bluuebunny/crossref_metadata_2025 huggingface dataset:
Sparse recovery by reduced variance stochastic approximation
Authors: Juditsky Anatoli , Kulunchakov Andrei , Tsyntseus Hlib
Published: November 2022

In this paper, we discuss application of iterative Stochastic Optimization routines to the problem of sparse signal recovery from noisy observation. Using Stochastic Mirror Descent algorithm as a building block, we develop a multistage procedure for recovery of sparse solutions to Stochastic Optimization problem under assumption of smoothness and quadratic minoration on the expected objective. An interesting feature of the proposed algorithm is linear convergence of the approximate solution during the preliminary phase of the routine when the component of stochastic error in the gradient observation, which is due to bad initial approximation of the optimal solution, is larger than the ‘ideal’ asymptotic error component owing to observation noise ‘at the optimal solution’. We also show how one can straightforwardly enhance reliability of the corresponding solution using Median-of-Means-like techniques.

We illustrate the performance of the proposed algorithms in application to classical problems of recovery of sparse and low-rank signals in the generalized linear regression framework. We show, under rather weak assumption on the regressor and noise distributions, how they lead to parameter estimates which obey (up to factors which are logarithmic in problem dimension and confidence level) the best known accuracy bounds.
The cost of dispensing errors in Iranian health system: a retrospective evaluation
Authors: Yousefi Nazila , Asadi Farideh , Sharif Zahra , Khani Akram , Baymaninezhad Dana , Salamzade Jamshid , Peiravian Farzad
Published: November 2022

Objective

The problem of medication errors (MEs) has constantly been receiving considerable attention worldwide due to their health impact and costly consequences. MEs occur in all phases of prescription, preparation, administration, distribution and delivery to the patient; however, dispensing errors are more common in this study, we have attempted to identify various MEs that occurred by pharmacists and calculate their financial and physical harm costs.

Design

This was a 8-year retrospective study.

Setting

This study evaluated the costs of MEs in the Iranian health system caused by dispensing mistakes from 2012 to 2019. We retrieved documents and reports from the Tehran Medical Council Archive. Then, we extracted dispensing error data from ME record forms and analyzed them using SPSS software.

Main outcome Measures

Cost of dispensing errors.

Results

Among 3000 available MEs documents, only 2.6% of cases were dispensing errors. Errors included dispensing of wrong medication (75.6%), delivering expired medicines (11.5%), wrong medication order (9%), wrong medicine compounding (2.6%) and wrong dose of medication (1.3%). The most common cause of dispensing errors was physicians’ poor handwriting (23.1%). Legal reactions, due to MEs, occurred in a range of actions from written reprimand in the professional records to some months of deprivation from professional activities.

Conclusion

The analysis of the MEs that lead to the legal prosecution in the Iranian Medical Council shows that most cases, according to the severity of harm, were dispensing wrong medicines which caused temporary patients harm.
Evaluation of HIV-1 capsid genetic variability and lenacapavir (GS-6207) drug resistance-associated mutations according to viral clades among drug-naive individuals
Authors: Nka Alex Durand , Bouba Yagai , Teto Georges , Semengue Ezéchiel Ngoufack Jagni , Takou Désiré Komego , Ngueko Aurelie Minelle Kengni , Fabeni Lavinia , Carioti Luca , Armenia Daniele , Pabo Willy , Dambaya Béatrice , Sosso Samuel Martin , Colizzi Vittorio , Perno Carlo-Federico , Ceccherini-Silberstein Francesca , Santoro Maria Mercedes , Fokam Joseph , Ndjolo Alexis
Published: November 2022

Objectives

We evaluated the HIV-1 capsid genetic variability and lenacapavir drug resistance-associated mutations (DRMs) among drug-naive individuals across HIV-1 clades.

Methods

A total of 2031 HIV-1 sequences from drug-naive patients were analysed for capsid amino acid modification and the prevalence of lenacapavir DRMs. Amino acid positions with <5% variability were considered as conserved and variability was analysed by HIV-1 clades.

Results

Overall, 63% (148/232) of amino acid positions were conserved in the capsid protein. Of note, conservation was consistent in specific binding residues of cellular factors involved in viral replication [CypA (G89, P90), CPSF6 (Q4, N57, N74, A77, K182) and TRIM-NUP153 (R143)], while N183 (12.31%) was the only non-conserved lenacapavir binding residue. The overall prevalence (95% CI) of lenacapavir DRMs was 0.14% (0.05–0.44) (3/2031), with M66I (0.05%) and Q67H (0.05%) observed in subtype C, and T107N (0.05%) observed in CRF01_AE. Moreover, polymorphic mutations M66C (n = 85; 4.18%), Q67K (n = 78; 3.84%), K70R (n = 7; 0.34%), N74R (n = 57; 2.81%) and T107L (n = 82; 4.03%) were observed at lenacapavir resistance-associated positions.

Conclusions

The low level of lenacapavir DRMs (<1%) supports its predicted effectiveness for treatment and prevention, regardless of HIV-1 clades. The established conserved regions hence serve as a hallmark for the surveillance of novel mutations potentially relevant for lenacapavir resistance.
Chinese Import Competition and Gendered Labor Market Outcomes: Evidence from Ethiopian Firm-Level Data
Authors: Afesorgbor Sylvanus Kwaku , Acquah Ruby Elorm , Ayele Yohannes
Published: November 2022

In this paper, we analyse the relationship between Chinese import competition and gendered labor market outcomes within the context of a developing country. To do this, we merge a rich manufacturing firm-level panel data set from Ethiopia with trade data covering the years 1997–2010. Thus, we map out the effect of trade shocks from import surges on labor force participation and compensation, decomposed by gender. Results from the study show that rising import competition from China had a heterogeneous effect on female and male labor market outcomes. Import competition from China is associated with a negative and statistically significant effect on female employment, but not male employment. Looking at workers’ occupation, we find that for production workers import competition is adversely related with female employment outcomes while there is no statistically significant association with employment of administrative workers. For wage inequality, male wages in general are negatively associated with import competition, while we found no effect on female wages.
Availability of aldo-keto reductase 1C3 and ATP-binding cassette B1 as therapeutic targets for alleviating paclitaxel resistance in breast cancer MCF7 cells
Authors: Matsunaga Toshiyuki , Horinouchi Misato , Saito Haruhi , Hisamatsu Aki , Iguchi Kazuhiro , Yoshino Yuta , Endo Satoshi , Ikari Akira
Published: November 2022

Paclitaxel (PTX) is frequently utilized for the chemotherapy of breast cancer, but its continuous treatment provokes hyposensitivity. Here, we established a PTX-resistant variant of human breast cancer MCF7 cells and found that acquiring the chemoresistance elicits a remarkable up-regulation of aldo-keto reductase (AKR) 1C3. MCF7 cell sensitivity to PTX toxicity was increased by pretreatment with AKR1C3 inhibitor and knockdown of this enzyme, and decreased by its overexpression, inferring a crucial role of AKR1C3 in the development of PTX resistance. The PTX-resistant cells were much less sensitive to 4-hydroxy-2-nonenal and acrolein, cytotoxic reactive aldehydes derived from ROS-mediated lipid peroxidation, compared with the parental cells. Additionally, the resistant cells lowered levels of 4-hydroxy-2-nonenal formed during PTX treatment, which was mitigated by pretreating with AKR1C3 inhibitor, suggesting that AKR1C3 procures the chemoresistance through facilitating the metabolism of the cytotoxic aldehyde. The gain of PTX resistance additively promoted the aberrant expression of an ATP-binding cassette (ABC) transporter ABCB1 among the ABC transporter isoforms. The combined treatment with AKR1C3 and ABCB1 inhibitors overcame the PTX resistance and cross-resistance to another taxane-based drug docetaxel. Collectively, combined treatment with AKR1C3 and ABCB1 inhibitors may exert an overcoming effect of PTX resistance in breast cancer.
Liposomal irinotecan with fluorouracil and leucovorin after gemcitabine-based therapy in Japanese patients with metastatic pancreatic cancer: additional safety analysis of a randomized phase 2 trial
Authors: Furuse Junji , Ueno Makoto , Ikeda Masafumi , Okusaka Takuji , Teng Zhaoyang , Furuya Momoko , Ioka Tatsuya
Published: November 2022

Background

Nanoliposomal irinotecan (nal-IRI) was recently authorized in Japan for unresectable pancreatic cancer after disease progression following chemotherapy. Physicians now consider certain aspects of nal-IRI safety profile as slightly different from conventional irinotecan. This report aims to explore additional aspects of the nal-IRI safety in Japanese phase 2 study.

Methods

We analyzed the incidence, time to first onset, and time to resolution for adverse events that require special attention and other selected toxicities in the nal-IRI combination group (n = 46).

Results

Leukopenia/neutropenia (76.1%/71.7%), diarrhea (58.7%) and hepatic dysfunction (41.3%) were the most commonly reported treatment-emergent adverse events, with a median time to onset of 21.0 days (range: 8, 97), 9.0 days (1, 61) and 22.0 days (2, 325), respectively, and a median time to resolution of 8.0 days (95% confidence intervals: 8, 9), 4.0 days (4, 8) and 40.0 days (9, –), respectively. Eight patients experienced Grade ≥ 3 diarrhea and their symptoms were well controlled by dose modification except one patient who had drug withdrawal. The median time to resolution for Grade ≥ 3 and Grade ≤ 2 diarrhea was 17.5 days (95% confidence intervals: 1, 31) and 4 days (3, 7), respectively. Anorexia occurred in 28/46 patients (60.9%) with a median time to onset of 4.0 days (range: 2, 132) and a median time to resolution of 12.0 days (95% confidence intervals: 6, 26).

Conclusions

We explored safety profile of nal-IRI combination regimen recognized as effective and tolerable treatment for Japanese unresectable pancreatic cancer patients. Although the treatment-emergent adverse events occurred were controllable, patients with prolonged toxicities should be closely managed.
Idiopathic parotid pain: a rare clinical presentation of first bite syndrome without history of head and neck surgery or underlying malignancies
Authors: Saleem Matthew I , Bhuiya Sabreen , Tham Tristan , Georgolios Alexandros
Published: November 2022

First bite syndrome (FBS) has been previously characterised as a surgical complication, following head and neck surgical procedures. There are also rare reports in the literature associating FBS with malignancies of the head and neck. The term ‘idiopathic parotid pain’ (IPP) has been used recently to describe an exceedingly rare clinical presentation similar to FBS, but without history of head and neck surgery or malignancy. We present the rare case of a 65-year-old male diagnosed with IPP, our work-up and management.
Establishment of a gene recombination method for a major human skin commensal fungus, Malassezia restricta, using Agrobacterium tumefaciens-mediated gene transfer system
Authors: Cho Otomi , Matsumoto Yasuhiko , Yamada Tsuyoshi , Sugita Takashi
Published: November 2022

Malassezia restricta is the most predominant fungus in the microbiome of human skin. This microorganism can cause or exacerbate Malassezia-associated skin dermatitis, seborrheic dermatitis, atopic dermatitis, and pityriasis versicolor. The virulence factors of M. restricta have not been analyzed because a gene recombination system has not been developed. In this study, we established an Agrobacterium tumefaciens-mediated gene transfer (ATMT) system, optimized for generating gene-deficient mutants of M. restricta. A mutant of FKB1 gene, which encodes the FKBP12 protein that binds to the calcineurin inhibitor tacrolimus, was generated using the ATMT system. Subsequently, the FKB1 gene was reintroduced into the FKB1 gene-deficient mutant for obtaining a gene-complemented strain. The wild-type strain of M. restricta was sensitive to tacrolimus, whereas the FKB1 gene-deficient mutant was resistant to tacrolimus; the phenotypic drug susceptibility in the mutant was restored by reintroducing the FKB1 gene. Contrastingly, the FKB1 gene-deficient mutant was not resistant to cyclosporine A, which also inhibits calcineurin by binding to cyclophilin A. The gene recombination system for M. restricta will facilitate in elucidating the molecular mechanisms causing Malassezia-associated dermatitis.
Fair Market Constitutionalism: From Neo-liberal to Democratic Liberal Economic Governance
Authors: Dixon Rosalind
Published: November 2022

Neo-liberalism was in crisis well before COVID-19; and COVID-19 has only further highlighted the gaps and fault lines in existing liberal democratic models. But this does not mean that we should walk away from liberal ideals, or the general idea of globalisation or market-based forms of ordering. Instead, we should seek a new, more ‘democratic’ or pro-social understanding of the liberal ideal, which emphasises the idea of fair rather over free markets. This idea of fair markets can be understood in numerous ways, but I suggest that it is best understood as entailing a commitment by the state to: (i) guaranteeing access to a public baseline of core goods, or access to a generous social minimum to all citizens, regardless of market outcomes; (ii) ensuring equality of access to certain ‘relative goods’; (iii) regulating market power or sources of monopoly power; and (iv) responding to or ‘internalising’ negative externalities or social costs associated with private market behaviour. The article explores what this entails for the design of constitutions, and especially constitutional property and social rights, and the scope and strength of judicial review. Ultimately, the article suggests, fair market constitutionalism points to the desirability of a combination of weak property and social rights—ie property rights that offer some but not complete protection for existing economic entitlements, coupled with legislative duties to implement fair market norms or limited weak social rights guarantees. But this does not mean that such guarantees can only be weakly enforced by courts: blockages in the democratic process may mean that courts can and should adopt a weak–strong—or responsive—approach to enforcing these fundamentally weak rights guarantees.
Conflict misperceptions between citizens and foreigners across the globe
Authors: Romano Angelo , Gross Jörg , De Dreu Carsten K W
Published: November 2022

In a globalizing world, conflict between citizens and foreigners hinders cooperation and hampers how well the global community can tackle shared problems. Here, we study conflict between citizens and foreigners and find that people substantially misperceive how competitive foreigners are. Citizens (from 51 countries; N = 12,863; 656,274 decisions) interacted with foreigners in incentivized contest experiments. People across the globe systematically failed to anticipate the competitiveness of foreigners and either competed too much or too little. Competition was poorly explained by differences in cultural values or environmental stress. By contrast, competition and concomitant conflict misperceptions were robustly accounted for by differences in the wealth of nations, institutions, and histories of engaging in international conflict. Our results reveal how macro-level socio-economic differences between countries create false stereotypes and might breed conflict.
Neuropathic upper extremity pain
Authors: Worthley Elizabeth
Published: November 2022

Neuropathic upper extremity pain has many causes. Cubital tunnel syndrome is the second most common compressive peripheral neuropathy after carpal tunnel syndrome. Entrapment, or compression, of the ulnar nerve at the elbow classically presents with elbow pain, numbness in the ulnar nerve distribution, and weakness in the hand. C8 radiculopathy and various brachial plexopathies can mimic cubital and carpal tunnel syndromes. Neoplastic brachial plexopathy typically is caused by local extension of a primary or metastatic tumor into the brachial plexus. Double-crush syndrome further complicates neuropathic upper extremity pain. This case report describes a patient with a double-crush lesion involving the ulnar nerve at the elbow and a metastatic mass involving the lower trunk of the brachial plexus. Because of overlapping symptoms and presentations of several upper extremity nerve conditions, clinicians must perform a thorough history and physical examination and understand the sensory and motor innervation of the upper extremity to arrive at a timely and accurate diagnosis.
A review of slipped capital femoral epiphysis
Authors: Cotton Emma V. , Fowler Samuel C. , Maday Kristopher R.
Published: November 2022

Hip pain in children is common, with causes ranging from the benign to destructive. This article reviews slipped capital femoral epiphysis (SCFE), one of the most common hip pathologies in preadolescents and adolescents, which often is missed or delayed in diagnosis because of its vague, atypical presentation.
Complicated appendicitis in a patient with myelodysplastic syndrome and pancytopenia
Authors: Gaffney Samantha , Dunson William
Published: November 2022

Patients with immunocompromise presenting with abdominal pain can present a diagnostic challenge, because they may have atypical or vague symptoms. This case report discusses nonoperative management of a patient with immunocompromise, complicated appendicitis, and intra-abdominal infection.
Impact of a Standardized Nutrition Bundle Including Donor Human Milk on Hospital Outcomes in Very Low Birth-Weight (VLBW) Infants in a Safety-Net Hospital
Authors: Stefanescu Beatrice M. , Camacho Jenny , Stefanescu Andrei R. , DuPont Tara , Leung Rachel
Published: November 2022

Background:

Standardized protocols have been shown to reduce clinical practice variation and improve patient outcomes.

Purpose:

To measure the impact of a standardized nutrition bundle inclusive of donor human milk (DHM) on hospital outcomes of very low birth-weight (VLBW) infants in a safety-net hospital.

Methods:

The study used the Model for Improvement methodology to drive improvement in practice. Outcome measures consisted of necrotizing enterocolitis (NEC), mortality, growth at 36 weeks' postmenstrual age and discharge, as well as volume and type of milk consumption during hospitalization.

Findings:

NEC rate decreased from 16.67% in the control group to 6.78% in the standardized nutrition bundle group (P = .07). Similarly, there was significant reduction in mortality with the bundled intervention (15.6% in the control group vs 1.6% in the nutrition bundle group; P = .006). Time to first (15 vs 27.5 hours of life; P < .001) and full-volume enteral feeding (8.5 vs 10 days; P = .086) were reduced in the standardized nutrition bundle group compared with the control group. The human milk volume almost doubled with the intervention.

Implications for Practice:

Our standardized nutrition bundle protocol inclusive of DHM resulted in lower NEC rates and reduced mortality. The implementation of the DHM program proved to be cost-effective and saved lives. Our findings may help guide development of a structured approach to nutrition protocols inclusive of DHM that can be adapted by other units located in safety-net hospitals.

Implications for Research:

Future research on ethnic and racial barriers to access and affordability of DHM is warranted and much needed.
Evaluation of 5 Fraction Stereotactic Body Radiation Therapy (SBRT) for Osseous Renal Cell Carcinoma Metastases
Authors: Dove Austin P.H. , Wells Alex , Gong Wu , Liu Dandan , Kirschner Austin N.
Published: November 2022

Objectives:

The best fractionation for stereotactic body radiotherapy (SBRT) in renal cell carcinoma (RCC) metastases has not been well defined. In addition, the literature on outcomes using 5-fraction SBRT in the setting of osseous metastases has not been well reported.

Materials and Methods:

Thirty-nine patients with 69 RCC osseous metastases were treated using 5-fraction SBRT at a single institution using 2 dose-fractionation schemes. Overall survival and local-control (LC) outcomes of the 2 fractionation schemes were studied using Kaplan-Meier curves.

Results:

Of the 69 lesions included in the study, 20 were treated with 30 grays (Gy) in 5 fractions and 49 were treated with 40 Gy in 5 fractions. The median age of patients at diagnosis was 58.4 years. The 1-year LC rate for all treated lesions was 85.5% (59/69) with an LC of 90% (18/20) for lesions receiving 30 Gy and 83.7% (41/49) in lesions receiving 40 Gy. There was no statistically significant difference in 1-year LC rate between the 2 fractionation schemes (P-value, 0.553).

Conclusions:

Patients with osseous RCC metastases undergoing 5 fractions of SBRT had favorable LC outcomes. There was no difference in survival or LC between the 40 Gy and 30 Gy treatment arms.
Reverse Ride-Alongs Connect Medical Caregivers With Their Community
Authors: Murphy Janice G.
Published: November 2022

Many police departments have ride-along programs in which community residents accompany police officers in the field. Community organizers in one Cleveland, Ohio, neighborhood took that concept and flipped it to create a “reverse ride-along” program. During a reverse ride-along, police officers take part in community tours and dialogues to learn more about the area they serve and explore issues involving trust and trauma. In 2019, the reverse ride-along program added medical care providers from St. Vincent Charity Medical Center. The program was designed to connect residents and medical professionals for conversations in which learned knowledge and lived knowledge are valued equally. Participants identify barriers that deter positive health outcomes and prohibit effective engagement with the medical system. They do that by defining the social constructs unique to the community, then developing opportunities to address the barriers.
Equity Rx: Boston Medical Center's Work to Accelerate Racial Health Justice
Authors: Walsh Kate
Published: November 2022

In November 2021, after more than a year of investigating the racial health disparities across its organization, Boston Medical Center launched the Health Equity Accelerator, a system-wide approach to holistically address the root causes of health inequities among people of different races and ethnicities and speed improvements in health outcomes. This article discusses lessons learned during the institution's process of discovery, shares examples of the work to dismantle a structural narrative that impedes health justice, and outlines interventions that can be applied to other healthcare systems across the United States.
Caring for Atypical Wounds in Patients With Severe Obesity
Authors: Ciabattoni Matthew , Ward Amanda C. , Preston Ave Maria
Published: November 2022

BACKGROUND:

The prevalence of obesity has grown over the past several decades. It exerts a negative effect on multiple body systems, including the integumentary system, and it increases the risk for development of chronic diseases. Caring for hospitalized patients with severe obesity presents unique challenges, especially when wounds are present.

CASES:

This article reviews 3 patients with severe obesity hospitalized with extensive full-thickness lower extremity wounds. In all 3 cases, the wounds were comparable to the presentation and evolution of a typical deep tissue pressure injury. In addition, none of the wounds were classified as pressure injuries. These extensive wounds seen in patients with severe obesity lack a clear etiology and pathophysiology, but present wound care nurses and other care providers with unique challenges well beyond evidence-based principles for selection of appropriate topical care.

CONCLUSION:

These cases illustrate lessons learned when caring for 3 patients during several months of hospitalization at a large academic medical center. Additional research is needed to enhance our knowledge of the etiology of these wounds, especially since the population of patients with severe obesity has become more prevalent.
Single-Cell ATAC-seq analysis via Network Refinement with peaks location information
Authors: Yu Jiating , Sun Duanchen , Hou Zhichao , Wu Ling-Yun
Published: November 2022

Single-cell ATAC-seq (scATAC-seq) data provided new insights into the elaboration of cellular heterogeneity and transcriptional regulation. However, scATAC-seq data posed challenges for data analysis because of its near binarization, high sparsity, and ultra-high dimensionality properties. Here we proposed a novel network diffusion-based method to comprehensively analyze scATAC-seq data, namedSingle-CellATAC-seq Analysis via NetworkRefinement withPeaks Location Information (SCARP). By modeling the prior probability of co-accessibility between adjacent peaks as a decreasing function of genomic distance, SCARP is the first scATAC-seq analysis method that utilizes the genomic information of peaks, which contributed to characterizing co-accessibility of peaks. SCARP used network to model the accessible relationships between cells and peaks, aggregated information with the diffusion method, and then performed dimensionality reduction to obtain low-dimensional cell embeddings as well as peak embeddings. We have demonstrated through sufficient experiments that SCARP facilitated superior analysis of scATAC-seq data. Specifically, SCARP exhibited outstanding cell clustering performance to better elucidate cell heterogeneity, and can be used to reveal new biologically significant cell subpopulations. SCARP was also instrumental in portraying co-accessibility relationships of accessible regions and providing new insight into transcriptional regulation, and those SCARP-derived genes were involved in some key KEGG pathways related to diseases. To sum up, our studies suggested that SCARP is a promising tool to comprehensively analyze the scATAC-seq data from a new perspective.
Alterations inPTPN11and other RAS-/MAP-Kinase pathway genes define ganglioglioma with adverse clinical outcome and atypic histopathological features
Authors: Hoffmann Lucas , Coras Roland , Kobow Katja , López-Rivera Javier A. , Lal Dennis , Leu Costin , Najm Imad , Nürnberg Peter , Herms Jochen , Harter Patrick N. , Bien Christian G. , Kalbhenn Thilo , Müller Markus , Pieper Tom , Hartlieb Till , Kudernatsch Manfred , Hamer Hajo , Brandner Sebastian , Rössler Karl , Blümcke Ingmar , Jabari Samir
Published: November 2022

ThePTPN11gene was recently described as a novel lesional epilepsy gene by extensive exome-wide sequencing studies. However, germline mutations ofPTPN11and otherRAS-/MAP-Kinase signaling pathwaygenescause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of thePTPN11gene compared to GG with other common MAP-Kinase signaling pathway alterations. Seventy-two GG were submitted to whole exome sequencing and genotyping and 86 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. Clinical data were retrieved from hospital files including postsurgical disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG withPTPN11alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains inFGFR4, RHEB, NF1, KRASas well asBRAFV600Ealterations. Histopathology revealed an atypical and complex glio-neuronal phenotype with subpial tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG andPTPN11alterations were free of disabling-seizures two years after surgery (38% Engel I). This was remarkably different from our series of GG withBRAFV600Emutations (85% Engel I). Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized byPTPN11and other Noonan syndrome-related alterations of theRAS-/MAP-Kinase signaling pathway. These findings need prospective validation in clinical practice as they argue for an adapted WHO grading system in developmental, glio-neuronal tumors associated with early-onset focal epilepsy. These findings also open avenues for targeted medical treatment.
Two-dimensional maps to predict the neurological recovery after cardiac arrest
Authors: Floyrac Aymeric , Doumergue Adrien , Legriel Stéphane , Deye Nicolas , Megarbane Bruno , Richard Alexandra , Meppiel Elodie , Masmoudi Sana , Lozeron Pierre , Vicaut Eric , Kubis Nathalie , Holcman David
Published: November 2022

Background

Severity of neuronal damage in comatose patients following anoxic brain injury is assessed through a multimodal evaluation. However, predicting the return to full consciousness of hospitalized post-anoxic comatose patients remains challenging.

Methods

We present here a method to predict the return to consciousness and good neurological outcome based on the analysis of responses to auditory periodic stimulations to auditory evoked potentials. We extracted several EEG features from the time series responses in a window of few hundreds of milliseconds from the standard and deviant auditory stimulations that we considered independently. By combining these features, we built a two-dimensional map to evaluate possible group clustering. Using Gaussian, K-neighbourhood and SVM classifiers, we could predict the neurological outcome of post-anoxic comatose patients, the validity of the method being tested by a cross-validation procedure. This method was developed using data acquired retrospectively in a cohort of 29 post-cardiac arrest comatose patients, recorded between day 3 and day 6 following admission. Data from event-related potentials (ERPs) were recorded non-invasively with four surface cranial electrodes at electro-encephalography (EEG), that we computed secondarily.

Results

Analysis in two-dimensions of the present data revealed two separated clusters of patients with good versus bad neurological outcome. When favouring the highest specificity of our mathematical algorithms (0.91), we found a sensitivity of 0.83 and an accuracy of 0.90, maintained when calculation was performed using data from only one central electrode.

To conclude

statistics of standard and deviant responses considered separately provide complementary and confirmatory predictions of the outcome of anoxic comatose patients, better assessed when combining these features on a two-dimensional statistical map. The benefit of this method compared to classical EEG and ERP predictors should be tested in a large prospective cohort. If validated, this method could provide an alternative tool to intensivists, to better evaluate neurological outcome and improve patient management, without neurophysiologist assistance.
Perceived barriers to cervical cancer screening and motivators for at-home human papillomavirus self-sampling during the COVID-19 pandemic: Results from a telephone survey
Authors: Parker Susan L. , Deshmukh Ashish A. , Chen Baojiang , Lairson David R. , Daheri Maria , Vernon Sally W. , Montealegre Jane R.
Published: November 2022

Home-based self-sample human papillomavirus (HPV) testing may be an alternative for women who do not attend clinic-based cervical cancer screening. We assessed barriers to care and motivators to use at-home HPV self-sampling kits during the COVID-19 pandemic as part of a randomized controlled trial evaluating kit effectiveness. Participants were women, aged 30-65 years and underscreened for cervical cancer in a safety-net healthcare system. We conducted telephone surveys in English/Spanish among a subgroup of trial participants, assessed differences between groups and determined statistical significance at p<0.05. Over half of 233 survey participants reported clinic-based screening (Pap) is uncomfortable (67.8%), embarrassing (52.4%), and discomfort seeing male providers (63.1%). The latter two factors were significantly more prevalent among Spanish versus English speakers (66.4% vs 30% and 69.9 vs 52.2%, respectively, p<0.01). Most women who completed the kit found Pap more embarrassing (69.3%), stressful (55.6%) and less convenient (55.6%) than the kit. The first factor was more prevalent among Spanish versus English speakers (79.6% vs 53.38%, p<0.05). The COVID-19 pandemic influenced most (59.5%) to participate in the trial due to fear of COVID, difficulty making appointments and ease of using kits. HPV self-sampling kits may reduce barriers among underscreened women in a safety-net system.
Costs and economic impacts of expanding marine protected area systems to 30%
Authors: Waldron Anthony , Heneghan Ryan , Steenbeek Jeroen , Coll Marta , Scherrer Kim J. N.
Published: November 2022

International proposals for marine biodiversity seek to expand marine protected area (MPA) coverage from 8% to 30%, known as 30×30. Quadrupling MPA coverage implies considerably higher MPA system costs and governments need early knowledge of these to inform debate. Ambitious MPA expansion also implies large potential losses or “opportunity costs” for fishers, putting pressure on governments to compromise and permit some fishing inside protected areas (a mixed high/low protection system). Crafting a balanced compromise needs to be informed by model projections of future fisheries outcomes under different protection regimes, climate change scenarios and behavioural adaptations. Here, we develop the first models for management costs at national MPA-system scale. We create scenarios of 30×30 at different compromises around protection strictness. We then examine how both MPA costs and opportunity costs vary with strictness, by simultaneously applying our management cost models and two Marine Ecosystem Models. We find that a no-take (high protection) MPA system could cost just $2 billion/year for the developing world and ~$8 billion overall, but would also create opportunity costs several times larger. A compromise mix of high and medium protection would have much higher MPA costs (e.g. $4.5 billion for the developing world) but much lower opportunity costs, to the point of fisheries actually benefiting in the future. Since lower protection also compromises on biodiversity goals, our results show the trade-offs that political decisions need to consider beyond COP15. More generally, the unusually large opportunity costs show how marine contexts generate very different economic issues from terrestrial ones, by attempting to protect a common pool resource area that envisages no automatic market compensation for income lost to conservation.
Homunculus Interruptus: A motor association area in the depth of the central sulcus
Authors: Jensen Michael A. , Huang Harvey , Valencia Gabriela Ojeda , Klassen Bryan T. , van den Boom Max A. , Kaufmann Timothy J. , Schalk Gerwin , Brunner Peter , Hermes Dora , Worrell Gregory A. , Miller Kai J.
Published: November 2022

Cells in the precentral gyrus of the human brain directly send signals to the periphery to generate movement and are topologically organized as a map of the body. We find that movement induced electrophysiological changes from implanted depth electrodes extend this map 3-dimensionally throughout the volume of the gyrus. Unexpectedly, this organization is interrupted by a motor association area in the depths of the central sulcus at its mid-lateral aspect that is active during many different types of movements from both sides of the body.
The velvet family proteins mediate low resistance to isoprothiolane inMagnaporthe oryzae
Authors: Meng Fan-Zhu , Wang Zuo-Qian , Luo Mei , Wei Wen-Kai , Yin Liang-Fen , Yin Wei-Xiao , Schnabel Guido , Luo Chao-Xi
Published: November 2022

Isoprothiolane (IPT) resistance has emerged inMagnaporthe oryzae, due to the long-term usage of IPT to control rice blast in China, yet the mechanisms of the resistance remain largely unknown. Through IPT adaptation on PDA medium, we obtained a variety of IPT-resistant mutants. Based on their EC50values to IPT, the resistant mutants were mainly divided into three distinct categories i.e., low resistance (LR, 6.5 ≤ EC50< 13.0 μg/mL), moderate resistance 1 (MR-1, 13.0 ≤ EC50< 25.0 μg/mL), and moderate resistance 2 (MR-2, 25.0 ≤ EC50< 35.0 μg/mL). Molecular analysis ofMoIRR(Magnaporthe oryzaeisoprothiolane resistance related) gene demonstrated that it was associated only with the moderate resistance in MR-2 mutants, indicating that other mechanisms were associated with resistance in LR and MR-1 mutants. In this study, we mainly focused on the characterization of low resistance to IPT inM. oryzae. Mycelial growth and conidial germination were significantly reduced, indicating fitness penalties in LR mutants. Based on the differences of whole genome sequences between parental isolate and LR mutants, we identified a conservedMoVelBgene, encoding the velvet family transcription factor, and genetic transformation of wild type isolate verified thatMoVelBgene was associated with the low resistance. Based on molecular analysis, we further demonstrated that the velvet family proteins VelB and VeA were indispensable for IPT toxicity and the deformation of the LaeA-VeA-VelB heterotrimer played a vital role for the low IPT-resistance inM. oryzae, most likely through the down-regulation of the secondary metabolism-related genes or CYP450 genes to reduce the toxicity of IPT.

Author summary

Isoprothiolane (IPT) resistance has emerged inMagnaporthe oryzae, due to the long-term usage of IPT to control rice blast in China, yet the mechanisms of the resistance remain largely unknown. Here, we explored the mechanisms of low IPT resistance inM. oryzae. Combining the whole genome sequencing and genetic transformation, we identified a conservedMoVelBgene, encoding the velvet family transcription factor to be a determinant for IPT toxicity. We further demonstrated that the deformation of the LaeA-VeA-VelB heterotrimer conferred the low IPT-resistance inM. oryzae, most likely through down-regulating the secondary metabolism-related genes or CYP450 genes to reduce the toxicity of IPT. This study improved our understanding of the resistance mechanism as well as the mode of action of IPT which will be helpful for making suitable strategies to manage the emerging resistance of IPT inM. oryzae.
Modeling rod and cone photoreceptor cell survivalin vivousing optical coherence tomography
Authors: Whitmore S. Scott , DeLuca Adam P. , Andorf Jeaneen L. , Cheng Justine L. , Mansoor Mahsaw , Fortenbach Christopher R. , Critser D. Brice , Russell Jonathan F. , Stone Edwin M. , Han Ian C.
Published: November 2022

Many retinal diseases involve the loss of light-sensing photoreceptor cells (rods and cones) over time. The severity and distribution of photoreceptor loss varies widely across diseases and affected individuals, so characterizing the degree and pattern of photoreceptor loss can clarify pathophysiology and prognosis. Currently,in vivovisualization of individual photoreceptors requires technology such as adaptive optics, which has numerous limitations and is not widely used. By contrast, optical coherence tomography (OCT) is nearly ubiquitous in daily clinical practice given its ease of image acquisition and detailed visualization of retinal structure. However, OCT cannot resolve individual photoreceptors, and no OCT-based method exists to distinguish between the loss of rods versus cones. Here, we present a computational model that quantitatively estimates rod versus cone photoreceptor loss from OCT. Using histologic data of human photoreceptor topography, we constructed an OCT-based reference model to simulate outer nuclear layer thinning caused by differential loss of rods and cones. The model was able to estimate rod and cone loss usingin vivoOCT data from patients with Stargardt disease and healthy controls. Our model provides a powerful new tool to quantify photoreceptor loss using OCT data alone, with potentially broad applications for research and clinical care.
Identification of an increased lifetime risk of major adverse cardiovascular events in UK Biobank participants with scoliosis
Authors: Santofimio Valentina Q. , Clement Adam , O’Regan Declan P. , Ware James S. , McGurk Kathryn A.
Published: November 2022

Background

Structural changes caused by spinal curvature may impact the organs within the thoracic cage, including the heart. Cardiac abnormalities in idiopathic scoliosis patients are often studied post-corrective surgery or secondary to diseases. To investigate cardiac structure, function, and outcomes in participants with scoliosis, phenotype and imaging data of the UK Biobank (UKB) adult population cohort was analysed.

Methods

Hospital episode statistics of 502,324 adults were analysed to identify participants with scoliosis. Summary 2D cardiac phenotypes from 39,559 cardiac magnetic resonance imaging (CMR) scans were analysed alongside a 3D surface-to-surface (S2S) analysis.

Results

A total of 4,095 (0.8%, 1 in 120) UKB participants were identified to have all-cause scoliosis. These participants had increased lifetime risk of major adverse cardiac events (MACE) (HR=1.45, P<0.001), driven by heart failure (HR=1.58, P<0.001) and atrial fibrillation (HR=1.54, P<0.001). Increased radial and decreased longitudinal peak diastolic strain rates were identified in participants with scoliosis (+0.29, Padj<0.05; −0.25, Padj<0.05; respectively). Cardiac compression of the top and bottom of the heart and decompression of the sides was observed through S2S analysis. Additionally, associations between scoliosis and older age, female sex, heart failure, valve disease, hypercholesterolemia, hypertension, and decreased enrolment for CMR, were identified.

Conclusion

The spinal curvature observed in participants with scoliosis alters the movement of the heart. The association with increased MACE may have clinical implications for whether to undertake surgical correction. This work identifies, in an adult population, evidence for altered cardiac function and increased lifetime risk of MACE in participants with scoliosis. Future genetic analyses would aid to assess causality.
Image Based Deep Learning in 12-Lead ECG Diagnosis
Authors: Ao Raymond , He George
Published: November 2022

Background

Most studies on machine learning classification of electrocardiogram (ECG) diagnoses focus on processing raw signal data rather than ECG images. In clinical practice, it is often the case where ECGs printed on paper or only digital images are easily accessible. This study aims to evaluate the accuracy of image based deep learning algorithms on 12 lead ECG diagnosis.

Methods

Deep learning models were trained on various 12-lead ECG datasets and evaluated for accuracy by testing on holdout test data as well as data from datasets not seen in training.

Results

The results demonstrated excellent AUROC, AUPRC, sensitivity and specificity on holdout test data from datasets used in training, but poorer accuracy on unseen datasets.

Discussion

This study demonstrates feasibility of image based deep learning algorithms in ECG diagnosis, and identifies directions for future research in order to develop clinically applicable deep-learning models in ECG diagnosis.
Monogenic causes of Premature Ovarian Insufficiency are rare and mostly recessive
Authors: Shekari Saleh , Stankovic Stasa , Gardner Eugene J. , Hawkes Gareth , Kentistou Katherine A. , Beaumont Robin N. , Mörseburg Alexander , Wood Andrew R. , Mishra Gita , Day Felix , Baptista Julia , Wright Caroline F. , Weedon Michael N. , Hoffmann Eva , Ruth Katherine S. , Ong Ken , Perry John R. B. , Murray Anna
Published: November 2022

Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ∼100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported natural menopause under the age of 40. In the largest study of POI to date, we found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes we were able to rule out even modest penetrance, with 99.9% (13,699/13,708) of all identified protein truncating variants found in reproductively healthy women. We found evidence of novel haploinsufficiency effects in several genes, includingTWNK(1.54 years earlier menopause,P=1.59*10−6) andSOHLH2(3.48 years earlier menopause,P=1.03*10−4). Collectively our results suggest that for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. We suggest that the majority of POI cases are likely oligogenic or polygenic in nature, which has major implications for future clinical genetic studies, and genetic counselling for families affected by POI.
Predictive efficacies of vaccine dose fractionation using neutralizing antibody levels
Authors: Du Zhanwei , Liu Caifen , Bai Yuan , Wang Lin , Lim Wey Wen , Lau Eric H. Y. , Cowling Benjamin J.
Published: November 2022

Background

With the emergence of SARS-CoV-2 variants that eluded immunity from vaccines and prior infections, vaccine shortages and their effectiveness pose unprecedented challenges for governments to expand booster vaccination programs. Fractionation of vaccine doses might be an effective strategy to help society to face these challenges, which may have comparable efficacies in contrast with the standard doses.

Methods

In this study, we analyzed the relationship between in-vitro neutralization levels and the observed efficacies against asymptomatic and symptomatic infection of ten types of COVID-19 vaccines using data from 13 studies from vaccination and convalescent cohorts. We further projected efficacies for fractional doses based on 51 studies included in our systematic review.

Results

By comparing with the convalescent level, vaccine efficacy increases from 8.8% (95% CI: 1.4%, 16.1%) to 71.8% (95% CI: 63.0%, 80.7%) against asymptomatic infection, and from 33.6% (95% CI: 23.6%, 43.6%) to 98.6% (95% CI: 97.6%, 99.7%) against symptomatic infection, respectively, along with the mean neutralization level from 0.1 to 10 folds of convalescent level. And mRNA vaccines provide the strongest protection, and decrease slowly for fractional dosing between 50% and 100% dosage.

Conclusions

Our results are consistent with studies for immune protection from COVID-19 infection. Based on our study, we expect that fractional dose vaccination could provide a partial immunity for SARS-CoV-2 virus. Fractional doses of vaccines could be a viable vaccination strategy compared to full-dose vaccination and deserves further exploration.

Key points

We analyzed the relationship between neutralization levels and efficacies against asymptomatic and symptomatic infection of ten types of COVID-19 vaccines from convalescent cohorts. Fractional doses of vaccines could be a viable strategy compared to full-dose vaccination and deserves further exploration.