensable models to study limb regeneration. Xenopus and axolotl are the key models for studying limb regeneration but recent studies on non-model amphibians have revealed species specific differences in regeneration mechanisms.

Results

The present study describes the de novo transcriptome of intact limbs and three-day post-amputation blastemas of tadpoles and froglets of the Asian tree frog Polypedates maculatus, a non-model amphibian species commonly found in India. Differential gene expression analysis between early tadpole and froglet limb blastemas discovered species-specific novel regulators of limb regeneration. The present study reports upregulation of proteoglycans, such as epiphycan, chondroadherin, hyaluronan and proteoglycan link protein 1, collagens 2,5,6, 9 and 11, several tumour suppressors and methyltransferases in the P. maculatus tadpole blastemas. Differential gene expression analysis between tadpole and froglet limbs revealed that in addition to the expression of larval-specific haemoglobin and glycoproteins, an upregulation of cysteine and serine protease inhibitors and downregulation of serine proteases, antioxidants, collagenases and inflammatory genes in the tadpole limbs were essential for creating an environment that would support regeneration. Dermal myeloid cells were GAG+, EPYC+, INMT+, LEF1+ and SALL4+ and seemed to migrate from the unamputated regions of the tadpole limb to the blastema. On the other hand, the myeloid cells of the froglet limb blastemas were few and probably contributed to sustained inflammation resulting in healing.

Conclusions

Studies on non-model amphibians give insights into alternate tactics for limb regeneration which can help devise a plethora of methods in regenerative medicine and engineering.
Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer’s disease
Authors: Shekarian Meysam , Salehi Iraj , Raoufi Safoura , Asadbegi Masoumeh , Kourosh-Arami Masoumeh , Komaki Alireza
Published: March 2023

Background

Vinpocetine (Vin) is known as a phosphodiesterase 1 inhibitor (PDE1-I) drug with multilateral effects, including antioxidant and anti-inflammatory activity. In this research, we investigated the neuroprotective and therapeutic effects of Vin through hippocampal synaptic plasticity on a rat’s model of Alzheimer’s disease (AD) induced by an intracerebroventricular (ICV) injection of beta-amyloid (Aβ).

Methods

Sixty adult male Wistar rats were randomly divided into six groups: 1. control, 2. sham, 3. Aβ, 4. pretreatment (Vin + Aβ): Vin (4 mg/kg, gavage) for 30 days and then, inducing an AD model by an ICV injection of Aβ(1–42), 5. treatment (Aβ + Vin): inducing an AD model and then receiving Vin for 30 days by gavage, and 7. pretreatment + treatment (Vin + Aβ + Vin): receiving Vin by gavage for 30 days before and 30 days after the induction of an AD model. After these procedures, via stereotaxic surgery, the stimulating electrodes were placed at the perforant pathway (PP) and the recording electrodes were implanted in the dentate gyrus.

Results

Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the Aβ group meaningfully diminished compared to the control group after the induction of long-term potentiation (LTP).

Conclusions

Vin could significantly prevent the Aβ effects on LTP. It can be concluded that pretreatment and treatment with Vin can be neuroprotective against harmful consequences of Aβ on hippocampal synaptic plasticity.
Factors influencing the timeliness of care for patients with lung cancer in Bangladesh
Authors: Ansar Adnan , Lewis Virginia , McDonald Christine Faye , Liu Chaojie , Rahman Muhammad Aziz
Published: March 2023

Background

This study explored the factors associated with timeliness of care in the healthcare seeking pathway among patients with lung cancer in Bangladesh.

Methods

A structured questionnaire was used for data collection from 418 patients with lung cancer through face-to-face interviews in three tertiary care hospitals. Log-rank tests were performed to test differences in the length of intervals between points in healthcare by socioeconomic characteristics and care seeking behaviours of the patients. Cox Proportional Hazard (PH) regression analysis was performed to identify the predictors of the intervals after adjustment for variations in other variables.

Results

A higher education level was associated significantly (p < 0.05) with a shorter interval between first contact with a healthcare provider (HCP) and diagnosis (median 81 days) and initiation of treatment (median 101 days). Higher monthly household income was associated significantly with a shorter time from first contact and diagnosis (median 91 days), onset of symptom and diagnosis (median 99 days), onset of symptom and treatment (median 122 days), and first contact with any HCP to treatment (median 111 days). Consulting with additional HCPs prior to diagnosis was associated significantly with longer intervals from first contact with any HCP and diagnosis (median 127 days), onset of symptom and diagnosis (median 154 days), onset of symptom and treatment (median 205 days), and first contact with any HCP to treatment (median 174 days). Consulting with informal HCPs was associated significantly with a longer time interval from symptom to treatment (median 171 days). Having more than one triggering symptom was associated significantly with a shorter interval between onset of symptoms and first contact with any HCP.

Conclusion

The predictors for timeliness of lung cancer care used in this study affected different intervals in the care seeking pathway. Higher education and income predicted shorter intervals whereas consulting informal healthcare providers and multiple providers were associated with longer intervals.
Predicting health services utilization using a score of perceived barriers to medical care: evidence from rural Senegal
Authors: Coste Marion , Bousmah Marwân-al-Qays
Published: March 2023

Background

Ensuring access to healthcare services is a key element to achieving the Sustainable Development Goal 3 of “promoting healthy lives and well-being for all” through Universal Health Coverage (UHC). However, in the context of low- and middle-income countries, most studies focused on financial protection measured through catastrophic health expenditures (CHE), or on health services utilization among specific populations exhibiting health needs (such as pregnancy or recent sickness).

Methods

This study aims at building an individual score of perceived barriers to medical care (PBMC) in order to predict primary care utilization (or non-utilization). We estimate the score on six items: (1) knowing where to go, (2) getting permission, (3) having money, (4) distance to the facility, (5) finding transport, and (6) not wanting to go alone, using individual data from 1787 adult participants living in rural Senegal. We build the score via a stepwise descendent explanatory factor analysis (EFA), and assess its internal consistency. Finally, we assess the construct validity of the factor-based score by testing its association (univariate regressions) with a wide range of variables on determinants of healthcare-seeking, and evaluate its predictive validity for primary care utilization.

Results

EFA yields a one-dimensional score combining four items with a 0.7 Cronbach’s alpha indicating good internal consistency. The score is strongly associated—p-values significant at the 5% level—with determinants of healthcare-seeking (including, but not limited to, sex, education, marital status, poverty, and distance to the health facility). Additionally, the score can predict non-utilization of primary care at the household level, utilization and non-utilization of primary care following an individual’s episode of illness, and utilization of primary care during pregnancy and birth. These results are robust to the use of a different dataset.

Conclusion

As a valid, sensitive, and easily documented individual-level indicator, the PBMC score can be a complement to regional or national level health services coverage to measure health services access and predict utilization. At the individual or household level, the PBMC score can also be combined with conventional metrics of financial risk protection such as CHE to comprehensively document deficits in, and progress towards UHC.
Synaptic modifications transform neural networks to function without oxygen
Authors: Amaral-Silva Lara , Santin Joseph M.
Published: March 2023

Background

Neural circuit function is highly sensitive to energetic limitations. Much like mammals, brain activity in American bullfrogs quickly fails in hypoxia. However, after emergence from overwintering, circuits transform to function for approximately 30-fold longer without oxygen using only anaerobic glycolysis for fuel, a unique trait among vertebrates considering the high cost of network activity. Here, we assessed neuronal functions that normally limit network output and identified components that undergo energetic plasticity to increase robustness in hypoxia.

Results

In control animals, oxygen deprivation depressed excitatory synaptic drive within native circuits, which decreased postsynaptic firing to cause network failure within minutes. Assessments of evoked and spontaneous synaptic transmission showed that hypoxia impairs synaptic communication at pre- and postsynaptic loci. However, control neurons maintained membrane potentials and a capacity for firing during hypoxia, indicating that those processes do not limit network activity. After overwintering, synaptic transmission persisted in hypoxia to sustain motor function for at least 2 h.

Conclusions

Alterations that allow anaerobic metabolism to fuel synapses are critical for transforming a circuit to function without oxygen. Data from many vertebrate species indicate that anaerobic glycolysis cannot fuel active synapses due to the low ATP yield of this pathway. Thus, our results point to a unique strategy whereby synapses switch from oxidative to exclusively anaerobic glycolytic metabolism to preserve circuit function during prolonged energy limitations.
Exogenous mitochondrial transplantation improves survival and neurological outcomes after resuscitation from cardiac arrest
Authors: Hayashida Kei , Takegawa Ryosuke , Endo Yusuke , Yin Tai , Choudhary Rishabh C. , Aoki Tomoaki , Nishikimi Mitsuaki , Murao Atsushi , Nakamura Eriko , Shoaib Muhammad , Kuschner Cyrus , Miyara Santiago J. , Kim Junhwan , Shinozaki Koichiro , Wang Ping , Becker Lance B.
Published: March 2023

Background

Mitochondrial transplantation (MTx) is an emerging but poorly understood technology with the potential to mitigate severe ischemia–reperfusion injuries after cardiac arrest (CA). To address critical gaps in the current knowledge, we test the hypothesis that MTx can improve outcomes after CA resuscitation.

Methods

This study consists of both in vitro and in vivo studies. We initially examined the migration of exogenous mitochondria into primary neural cell culture in vitro. Exogenous mitochondria extracted from the brain and muscle tissues of donor rats and endogenous mitochondria in the neural cells were separately labeled before co-culture. After a period of 24 h following co-culture, mitochondrial transfer was observed using microscopy. In vitro adenosine triphosphate (ATP) contents were assessed between freshly isolated and frozen-thawed mitochondria to compare their effects on survival. Our main study was an in vivo rat model of CA in which rats were subjected to 10 min of asphyxial CA followed by resuscitation. At the time of achieving successful resuscitation, rats were randomly assigned into one of three groups of intravenous injections: vehicle, frozen-thawed, or fresh viable mitochondria. During 72 h post-CA, the therapeutic efficacy of MTx was assessed by comparison of survival rates. The persistence of labeled donor mitochondria within critical organs of recipient animals 24 h post-CA was visualized via microscopy.

Results

The donated mitochondria were successfully taken up into cultured neural cells. Transferred exogenous mitochondria co-localized with endogenous mitochondria inside neural cells. ATP content in fresh mitochondria was approximately four times higher than in frozen-thawed mitochondria. In the in vivo survival study, freshly isolated functional mitochondria, but not frozen-thawed mitochondria, significantly increased 72-h survival from 55 to 91% (P = 0.048 vs. vehicle). The beneficial effects on survival were associated with improvements in rapid recovery of arterial lactate and glucose levels, cerebral microcirculation, lung edema, and neurological function. Labeled mitochondria were observed inside the vital organs of the surviving rats 24 h post-CA.

Conclusions

MTx performed immediately after resuscitation improved survival and neurological recovery in post-CA rats. These results provide a foundation for future studies to promote the development of MTx as a novel therapeutic strategy to save lives currently lost after CA.
Relative role of border restrictions, case finding and contact tracing in controlling SARS-CoV-2 in the presence of undetected transmission: a mathematical modelling study
Authors: Pung Rachael , Clapham Hannah E. , Russell Timothy W. ,   CMMID COVID-19 Working Group, Lee Vernon J. , Kucharski Adam J.
Published: March 2023

Background

Understanding the overall effectiveness of non-pharmaceutical interventions to control the COVID-19 pandemic and reduce the burden of disease is crucial for future pandemic planning. However, quantifying the effectiveness of specific control measures and the extent of missed infections, in the absence of early large-scale serological surveys or random community testing, has remained challenging.

Methods

Combining data on notified local COVID-19 cases with known and unknown sources of infections in Singapore with a branching process model, we reconstructed the incidence of missed infections during the early phase of the wild-type SARS-CoV-2 and Delta variant transmission. We then estimated the relative effectiveness of border control measures, case finding and contact tracing when there was no or low vaccine coverage in the population. We compared the risk of ICU admission and death between the wild-type SARS-CoV-2 and the Delta variant in notified cases and all infections.

Results

We estimated strict border control measures were associated with 0.2 (95% credible intervals, CrI 0.04–0.8) missed imported infections per notified case between July and December 2020, a decline from around 1 missed imported infection per notified case in the early phases of the pandemic. Contact tracing was estimated to identify 78% (95% CrI 62–93%) of the secondary infections generated by notified cases before the partial lockdown in Apr 2020, but this declined to 63% (95% CrI 56–71%) during the lockdown and rebounded to 78% (95% CrI 58–94%) during reopening in Jul 2020. The contribution of contact tracing towards overall outbreak control also hinges on ability to find cases with unknown sources of infection: 42% (95% CrI 12–84%) of such cases were found prior to the lockdown; 10% (95% CrI 7–15%) during the lockdown; 47% (95% CrI 17–85%) during reopening, due to increased testing capacity and health-seeking behaviour. We estimated around 63% (95% CrI 49–78%) of the wild-type SARS-CoV-2 infections were undetected during 2020 and around 70% (95% CrI 49–91%) for the Delta variant in 2021.

Conclusions

Combining models with case linkage data enables evaluation of the effectiveness of different components of outbreak control measures, and provides more reliable situational awareness when some cases are missed. Using such approaches for early identification of the weakest link in containment efforts could help policy makers to better redirect limited resources to strengthen outbreak control.
Light at night and cause-specific mortality risk in Mainland China: a nationwide observational study
Authors: Lu Yao , Yin Peng , Wang Jie , Yang Yiping , Li Fei , Yuan Hong , Li Shenxin , Long Zheng , Zhou Maigeng
Published: March 2023

Background

While epidemiological studies have found correlations between light at night (LAN) and health effects, none has so far investigated the impacts of LAN on population mortality yet. We aimed to estimate the relative risk for mortality from exposure to LAN in Mainland China.

Methods

This time-stratified case-crossover nationwide study used NPP-VIIRS to obtain daily LAN data of Mainland China between 2015 and 2019. The daily mortality data were obtained from the Disease Surveillance Point System in China. Conditional Poisson regression models were applied to examine the relative risk (RR) for mortality along daily LAN in each county, then meta-analysis was performed to combine the county-specific estimates at the national or regional level.

Results

A total of 579 counties with an average daily LAN of 4.39 (range: 1.02–35.46) were included in the main analysis. The overall RRs per 100 nW/cm2/sr increases in daily LAN were 1.08 (95%CI: 1.05–1.11) for all-cause mortality and 1.08 (95%CI: 1.05–1.11) for natural-cause mortality. A positive association between LAN and all natural cause-specific mortality was observed, of which the strongest effect was observed on mortality caused by neuron system disease (RR = 1.32, 95%CI: 1.14–1.52). The results were robust in both younger and old, as well as in males and females. The more pronounced effect of LAN was observed in median LAN-level regions. Combined with an exposure–response curve, our study suggests a non-linear association between LAN and mortality in China.

Conclusions

Our study shows LAN is associated with mortality in China, particularly for neuron system disease-related mortality. These findings have important implications for public health policy establishment to minimize the health consequences of light pollution.
CVOT Summit 2022 Report: new cardiovascular, kidney, and glycemic outcomes
Authors: Schnell Oliver , Battelino Tadej , Bergenstal Richard , Birkenfeld Andreas L. , Ceriello Antonio , Cheng Alice , Davies Melanie , Edelman Steve , Forst Thomas , Giorgino Francesco , Green Jennifer , Groop Per-Henrik , Hadjadj Samy , J.L.Heerspink Hiddo , Hompesch Marcus , Izthak Baruch , Ji Linong , Kanumilli Naresh , Mankovsky Boris , Mathieu Chantal , Miszon Martin , Mustafa Reem , Nauck Michael , Pecoits-Filho Roberto , Pettus Jeremy , Ranta Kari , Rodbard Helena W. , Rossing Peter , Ryden Lars , Schumm-Draeger Petra-Maria , Solomon Scott D. , Škrha Jan , Topsever Pinar , Vilsbøll Tina , Wilding John , Standl Eberhard
Published: March 2023

The 8th Cardiovascular Outcome Trial (CVOT) Summit on Cardiovascular, Kidney, and Glycemic Outcomes was held virtually on November 10–12, 2022. Following the tradition of previous summits, this reference congress served as a platform for in-depth discussion and exchange on recently completed outcomes trials as well as key trials important to the cardiovascular (CV) field. This year’s focus was on the results of the DELIVER, EMPA-KIDNEY and SURMOUNT-1 trials and their implications for the treatment of heart failure (HF) and chronic kidney disease (CKD) with sodium-glucose cotransporter-2 (SGLT2) inhibitors and obesity with glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonists. A broad audience of primary care physicians, diabetologists, endocrinologists, cardiologists, and nephrologists participated online in discussions on new consensus recommendations and guideline updates on type 2 diabetes (T2D) and CKD management, overcoming clinical inertia, glycemic markers, continuous glucose monitoring (CGM), novel insulin preparations, combination therapy, and reclassification of T2D. The impact of cardiovascular outcomes on the design of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) trials, as well as the impact of real-world evidence (RWE) studies on the confirmation of CVOT outcomes and clinical trial design, were also intensively discussed. The 9th Cardiovascular Outcome Trial Summit will be held virtually on November 23–24, 2023 (http://www.cvot.org).
Role of microglia in HIV-1 infection
Authors: Bai Ruojing , Song Chengcheng , Lv Shiyun , Chang Linlin , Hua Wei , Weng Wenjia , Wu Hao , Dai Lili
Published: March 2023

The usage of antiretroviral treatment (ART) has considerably decreased the morbidity and mortality related to HIV-1 (human immunodeficiency virus type 1) infection. However, ART is ineffective in eradicating the virus from the persistent cell reservoirs (e.g., microglia), noticeably hindering the cure for HIV-1. Microglia participate in the progression of neuroinflammation, brain aging, and HIV-1-associated neurocognitive disorder (HAND). Some methods have currently been studied as fundamental strategies targeting microglia. The purpose of this study was to comprehend microglia biology and its functions in HIV-1 infection, as well as to look into potential therapeutic approaches targeting microglia.
Sickness absenteeism among primary health care workers in Qatar before and during the COVID-19 pandemic
Authors: Al-Nuaimi Asma Ali , Abdeen Sami , Abed Alah Muna , AlHajri Sameera , Semaan Sandy , Al-Kuwari Mohamed Ghaith
Published: March 2023

Objectives

To explore the patterns, trends, nature, and extent of changes in sickness absence among health care workers (HCWs) at the Primary Health Care Corporation (PHCC) in Qatar-during the COVID-19 pandemic compared to previous years and uncover the main associated factors.

Methods

We conducted a retrospective analysis of all sick leaves’ records of PHCC HCWs regardless of their profession from January 2019 till August 2021.

Results

A total of 41,132 sick leaves were taken during the studied period. The majority of HCWs who availed sick leaves were between 30–39 years (45.9%), females (65.1%), and expatriates (65.1%). Compared with pre-COVID-19 (Jan 2019-Feb 2020), Wave 1 of COVID-19 had significantly less incidence of sick leaves per day per 1000 HCWs. While wave 2 had significantly higher incidence of sick leaves compared to both pre-COVID-19 and wave 1. The number of sick leaves per person among female HCWs was significantly higher than that of male HCWs. Moreover, the number of sick leaves per person among locals were about two times the number among expatriate HCWs. Physicians and nurses had significantly lower number of sick leave per person compared to other professions. The rates of sick leaves due to suspected or confirmed COVID-19 infection, back/neck pain and gastroenteritis were significantly higher in the second wave compared to the first wave of COVID-19.

Conclusion

Overall and cause specific sick leave rates among HCWs varied significantly across different periods of the COVID-19 pandemic. COVID-19 related sick leave rate was higher during the second wave compared to first one. By addressing the root causes of sick leaves, it is possible to reduce the burden on HCWs and ensure their continued ability to provide essential care to those in need.
Effect of antenatal milk expression education on lactation outcomes in birthing people with pre-pregnancy body mass index ≥25: protocol for a randomized, controlled trial
Authors: Demirci Jill R. , Glasser Melissa , Bogen Debra L. , Sereika Susan M. , Ren Dianxu , Ray Kristin , Bodnar Lisa M. , O’Sullivan Therese A. , Himes Katherine
Published: March 2023

Background

Birthing people with pre-pregnancy body mass indices (BMIs) ≥ 25 kg/m2, particularly those without prior breastfeeding experience, are at increased risk for suboptimal lactation outcomes. Antenatal milk expression (AME) may be one way to counteract the negative effects of early infant formula supplementation common in this population.

Methods

This ongoing, randomized controlled trial in the United States evaluates the efficacy of a telelactation-delivered AME education intervention versus an attention control condition on lactation outcomes to 1 year postpartum among 280 nulliparous-to-primiparous, non-diabetic birthing people with pre-pregnancy BMI ≥ 25 kg/m2. The assigned study treatment is delivered via four weekly online video consultations between gestational weeks 37–40. Participants assigned to AME meet with study personnel and a lactation consultant to learn and practice AME. Instructions are provided for home practice of AME between study visits. Control group participants view videos on infant care/development at study visits. Participants complete emailed surveys at enrollment (340/7–366/7gestational weeks) and 2 weeks, 6 weeks, 12 weeks, 6 months, and 12 months postpartum. Surveys assess lactation and infant feeding practices; breastfeeding self-efficacy, attitudes, and satisfaction; perception of insufficient milk; onset of lactogenesis-II; lactation support and problems; and reasons for breastfeeding cessation. Surveys also assess factors associated with lactation outcomes, including demographic characteristics, health problems, birth trauma, racial discrimination, and weight stigma. Health information and infant feeding data are abstracted from the pregnancy and birth center electronic health record. Milk samples are collected from the intervention group at each study visit and from both groups at each postpartum follow-up for future analyses. Qualitative interviews are conducted at 6 weeks postpartum to understand AME experiences. Primary outcomes of interest are breastfeeding exclusivity and breastfeeding self-efficacy scores at 2 weeks postpartum. Outcomes will be examined longitudinally with generalized linear mixed-effects modeling.

Discussion

This is the first adequately powered trial evaluating the effectiveness of AME among U.S. birthing people and within a non-diabetic population with pre-pregnancy BMI ≥ 25 kg/m2. This study will also provide the first evidence of acceptability and effectiveness of telelactation-delivered AME.

Trial registration

ClinicalTrials.gov: NCT04258709.
Brain malformations in diprosopia observed in clinical cases, museum specimens and artistic representations
Authors: Rehder Helga , Kircher Susanne G. , Schoner Katharina , Smogavec Mateja , Behunova Jana , Ihm Ulrike , Plassmann Margit , Hofer Manuel , Ringl Helmut , Laccone Franco
Published: March 2023

Background

Diprosopus is a rare malformation of still unclear aetiology. It describes a laterally double faced monocephalic and single-trunk individual and has to be distinguished from the variant Janus type diprosopus.

Results

We examined seven double-faced foetuses, five showing true diprosopus, and one each presenting as monocephalic Janiceps and parasitic conjoined twins. Four of the foetuses presented with (cranio)rachischisis, and two had secondary hydrocephaly. Three foetuses showed cerebral duplication with concordant holoprosencephaly, Dandy-Walker cyst and/or intracranial anterior encephalocele. In the Janiceps twins, cerebral duplication was accompanied by cerebral di-symmetry. In the parasitic twins the cyclopic facial aspects were suggestive of concordant holoprosencephaly. In one of the true diprosopus cases, pregnancy was achieved after intracytoplasmic sperm injection. Whole-exome sequencing, perfomed in one case, did not reveal any possible causative variants.The comparison of our double-faced foetuses to corresponding artistic representations from the Tlatilco culture allowed retrospective assignment of hairstyles to brain malformations.

Conclusion

Brain malformations in patients with diprosopus may not be regarded as an independent event but rather as a sequel closely related to the duplication of the notochord and neural plate and as a consequence of the cerebral and associated craniospinal structural instabilities.
The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades
Authors: Jabbour Elias , Short Nicholas J. , Jain Nitin , Haddad Fadi G. , Welch Mary Alma , Ravandi Farhad , Kantarjian Hagop
Published: March 2023

Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B Philadelphia chromosome-negative ALL, the integration of blinatumomab and inotuzumab into the frontline therapy has improved the estimated 3-year survival rate to 85% across all risk categories. Our future strategy is to evaluate the early integration of both immunotherapy agents, inotuzumab and blinatumomab, with low-dose chemotherapy (dose-dense mini-Hyper-CVD-inotuzumab-blinatumomab) into the frontline setting followed by CAR T cells consolidation in high-risk patients, without any further maintenance therapy. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year survival rate to 50%. Among patients ≥ 65–70 years, the mortality in complete remission (CR) is still high and is multifactorial (old age, death in CR with infections, development of myelodysplastic syndrome or acute myeloid leukemia). A chemotherapy-free regimen with inotuzumab and blinatumomab is being investigated. The assessment of measurable residual disease (MRD) by next-generation sequencing (NGS) is superior to conventional assays, with early MRD negativity by NGS being associated with the best survival. We anticipate that the future therapy in B-ALL will involve less intensive and shorter chemotherapy regimens in combination with agents targeting CD19 (blinatumomab), CD20, and CD22 (inotuzumab). The optimal timing and use of CAR T cells therapy may be in the setting of minimal disease, and future trials will assess the role of CAR T cells as a consolidation among high-risk patients to replace allogeneic SCT. In summary, the management of ALL has witnessed significant progress during the past four decades. Novel combination regimens including newer-generation BCR::ABL1 TKIs and novel antibodies are questioning the need and duration of intensive chemotherapy and allogeneic SCT.
Stoichiometric balance ratio of cellobiose and gentiobiose induces cellulase production in Talaromyces cellulolyticus
Authors: Aggarwal Shivam , Dorairaj Sathish , Adlakha Nidhi
Published: March 2023

Background

The exact mechanism by which fungal strains sense insoluble cellulose is unknown, but research points to the importance of transglycosylation products generated by fungi during cellulose breakdown. Here, we used multi-omics approach to identify the transglycosylation metabolites and determine their function in cellulase induction in a model strain,Talaromyces cellulolyticusMTCC25456.

Results

Talaromycessp. is a novel hypercellulolytic fungal strain. Based on genome scrutiny and biochemical analysis, we predicted the presence of cellulases on the surface of its spores. We performed metabolome analysis to show that these membrane-bound cellulases act on polysaccharides to form a mixture of disaccharides and their transglycosylated derivatives. Inevitably, a high correlation existed between metabolite data and the KEGG enrichment analysis of differentially expressed genes in the carbohydrate metabolic pathway. Analysis of the contribution of the transglycosylation product mixtures to cellulase induction revealed a 57% increase in total cellulase. Further research into the metabolites, using in vitro induction tests and response surface methodology, revealed thatTalaromycessp. produces cell wall-breaking enzymes in response to cellobiose and gentiobiose as a stimulant. Precisely, a 2.5:1 stoichiometric ratio of cellobiose to gentiobiose led to a 2.4-fold increase in cellulase synthesis. The application of the optimized inducers in cre knockout strain significantly increased the enzyme output.

Conclusion

This is the first study on the objective evaluation and enhancement of cellulase production using optimized inducers. Inducer identification and genetic engineering boosted the cellulase production in the cellulolytic fungusTalaromycessp.
Lithium levels and lifestyle in patients with bipolar disorder: a new tool for self-management
Authors: Zorrilla I. , Lopez-Zurbano S. , Alberich S. , Barbero I. , Lopez-Pena P. , García-Corres E. , Chart Pascual J. P. , Crespo J. M. , de Dios C. , Balanzá-Martínez V. , Gonzalez-Pinto A.
Published: March 2023

Background

Patients should get actively involved in the management of their illness. The aim of this study was to assess the influence of lifestyle factors, including sleep, diet, and physical activity, on lithium levels in patients with bipolar disorder.

Methods

A multicenter study was performed. In total, 157 lithium measurements were done biweekly in a sample of 65 patients (35 women) over 6 weeks. Lifestyle, based on total sleep hours and physical activity, was assessed by actigraphy. Diet was evaluated using the Mediterranean Lifestyle Index (Medlife).

Results

35.4% of patients had a normal weight. The mean Medlife score was 14.5 (± 2.5) (moderate-good adherence to Mediterranean diet). BMI, daily dose of lithium and intensity of physical activity had a combined effect on lithium levels, after adjustment for other variables. Patients who practiced intense physical exercise, who took lower doses and had a higher BMI exhibited lower levels of lithium.

Conclusions

Higher physical activity and BMI contribute to lower lithium levels. Patients should be made aware of these relationships to improve their perception of control and self-management. Lifestyle-based interventions contribute to establishing a more personalized medicine.
Stopping inappropriate medication of children with intellectual disability, autism or both: the STOMP–STAMP initiative
Authors: Swanepoel Annie , Lovell Mark
Published: March 2023

Children with intellectual disability are often prescribed psychotropic medication to manage behaviours that challenge. Unfortunately, many receive medication with potentially serious long-term side-effects that has been prescribed inappropriately or for longer than is necessary. NHS England launched STOMP (stopping the over-medication of people with intellectual disability, autism or both with psychotropic medicines) in 2016 to reduce the inappropriate prescribing in adults. This was broadened to include children in 2018 by the addition of STAMP (supporting treatment and appropriate medication in paediatrics). In this article we review the rationale for STOMP–STAMP, highlight the Royal College of Psychiatrists’ position statement on STOMP–STAMP and give clinical advice for psychiatrists who treat children with intellectual disability, autism and/or attention-deficit hyperactivity disorder (ADHD). Importantly, it is essential to consider that ADHD may have been missed and that by diagnosing and treating it, the need for inappropriate antipsychotic medication may be reduced.
Effect of Distance From Fertility Center on Utilization of Fertility Preservation Referral in Men
Authors: Pelzman Daniel , Dederer Gregory , Joolharzadeh Pouya , Morrill Christian , Orwig Kyle , Pulaski Hanna , Hwang Kathleen
Published: March 2023

PURPOSE:

Fertility preservation (FP) is underutilized in males with cancer or other diseases requiring gonadotoxic therapies. We sought to evaluate whether patient distance from FP center affected rates of providing a semen analysis after referral.

MATERIALS AND METHODS:

We performed a retrospective analysis of all males who were referred for FP at a single institution between 2013 and 2021. A multiple logistic regression model was conducted with semen sample submission as the variable of interest. Predictor variables were disease type, distance, and payment method. Secondary outcomes were number of semen samples submitted and number of vials collected.

RESULTS:

Records of 461 males referred to our center were analyzed. Of these patients, 326 (71%) provided a semen sample after referral and 135 (30%) did not. Further distance from our center was associated with lower odds of submitting a semen sample (OR, 0.85; 95% CI, 0.75 to 0.97; P < .05). For patients who submitted at least one sample, distance did not affect the total number of samples submitted but was associated with a small increase in total vials cryopreserved.

CONCLUSION:

Men referred for FP exhibit a high rate of sperm cryopreservation. Further distance from FP center was associated with decreased odds to provide semen sample after referral. Our model estimated a 15% decrease in odds of collection with every doubling of distance from our center. Efforts must be made to improve FP utilization for patients traveling far distances, but distance alone should not preclude referral.
Real-world Experience With Neurotrophic Tyrosine Receptor Kinase Fusion–positive Tumors and Tropomyosin Receptor Kinase Inhibitors in Veterans
Authors: Zhou Katherine I. , Vashistha Vishal , Guo Aixia , Ahmed Sara , Kelley Michael J.
Published: March 2023

PURPOSE

Neurotrophic tyrosine receptor kinase 1-3 ( NTRK1-3) gene fusions are found in a broad range of tumor types. Clinical trials demonstrated high response rates to tropomyosin receptor kinase (TRK) inhibitors in NTRK fusion–positive cancers, but few reports have described real-world experience with these targeted agents. We evaluated the prevalence of NTRK fusions and the outcomes with TRK inhibitor therapy in a real-world population of patients in the Veterans Health Administration.

METHODS

Patients with NTRK fusions or rearrangements were identified from the Veterans Affairs (VA) National Precision Oncology Program (NPOP), and patients who were prescribed TRK inhibitors were identified from the Corporate Data Warehouse. Baseline data and clinical outcomes were obtained by retrospective review of medical records.

RESULTS

A total of 33 patients with NTRK fusions or rearrangements were identified, including 25 patients comprising 0.12% of all patients with solid tumors sequenced through VA NPOP. Twelve patients with NTRK fusions or rearrangements were treated with TRK inhibitors, none of whom had objective responses. Eight patients experienced toxicities leading to drug interruption, dose reduction, or discontinuation.

CONCLUSION

In this retrospective study of VA patients, NTRK fusions and rearrangements were less common than in previous studies, and objective responses to TRK inhibitors were not observed. Real-world experience with TRK inhibitors differs markedly from clinical trial findings, possibly due to differences in patient demographics, tumor types, and sequencing methods. Our findings highlight the need to study TRK inhibitors in the real-world setting and in populations underrepresented in clinical trials.
Gauge symmetry of the chiral Schwinger model from an improved gauge unfixing formalism
Authors: Ambrósio Gabriella V. , Costa Cleber N. , Alves Paulo R. F. , Abreu Everton M. C. , Neto Jorge Ananias , Thibes Ronaldo
Published: March 2023

In this paper, the Hamiltonian structure of the bosonized chiral Schwinger model (BCSM) is analyzed. From the consistency condition of the constraints obtained from the Dirac method, we can observe that this model presents, for certain values of the α parameter, two second-class constraints, which means that this system does not possess gauge invariance. However, we know that it is possible to disclose gauge symmetries in such a system by converting the original second-class system into a first-class one. This procedure can be done through the gauge unfixing (GU) formalism by acting with a projection operator directly on the original second-class Hamiltonian, without adding any extra degrees of freedom in the phase space. One of the constraints becomes the gauge symmetry generator of the theory and the other one is disregarded. At the end, we have a first-class Hamiltonian satisfying a first-class algebra. Here, our goal is to apply a new scheme of embedding second-class constrained systems based on the GU formalism, named improved GU formalism, in the BCSM. The original second-class variables are directly converted into gauge invariant variables, called GU variables. We have verified that the Poisson brackets involving the GU variables are equal to the Dirac brackets between the original second-class variables. Finally, we have found that our improved GU variables coincide with those obtained from an improved BFT method after a particular choice for the Wess-Zumino terms.
114 Angiographic Evaluation and Treatment Outcomes in Suspected Cerebrovascular Causes of Pulsatile Tinnitus
Authors: Cummins Daniel Dighton , Caton Michael Travis , Hemphill Kafi , Narsinh Kazim , Tu-Chan Adelyn , Meisel Karl , Amans Matthew
Published: March 2023

INTRODUCTION:

Pulsatile tinnitus (PT) can cause significant detriment to quality of life and may herald a life-threatening cerebrovascular etiology. Digital subtraction angiography (DSA) can both provide a definitive diagnostic etiology of PT and offer endovascular treatment, yet the distribution of causes for PT and treatment efficacies remain to be determined.

METHODS:

Patients suspected to have a cerebrovascular source of PT who were evaluated by endovascular techniques at one large-volume PT center were retrospectively assessed. Baseline clinical features and treatment results by final etiology of PT were compared.

RESULTS:

164 patients who underwent endovascular evaluation of PT were included. Mean age was 54.3 ± 14.1 (25–89 years); 111 patients (67.7%) identified as female; and duration of PT was a median 365 days at presentation (range 11–7665 days). Causes of PT were 75.6% cerebrovascular and 24.4% non-vascular. Arteriovenous shunting lesions caused 20.7% of cases; venous etiologies 48.2%; and arterial etiologies 6.7%. Of patients with a shunting lesion treated endovascularly, 96.9% had lasting significant improvement or resolution in PT. Endovascular treatment was also associated with significant improvement in PT due to venous etiologies (73.4% with endovascular treatment vs 17.2% without; p < 1E-5). Arterial PT (18.2%) and non-vascular etiologies (0%) had fewer patients treated endovascularly and less improvement in PT symptoms.

CONCLUSIONS:

PT with a suspected cerebrovascular cause is most often attributable to venous etiologies. Arteriovenous shunting is a less common etiology of PT, but is the most responsive to treatment, and has the best symptomatic outcomes.
116 Switching from System-Based to Problem-Based Charting Increases the Patient-Specific Expected Mortality Rate and Length of Stay on a Neurosurgery Service
Authors: Ali Rohaid , Hagan Matthew , Tang Oliver Young , Sastry Rahul , O'Brien Jill , Dean Roye G. , Toms Steven A. , Asaad Wael , Doberstein Curtis E. , Oyelese Adetokunbo , Gokaslan Ziya L. , Telfeian Albert Edward
Published: March 2023

INTRODUCTION:

To date, limited research has focused on how charting styles can affect quality metrics in neurosurgery.

METHODS:

We performed a comparative interrupted time-series analysis at an urban, academic, level I trauma center. The intervention consisted of adjusting the charting style from system-based to problem-based charting on an inpatient neurosurgery service line and providing a one-hour educational session targeting improved documentation of three problems with high clinical relevance to neurosurgery.

RESULTS:

Among patients whose providers were exposed to the charting improvement intervention, there was a significant increase in the E-MR (p = 0.029). Average E-LOS also increased to a degree that approached significance (p = 0.085). In a multivariate model adjusting for elective status, length of stay, cost of admission, and hospital associated complications, the increases in both E-MR (p = 0.029) and E-LOS (p = 0.091) persisted. The switch from SBC to PBC resulted in noninferior rates of documentation (p>0.05) for the six most common complications not targeted as documentation opportunities during the educational intervention. Among patients in the reference group, whose providers did not receive the charting intervention, there was no significant change in either the E-MR (p = 0.198) or the E-LOS (p = 0.341), both of which slightly decreased over the course of the study period.

CONCLUSIONS:

Switching from SBC to specialty-focused PBC on a neurosurgery service line at an urban, academic, level I trauma center led to a statistically significant increase in the average patient-specific E-MR and a trend toward significant increase in the average patient-specific E-LOS. The study illustrates the degree to which a low-cost intervention on documentation patterns can impact neurosurgical risk-adjusted quality metrics.
120 Blast-Related Traumatic Brain Injuries Secondary to Thermobaric Explosives: Implications for the War in Ukraine
Authors: Zhang Justin , Botterbush Kathleen , Bagdady Kazimir , Mercier Philippe , Mattei Tobias A.
Published: March 2023

INTRODUCTION:

Advancements in modern weaponry have vastly increased the incidence and severity of craniospinal injuries. Specifically, thermobaric weapons can cause devastating blast-related traumatic brain injury (bTBI). With recent use of these weapons in the war in Ukraine, clinicians and laypersons alike may benefit from an improved understanding behind the dynamic interplay between explosive weaponry, its potential for bTBI, and the subsequent short and long-term consequences of these injuries.

METHODS:

A comprehensive review of thermobaric weapons and their use throughout history was performed. Mechanisms of action behind blast injuries and subsequent therapeutic advancements in neurosurgical management from pioneers of neurosurgery was conducted. We document long term neuropsychiatric sequela following bTBI and discuss its relevance in the current conflict in Ukraine. In addition, a quantitative analysis of the potential of thermobaric weapons to cause bTBI in a hypothetical scenario of its use in Ukrainian civilian zones was performed.

RESULTS:

A thermobaric weapon causes a prolonged blast pressure wave which can cause devastating injury through several mechanisms, including long-term neuropsychiatric sequela (notably PTSD). The origins of bTBI sequela date back to documentations in WWI of “shell-shock”, now widely known as PTSD. Trailblazers in neurosurgery, such as Harvey Cushing, and prominent psychologists, such as Charles Myers, were pivotal in identifying and treating early cases of bTBI. Our quantitative analysis demonstrates the significant potential of thermobaric weapons in causing bTBI. Construction of underground shelters may mitigate damage from the blast pressure wave.

CONCLUSIONS:

As humanitarian relief efforts set foot in Ukraine, results from our brief report may inform and assist the development of focused mitigation and rehabilitation strategies, especially in post-war reconstruction