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1.
Cult Health Sex ; : 1-17, 2024 Mar 13.
Article in English | MEDLINE | ID: mdl-38478464

ABSTRACT

Women living with HIV often face intersecting challenges of stigma and gender inequality. In Vietnam, this issue is potentially exacerbated by the patriarchal culture. From December 2021 to March 2022, we conducted in-depth interviews with 30 women living with HIV in Hanoi to better understand their experiences and the coping mechanisms to navigate HIV stigma, cultural beliefs and gender norms. The interviews explored various topics including women's social and family roles in Vietnam, HIV-related beliefs, stigma and its impact on one's health and coping strategies. Participants reported stereotypes that assumed that women living with HIV had either engaged in sex work or behaved promiscuously. These stereotypes render them vulnerable to judgement and discrimination owing to widespread expectations of female virtue. As a result, women living with HIV often enacted non-disclosure and self-isolation to avoid stigma. This self-stigmatisation negatively impacted their healthcare-seeking, employment opportunities and ability to fulfil traditional family-caring roles. Conversely, many participants exhibited resilience with the support of family and peers. Overall, the complex interplay between gender, culture and HIV stigma underscores the importance of developing culturally appropriate, multifaceted approaches to engaging family and peers, modifying gender-based discriminatory social practices and enhancing women's self-efficacy and empowerment in Vietnam.

2.
Nat Prod Res ; : 1-8, 2024 Mar 22.
Article in English | MEDLINE | ID: mdl-38516731

ABSTRACT

The phytochemical composition of the Combretum trifoliatum leaves was studied for the first time. Two new triterpenoid saponins, named comtrifoside A (1) and comtrifoside B (2), together with two other saponins (3-4) were purified by variously chromatographic techniques. For the first time, compound 3 was informed from the Combretum genus, as well as all of the isolated compounds (1-4) were reported from C. trifoliatum. The chemical structures of them were clearly characterised using extensive UV-VIS, IR, HRMS-ESI, and NMR experimental data. The in vitro anti-inflammatory activities of 1 & 2 were examined against NO overproduction in LPS activation of RAW264.7.

3.
Reprod Health ; 21(1): 34, 2024 Mar 11.
Article in English | MEDLINE | ID: mdl-38468301

ABSTRACT

BACKGROUND: Human Immunodeficiency Virus (HIV) remains a significant public health concern worldwide. Women living with HIV/AIDS (WLHA) have the additional and unique need to seek sexual and reproductive health services. WLHA's maternal health journeys can be shaped by the cultural norms and resources that exist in their society. This study sought to understand if and how WLHA's family planning, pregnancy, and motherhood experiences could be influenced by the patriarchal culture, gender roles, and HIV stigma in Vietnam, specifically. METHODS: Between December 2021 and March 2022, 30 WLHA with diverse socioeconomic backgrounds and childbirth experiences were interviewed in Hanoi, Vietnam. These semi-structured interviews covered topics including HIV stigma, gender norms, pregnancy experiences, and child-rearing challenges. Interviews were audio recorded, transcribed, and analysed using ATLAS.ti. RESULTS: Qualitative analyses of participant quotes revealed how limited information on one's health prospects and reproductive options posed a significant challenge to family planning. Societal and familial expectations as well as economic circumstances also influenced reproductive decision-making. WLHA often encountered substandard healthcare during pregnancy, labor, and delivery. Stigma and lack of provider attentiveness resulted in cases where women were denied pain relief and other medical services. Communication breakdowns resulted in failure to administer antiretroviral therapy for newborns. Motherhood for WLHA was shadowed by concerns for not only their own health, but also the wellbeing of their children, as HIV stigma affected their children at school and in society as well. Many WLHA highlighted the constructive or destructive role that family members could play in their childbirth decision-making and care-giving experiences. CONCLUSIONS: Overall, this study underscores the complex ways that cultural expectations, family support, and stigma in healthcare impact WLHA. Efforts to educate and engage families and healthcare providers are warranted to better understand and address the needs of WLHA, ultimately improving their reproductive and maternal health.


HIV-related stigma and discrimination have consequential impacts on health and quality of life for women living with HIV (WLHA). WLHA in Vietnam must navigate the additional challenges of a traditionally patriarchal and hierarchical society. Women typically face less educational and occupational opportunities and are often expected to defer to expectations of family and virtue. Stigma among family members, friends, employers, and healthcare providers poses a significant challenge to WLHA autonomy, especially as it relates to their reproductive health decision-making and maternal health experiences. This study aims to better understand the experiences of WLHA throughout family planning, pregnancy, and motherhood. The findings will hopefully shed light on strategies to empower WLHA and to combat HIV- and gender-based stigma not only in Vietnam, but also globally.


Subject(s)
Acquired Immunodeficiency Syndrome , HIV Infections , Pregnancy , Humans , Female , Infant, Newborn , HIV , Maternal Health , Vietnam/epidemiology , HIV Infections/drug therapy , HIV Infections/epidemiology , Qualitative Research
4.
Nanoscale Horiz ; 9(4): 544-554, 2024 Mar 25.
Article in English | MEDLINE | ID: mdl-38323517

ABSTRACT

Current methodology used to investigate how shifts in brain states associated with regional cerebral blood volume (CBV) change in deep brain areas, are limited by either the spatiotemporal resolution of the CBV techniques, and/or compatibility with electrophysiological recordings; particularly in relation to spontaneous brain activity and the study of individual events. Additionally, infraslow brain signals (<0.1 Hz), including spreading depolarisations, DC-shifts and infraslow oscillations (ISO), are poorly captured by traditional AC-coupled electrographic recordings; yet these very slow brain signals can profoundly change CBV. To gain an improved understanding of how infraslow brain signals couple to CBV we present a new method for concurrent CBV with wide bandwidth electrophysiological mapping using simultaneous functional ultrasound imaging (fUS) and graphene-based field effect transistor (gFET) DC-coupled electrophysiological acquisitions. To validate the feasibility of this methodology visually-evoked neurovascular coupling (NVC) responses were examined. gFET recordings are not affected by concurrent fUS imaging, and epidural placement of gFET arrays within the imaging window did not deteriorate fUS signal quality. To examine directly the impact of infra-slow potential shifts on CBV, cortical spreading depolarisations (CSDs) were induced. A biphasic pattern of decreased, followed by increased CBV, propagating throughout the ipsilateral cortex, and a delayed decrease in deeper subcortical brain regions was observed. In a model of acute seizures, CBV oscillations were observed prior to seizure initiation. Individual seizures occurred on the rising phase of both infraslow brain signal and CBV oscillations. When seizures co-occurred with CSDs, CBV responses were larger in amplitude, with delayed CBV decreases in subcortical structures. Overall, our data demonstrate that gFETs are highly compatible with fUS and allow concurrent examination of wide bandwidth electrophysiology and CBV. This graphene-enabled technological advance has the potential to improve our understanding of how infraslow brain signals relate to CBV changes in control and pathological brain states.


Subject(s)
Graphite , Humans , Brain/diagnostic imaging , Seizures , Electrophysiology , Cerebrovascular Circulation/physiology , Ultrasonography
5.
BJU Int ; 133 Suppl 3: 25-32, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37943964

ABSTRACT

OBJECTIVES: To compare the diagnostic performance and radiological staging impact of 68 Ga-prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) compared to 99 Tc whole-body bone scan (WBBS) for the detection of skeletal metastasis in the primary staging of prostate cancer (PCa). PATIENTS AND METHODS: A prospective institutional database was retrospectively examined for patients who underwent both PSMA PET and WBBS within a 1 week interval for PCa primary staging. Lesions were categorised as 'negative', 'equivocal', or 'definite' based on nuclear medicine physician interpretation. Metastatic burden was characterised for each imaging modality according to three groups: (i) local disease (no skeletal metastases), (ii) oligometastatic disease (three or fewer skeletal metastases), or (iii) polymetastatic disease (more than three skeletal metastases). RESULTS: There were 667 patients included. The median (interquartile range) prostate-specific antigen level was 9.2 (6.2-16) ng/mL and 60% of patients were high risk according to a modified D'Amico risk classification. The overall distribution of skeletal metastasis detection changed across the two scans overall (P = 0.003), being maintained within high-risk (P = 0.030) and low-risk (P = 0.018) groups. PSMA PET/CT identified more definite skeletal metastases compared to WBBS overall (10.3% vs 7.3%), and according to risk grouping (high: 12% vs 9%, intermediate: 4% vs 1%). Upstaging was more common with PSMA PET/CT than WBBS (P = 0.001). The maximum standardised uptake value (SUVmax ) of the primary tumour was associated with upstaging of skeletal metastases on PSMA PET/CT (P = 0.025), while age was associated with upstaging on WBBS (P = 0.021). The SUVmax of the primary tumour and metastases were both higher according to extent of metastatic disease (P = 0.001 and P < 0.001, respectively). CONCLUSIONS: More skeletal metastases were detected with PSMA PET/CT than WBBS, resulting in a higher upstaging rate mostly in high-risk patients. The SUVmax of the primary tumour and metastases was associated with upstaging.


Subject(s)
Prostate , Prostatic Neoplasms , Male , Humans , Prostate/pathology , Positron Emission Tomography Computed Tomography/methods , Retrospective Studies , Prospective Studies , Gallium Radioisotopes , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/pathology
6.
Nat Med ; 29(12): 3059-3066, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38087116

ABSTRACT

To support a strategy to eliminate cervical cancer as a public health problem, the World Health Organisation (WHO) reviewed its guidelines for screening and treatment of cervical pre-cancerous lesions in 2021. Women living with HIV have 6-times the risk of cervical cancer compared to women in the general population, and we harnessed a model platform ('Policy1-Cervix-HIV') to evaluate the benefits and harms of a range of screening strategies for women living with HIV in Tanzania, a country with endemic HIV. Assuming 70% coverage, we found that 3-yearly primary HPV screening without triage would reduce age-standardised cervical cancer mortality rates by 72%, with a number needed to treat (NNT) of 38.7, to prevent a cervical cancer death. Triaging HPV positive women before treatment resulted in minimal loss of effectiveness and had more favorable NNTs (19.7-33.0). Screening using visual inspection with acetic acid (VIA) or cytology was less effective than primary HPV and, in the case of VIA, generated a far higher NNT of 107.5. These findings support the WHO 2021 recommendation that women living with HIV are screened with primary HPV testing in a screen-triage-and-treat approach starting at 25 years, with regular screening every 3-5 years.


Subject(s)
HIV Infections , Papillomavirus Infections , Uterine Cervical Neoplasms , Humans , Female , Cervix Uteri/pathology , Uterine Cervical Neoplasms/diagnosis , Uterine Cervical Neoplasms/therapy , Triage , Early Detection of Cancer/methods , Papillomavirus Infections/complications , Papillomavirus Infections/diagnosis , Acetic Acid , HIV Infections/diagnosis , HIV Infections/drug therapy , HIV Infections/pathology
7.
Nat Med ; 29(12): 3050-3058, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38087115

ABSTRACT

In 2020, the World Health Organization (WHO) launched a strategy to eliminate cervical cancer as a public health problem. To support the strategy, the WHO published updated cervical screening guidelines in 2021. To inform this update, we used an established modeling platform, Policy1-Cervix, to evaluate the impact of seven primary screening scenarios across 78 low- and lower-middle-income countries (LMICs) for the general population of women. Assuming 70% coverage, we found that primary human papillomavirus (HPV) screening approaches were the most effective and cost-effective, reducing cervical cancer age-standardized mortality rates by 63-67% when offered every 5 years. Strategies involving triaging women before treatment (with 16/18 genotyping, cytology, visual inspection with acetic acid (VIA) or colposcopy) had close-to-similar effectiveness to HPV screening without triage and fewer pre-cancer treatments. Screening with VIA or cytology every 3 years was less effective and less cost-effective than HPV screening every 5 years. Furthermore, VIA generated more than double the number of pre-cancer treatments compared to HPV. In conclusion, primary HPV screening is the most effective, cost-effective and efficient cervical screening option in LMICs. These findings have directly informed WHO's updated cervical screening guidelines for the general population of women, which recommend primary HPV screening in a screen-and-treat or screen-triage-and-treat approach, starting from age 30 years with screening every 5 years or 10 years.


Subject(s)
Papillomavirus Infections , Uterine Cervical Neoplasms , Humans , Female , Child, Preschool , Adult , Cervix Uteri , Uterine Cervical Neoplasms/therapy , Uterine Cervical Neoplasms/prevention & control , Cost-Benefit Analysis , Triage , Papillomavirus Infections/diagnosis , Early Detection of Cancer
8.
Influenza Other Respir Viruses ; 17(12): e13245, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38149927

ABSTRACT

BACKGROUND: Highly pathogenic avian influenza A(H5) human infections are a global concern, with many A(H5) human cases detected in Vietnam, including a case in October 2022. Using avian influenza virus surveillance from March 2017-September 2022, we described the percent of pooled samples that were positive for avian influenza A, A(H5), A(H5N1), A(H5N6), and A(H5N8) viruses in live bird markets (LBMs) in Vietnam. METHODS: Monthly at each LBM, 30 poultry oropharyngeal swab specimens and five environmental samples were collected. Samples were pooled in groups of five and tested for influenza A, A(H5), A(H5N1), A(H5N6), and A(H5N8) viruses by real-time reverse-transcription polymerase chain reaction. Trends in the percent of pooled samples that were positive for avian influenza were summarized by LBM characteristics and time and compared with the number of passively detected avian influenza outbreaks using Spearman's rank correlation. RESULTS: A total of 25,774 pooled samples were collected through active surveillance at 167 LBMs in 24 provinces; 36.9% of pooled samples were positive for influenza A, 3.6% A(H5), 1.9% A(H5N1), 1.1% A(H5N6), and 0.2% A(H5N8). Influenza A(H5) viruses were identified January-December and at least once in 91.7% of sampled provinces. In 246 A(H5) outbreaks in poultry; 20.3% were influenza A(H5N1), 60.2% A(H5N6), and 19.5% A(H5N8); outbreaks did not correlate with active surveillance. CONCLUSIONS: In Vietnam, influenza A(H5) viruses were detected by active surveillance in LBMs year-round and in most provinces sampled. In addition to outbreak reporting, active surveillance for A(H5) viruses in settings with high potential for animal-to-human spillover can provide situational awareness.


Subject(s)
Influenza A Virus, H5N1 Subtype , Influenza A Virus, H5N8 Subtype , Influenza A virus , Influenza in Birds , Influenza, Human , Animals , Humans , Influenza, Human/epidemiology , Influenza in Birds/epidemiology , Vietnam/epidemiology , Influenza A Virus, H5N1 Subtype/genetics , Disease Outbreaks , Influenza A virus/genetics
9.
Front Public Health ; 11: 1150228, 2023.
Article in English | MEDLINE | ID: mdl-37920576

ABSTRACT

Introduction: Dog-mediated rabies is enzootic in Vietnam, resulting in at least 70 reported human deaths and 500,000 human rabies exposures annually. In 2016, an integrated bite cases management (IBCM) based surveillance program was developed to improve knowledge of the dog-mediated rabies burden in Phu Tho Province of Vietnam. Methods: The Vietnam Animal Rabies Surveillance Program (VARSP) was established in four stages: (1) Laboratory development, (2) Training of community One Health workers, (3) Paper-based-reporting (VARSP 1.0), and (4) Electronic case reporting (VARSP 2.0). Investigation and diagnostic data collected from March 2016 to December 2019 were compared with historical records of animal rabies cases dating back to January 2012. A risk analysis was conducted to evaluate the probability of a rabies exposure resulting in death after a dog bite, based on data collected over the course of an IBCM investigation. Results: Prior to the implementation of VARSP, between 2012 and 2015, there was an average of one rabies investigation per year, resulting in two confirmed and two probable animal rabies cases. During the 46 months that VARSP was operational (2016 - 2019), 1048 animal investigations were conducted, which identified 79 (8%) laboratory-confirmed rabies cases and 233 (22%) clinically-confirmed(probable) cases. VARSP produced a 78-fold increase in annual animal rabies case detection (one cases detected per year pre-VARSP vs 78 cases per year under VARSP). The risk of succumbing to rabies for bite victims of apparently healthy dogs available for home quarantine, was three deaths for every 10,000 untreated exposures. Discussion: A pilot IBCM model used in Phu Tho Province showed promising results for improving rabies surveillance, with a 26-fold increase in annual case detection after implementation of a One Health model. The risk for a person bitten by an apparently healthy dog to develop rabies in the absence of rabies PEP was very low, which supports the WHO recommendations to delay PEP for this category of bite victims, when trained animal assessors are available and routinely communicate with the medical sector. Recent adoption of an electronic IBCM system is likely to expedite adoption of VARSP 2.0 to other Provinces and improve accuracy of field decisions and data collection.


Subject(s)
Bites and Stings , Rabies , Humans , Dogs , Animals , Rabies/epidemiology , Rabies/therapy , Rabies/veterinary , Case Management , Vietnam/epidemiology , Patient Acceptance of Health Care , Risk Assessment , Bites and Stings/epidemiology
10.
Heliyon ; 9(10): e20445, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37790968

ABSTRACT

This paper investigates the interconnection between Chief Executive Officer (CEO) power, green credit, and core competence of commercial banks in Vietnam. Our data sample consists of 373 annual observations from 2010 to 2021. We employ a dynamic system Generalized Method of Moments to analyze an unbalanced panel comprised of 373 annual observations from 2010 to 2021. The findings indicate an inverse U-shape relationship between CEO overpower and commercial banks' core competence. Moreover, the study reports that banks with green lending activities reduce core competence by about 0.1598 points more than other banks. In addition, the results indicate that CEO power moderates the relationship between green credit and core competence. Our findings align with stewardship, management entrenchment, first-mover advantage, stakeholder theories, and prior literature. The study has practical implications for policymakers to develop the banking system sustainably in emerging markets.

11.
JCO Precis Oncol ; 7: e2300208, 2023 09.
Article in English | MEDLINE | ID: mdl-37738545

ABSTRACT

PURPOSE: The main dose-limiting toxicity of anthracyclines is cardiotoxicity. Clonal hematopoiesis (CH), somatic mutations in hematopoietic stem or progenitor cells in patients without hematologic malignancy, is also associated with risk for adverse cardiovascular events and worse outcomes overall. We hypothesize that CH increases risk for doxorubicin-induced cardiotoxicity (DIC). METHODS: We conducted a retrospective cohort study in patients treated with doxorubicin for cancer (N = 100). Patients (n = 25) had incident symptomatic heart failure, decline in left ventricular ejection fraction, or arrhythmia. CH was identified using paired peripheral blood and tumor DNA. RESULTS: After adjusting for age at doxorubicin initiation, diabetes, dyslipidemia, and chest radiation, high cumulative dose of doxorubicin (>240 mg/m2; odds ratio [OR], 7.00; 95% CI, 1.77 to 27.74; P = .0056), CH (OR, 8.58; 95% CI, 2.05 to 35.99; P = .0033), and history of smoking (OR, 3.15; 95% CI, 1.00 to 9.93; P = .0495) were associated with DIC. CONCLUSION: This study provides preliminary evidence for CH as a predictive risk factor for DIC, which, with further investigation, could serve as an important precision medicine biomarker for the large number of patients with cancer who have CH.


Subject(s)
Cardiotoxicity , Clonal Hematopoiesis , Humans , Cardiotoxicity/etiology , Clonal Hematopoiesis/genetics , Retrospective Studies , Stroke Volume , Ventricular Function, Left , Risk Factors , Doxorubicin/adverse effects
12.
ACS Appl Mater Interfaces ; 15(37): 43756-43766, 2023 Sep 20.
Article in English | MEDLINE | ID: mdl-37695888

ABSTRACT

Galvanic exchange seeds the growth of Pt nanostructures on the Ni foam monolith. Subsequent atomic layer deposition of ultrathin Al2O3 followed by annealing under air affords supported Pt catalysts with ultralow loading (0.020 ppm). In addition to the expected enhancement of the stability of the Pt particles on the surface, the ∼2 nm Al2O3 overcoat appears to also play a crucial role in the overall structural integrity of the NiOx nanoplates that grow on the Ni foam surface as a result of the preparative route. The resulting material is physically robust toward repeated handling and showcases retention of catalytic activity over 10 standard catalyst recycling trials, standing in marked contrast to the uncoated samples. Catalyst activity was tested via the hydrogenation of various functionalized styrenes at low temperatures and low hydrogen pressure in ethanol as a solvent, with a TOF as high as 9.5 × 106 h-1 for unfunctionalized styrene. Notably, the catalysts show excellent tolerance toward F, Cl, and Br substituents and no hydrogenation of the aromatic ring.

13.
J Pediatr Endocrinol Metab ; 36(10): 903-908, 2023 Oct 26.
Article in English | MEDLINE | ID: mdl-37589444

ABSTRACT

Artificial Intelligence (AI) is integrating itself throughout the medical community. AI's ability to analyze complex patterns and interpret large amounts of data will have considerable impact on all areas of medicine, including pediatric endocrinology. In this paper, we review and update the current studies of AI in pediatric endocrinology. Specific topics that are addressed include: diabetes management, bone growth, metabolism, obesity, and puberty. Becoming knowledgeable and comfortable with AI will assist pediatric endocrinologists, the goal of the paper.


Subject(s)
Artificial Intelligence , Endocrinology , Child , Humans
14.
Front Endocrinol (Lausanne) ; 14: 1184360, 2023.
Article in English | MEDLINE | ID: mdl-37435481

ABSTRACT

G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A1 receptor (A1R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A1R has well-established roles in the regulation of the cardiovascular and nervous systems, where it has been identified as a potential therapeutic target for a number of conditions, including cardiac ischemia-reperfusion injury, cognition, epilepsy, and neuropathic pain. A1R small molecule drugs, typically orthosteric ligands, have undergone clinical trials. To date, none have progressed into the clinic, predominantly due to dose-limiting unwanted effects. The development of A1R allosteric modulators that target a topographically distinct binding site represent a promising approach to overcome current limitations. Pharmacological parameters of allosteric ligands, including affinity, efficacy and cooperativity, can be optimized to regulate A1R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A1R as a potential therapeutic target and highlight recent advances in the structural understanding of A1R allosteric modulation.


Subject(s)
Cognition , Receptor, Adenosine A1 , Humans , Adenosine , Binding Sites , Heart , Ligands
15.
Front Neurol ; 14: 1193220, 2023.
Article in English | MEDLINE | ID: mdl-37388541

ABSTRACT

Background: Although essential tremor (ET) patients have greater odds of mild cognitive impairment (MCI) and dementia than age-matched controls, the functional consequences of these enhanced odds are unknown. We examined associations between cognitive diagnosis and the occurrence of near falls, falls, use of a walking aid or a home health aide, non-independent living, or hospitalizations within a prospective, longitudinal study of ET patients. Methods: A total of 131 ET patients (mean baseline age = 76.4 ± 9.4 years) completed a battery of neuropsychological tests and questions about life events and were assigned diagnoses of normal cognition (NC), MCI, or dementia at the baseline and at 18-, 36-, and 54-month follow-ups. Kruskall-Wallis, chi-square, and Mantel-Haenszel tests assessed whether the diagnosis was associated with the occurrence of these life events. Results: Patients with final diagnoses of dementia were more often reported as living non-independently than NC or MCI patients and more often used walking aids than NC patients, with a p-value of <0.05. Patients with a final MCI or dementia diagnosis more often employed a home health aide than NC patients, with a p-value of <0.05. Moreover, Mantel-Haenzsel tests revealed linear associations between the occurrence of these outcomes and the level of cognitive impairment, with a p-value of <0.001 (i.e., dementia > MCI > NC). Conclusion: Cognitive diagnosis was associated with reported life events of ET patients, including the use of a mobility aid, employment of a home health aide, and removal from an independent living situation. These data provide rare insights into the important role cognitive decline plays in the experiences of ET patients.

16.
Br J Pharmacol ; 2023 May 10.
Article in English | MEDLINE | ID: mdl-37161878

ABSTRACT

The application of artificial intelligence (AI) approaches to drug discovery for G protein-coupled receptors (GPCRs) is a rapidly expanding area. Artificial intelligence can be used at multiple stages during the drug discovery process, from aiding our understanding of the fundamental actions of GPCRs to the discovery of new ligand-GPCR interactions or the prediction of clinical responses. Here, we provide an overview of the concepts behind artificial intelligence, including the subfields of machine learning and deep learning. We summarise the published applications of artificial intelligence to different stages of the GPCR drug discovery process. Finally, we reflect on the benefits and limitations of artificial intelligence and share our vision for the exciting potential for further development of applications to aid GPCR drug discovery. In addition to making the drug discovery process "faster, smarter and cheaper," we anticipate that the application of artificial intelligence will create exciting new opportunities for GPCR drug discovery.

17.
Appl Environ Microbiol ; 89(6): e0001223, 2023 06 28.
Article in English | MEDLINE | ID: mdl-37162365

ABSTRACT

Genetic engineering of hyperthermophilic organisms for the production of fuels and other useful chemicals is an emerging biotechnological opportunity. In particular, for volatile organic compounds such as ethanol, fermentation at high temperatures could allow for straightforward separation by direct distillation. Currently, the upper growth temperature limit for native ethanol producers is 72°C in the bacterium Thermoanaerobacter ethanolicus JW200, and the highest temperature for heterologously-engineered bioethanol production was recently demonstrated at 85°C in the archaeon Pyrococcus furiosus. Here, we describe an engineered strain of P. furiosus that synthesizes ethanol at 95°C, utilizing a homologously-expressed native alcohol dehydrogenase, termed AdhF. Ethanol biosynthesis was compared at 75°C and 95°C with various engineered strains. At lower temperatures, the acetaldehyde substrate for AdhF is most likely produced from acetate by aldehyde ferredoxin oxidoreductase (AOR). At higher temperatures, the effect of AOR on ethanol production is negligible, suggesting that acetaldehyde is produced by pyruvate ferredoxin oxidoreductase (POR) via oxidative decarboxylation of pyruvate, a reaction known to occur only at higher temperatures. Heterologous expression of a carbon monoxide dehydrogenase complex in the AdhF overexpression strain enabled it to use CO as a source of energy, leading to increased ethanol production. A genome reconstruction model for P. furiosus was developed to guide metabolic engineering strategies and understand outcomes. This work opens the door to the potential for 'bioreactive distillation' since fermentation can be performed well above the normal boiling point of ethanol. IMPORTANCE Previously, the highest temperature for biological ethanol production was 85°C. Here, we have engineered ethanol production at 95°C by the hyperthermophilic archaeon Pyrococcus furiosus. Using mutant strains, we showed that ethanol production occurs by different pathways at 75°C and 95°C. In addition, by heterologous expression of a carbon monoxide dehydrogenase complex, ethanol production by this organism was driven by the oxidation of carbon monoxide. A genome reconstruction model for P. furiosus was developed to guide metabolic engineering strategies and understand outcomes.


Subject(s)
Pyrococcus furiosus , Fermentation , Pyrococcus furiosus/genetics , Pyrococcus furiosus/metabolism , Carbon Monoxide/metabolism , Ethanol/metabolism , Metabolic Engineering , Pyruvic Acid/metabolism , Acetaldehyde/metabolism
18.
J Neurol Sci ; 450: 120675, 2023 07 15.
Article in English | MEDLINE | ID: mdl-37196573

ABSTRACT

BACKGROUND: Although essential tremor (ET) is associated with cognitive decline, we know little about how specific cognitive changes predict significant events in patients' lives. We examined the relations of attention, executive function, language, memory, and visuospatial performance to the occurrence of near falls, falls, walking aid use, home health aide use, non-independent living and hospitalizations within a prospective, longitudinal study of ET cases. We expected executive function and memory to be most strongly associated with these events. METHODS: 131 ET cases (mean age at baseline = 76.4 ± 9.4 years; 109 normal cognition; 17 mild cognitive impairment, 5 demented) completed questionnaires (clinical history and occurrence of life events) and a battery of neuropsychological tests at baseline and at 18, 36, and 54 months. We assessed associations between cognitive functioning and outcomes via regression equations. RESULTS: Cases with lower baseline levels of executive function reported more near falls, p < 0.006, and were more likely to use a walking aid, p < 0.03, odds ratio (OR) = 2.89 during the follow-up period, than were other cases. Decline in executive function was associated with home health aide use during follow-up, p < 0.04, OR = 3.34. Baseline visuospatial performance also bore a marginally significant association with non-independent living arrangements during follow-up, p < 0.06, OR = 2.13. These effects were independent of age and tremor severity. CONCLUSION: These data establish the important role that cognitive decline, and executive function specifically, play in the experiences of ET patients. Moreover, these associations are of sufficient magnitude to have significant clinical implications.


Subject(s)
Cognitive Dysfunction , Essential Tremor , Humans , Aged , Aged, 80 and over , Cohort Studies , Longitudinal Studies , Essential Tremor/complications , Prospective Studies , Cognition , Executive Function , Cognitive Dysfunction/psychology , Neuropsychological Tests
19.
Surg Pract Sci ; 13: 100172, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37139165

ABSTRACT

Background: The COVID-19 pandemic presented patients with barriers to receiving healthcare. We sought to determine whether changes in healthcare access and practice during the pandemic affected perioperative outcomes after robotic-assisted pulmonary lobectomy (RAPL). Methods: We retrospectively analyzed 721 consecutive patients who underwent RAPL. With March 1st, 2020, defining the start of the COVID-19 pandemic, we grouped 638 patients as "PreCOVID-19" and 83 patients as "COVID-19-Era" based on surgical date. Demographics, comorbidities, tumor characteristics, intraoperative complications, morbidity, and mortality were analyzed. Variables were compared utilizing Student's t-test, Wilcoxon rank-sum test, and Chi-square (or Fisher's exact) test, with significance at p ≤ 0.05 . Multivariable generalized linear regression was used to investigate predictors of postoperative complication. Results: COVID-19-Era patients had significantly higher preoperative FEV1%, lower cumulative smoking history and higher incidences of preoperative atrial fibrillation, peripheral vascular disease (PVD), and bleeding disorders compared to PreCOVID-19 patients. COVID-19-Era patients had lower intraoperative estimated blood loss (EBL), reduced incidence of new-onset postoperative atrial fibrillation (POAF), but higher incidence of effusion or empyema postoperatively. Overall postoperative complication rates between the groups were similar. Older age, increased EBL, lower preoperative FEV1%, and preoperative COPD are all predictive of an increased risk for postoperative complication. Conclusions: COVID-19-Era patients having lower EBL and less new-onset POAF, despite greater incidences of multiple preoperative comorbidities, demonstrates that RAPL is safe during the COVID-19 era. Risk factors for development of postoperative effusion should be determined to minimize risk of empyema in COVID-19-Era patients. Age, preoperative FEV1%, COPD, and EBL should all be considered when planning for complication risk.

20.
Nat Nanotechnol ; 18(6): 667-676, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37012508

ABSTRACT

Remote and precisely controlled activation of the brain is a fundamental challenge in the development of brain-machine interfaces for neurological treatments. Low-frequency ultrasound stimulation can be used to modulate neuronal activity deep in the brain, especially after expressing ultrasound-sensitive proteins. But so far, no study has described an ultrasound-mediated activation strategy whose spatiotemporal resolution and acoustic intensity are compatible with the mandatory needs of brain-machine interfaces, particularly for visual restoration. Here we combined the expression of large-conductance mechanosensitive ion channels with uncustomary high-frequency ultrasonic stimulation to activate retinal or cortical neurons over millisecond durations at a spatiotemporal resolution and acoustic energy deposit compatible with vision restoration. The in vivo sonogenetic activation of the visual cortex generated a behaviour associated with light perception. Our findings demonstrate that sonogenetics can deliver millisecond pattern presentations via an approach less invasive than current brain-machine interfaces for visual restoration.


Subject(s)
Ectopic Gene Expression , Visual Cortex , Neurons/metabolism , Retina , Vision, Ocular
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