Molecular Pumps and Motors.

Pumps and motors are essential components of the world as we know it. From the complex proteins that sustain our cells, to the mechanical marvels that power industries, much we take for granted is only possible because of pumps and motors. Although molecular pumps and motors have supported life for eons, it is only recently that chemists have made progress toward designing and building artificial forms of the microscopic machinery present in nature. The advent of artificial molecular machines has granted scientists an unprecedented level of control over the relative motion of components of molecules through the development of kinetically controlled, away-from-thermodynamic equilibrium chemistry. We outline the history of pumps and motors, focusing specifically on the innovations that enable the design and synthesis of the artificial molecular machines central to this Perspective. A key insight connecting biomolecular and artificial molecular machines is that the physical motions by which these machines carry out their function are unambiguously in mechanical equilibrium at every instant. The operation of molecular motors and pumps can be described by trajectory thermodynamics, a theory based on the work of Onsager, which is grounded on the firm foundation of the principle of microscopic reversibility. Free energy derived from thermodynamically non-equilibrium reactions kinetically favors some reaction pathways over others. By designing molecules with kinetic asymmetry, one can engineer potential landscapes to harness external energy to drive the formation and maintenance of geometries of component parts of molecules away-from-equilibrium, that would be impossible to achieve by standard synthetic approaches.

Convergent Strategy for the Synthesis of Oxa-, Thia-, and Selena[5]helicenes by Acetylene-Activated SNAr Reactions.

A tandem acetylene-activated SNAr-anionic cyclization strategy is presented for the synthesis of chalcogen-containing hetero[5]helicenes. Oxa-, thia-, and selena[5]helicenes are accessed from common ortho-fluoro-ethynylarene precursors, allowing the heteroatoms to be installed at the 1-position or 1- and 12-positions of the hetero[5]helicene inner core surface.

Factors associated with poor CD4 and viral load outcomes in patients with HIV/AIDS.

Suboptimal viral suppression and CD4 response to antiretroviral treatment (HAART) is known to cause poor outcomes with the increase cost of treatment. We aimed to assess factors associated with such control among HIV/AIDS patients in Malaysia. Four hundred and six HIV/AIDS patients, using Antiretroviral Therapy (ART) for at least the past three months, treated as outpatients at medication therapy adherence clinics (MTAC) were recruited. CD4 cell counts, viral load readings along with co-variants such as socio-demographic factors, adverse drug reactions, comorbidities, and medication record were obtained. Statistical Package for Social Sciences (SPSS(®)) version 18 and STATA IC(®) version 12 were used for data analysis. CD4 counts were found highest among those within the age category 41-50 years (390.43 ± 272.28), female (402.64 ± 276.14), other ethnicities (400.20 ± 278.04), and participants with no formal education (414.87 ± 290.90). Patients experiencing adverse effects had a 2.28 (95%CI:1.25-4.18) fold greater risk of poor CD4 control, while patients with comorbidities had 2.46 (95%CI:1.02-5.91) fold greater risk of mild viral suppression. Adverse drug reactions, co-morbidities were found to be significantly associated with poor immunological and virological outcomes in HIV/AIDS patients. However, a comprehensive evaluation is needed to better understand other confounders.

A qualitative insight of HIV/AIDS patients' perspective on disease and disclosure.

BACKGROUND: Understanding patients' knowledge and belief towards disease could play a vital role from an outcome perspective of disease management and HIV/AIDS patients are not exception to that. METHODS: Qualitative methodology was used to explore Malaysian HIV/AIDS patients' perspectives on disease and status disclosure. A semi structured interview guide was used to interview the patients and a saturation point was reached after the 13th interview. All interviews were audio-recorded and subjected to a standard content analysis framework. RESULTS: Understandings and beliefs towards HIV/AIDS and Perspective on disease disclosures were two main themes derived from patients' data. Beliefs towards causes and cure emerged as sub-themes under disease understandings while reasons for disclosure and non-disclosure were resulted as main sub-themes under disease disclosure. Majority of patients apprehended HIV/AIDS and its causes to acceptable extent, there were elements of spirituality and lack of education involved with such understandings. Though beliefs existed that knowing status is better than being ignorant, fear of stigma and discrimination, social consequences and family emotions were found important elements linked to disease non-disclosure. CONCLUSIONS: The outcomes provided basic information about patients' perceptions towards disease and status disclosure among HIV/AIDS patients which can help in the designing and improvising existing strategies to enhance disease awareness and acceptance and will also serve as baseline data for future research further focusing on this subject.

Assessing HIV and AIDS treatment safety and health-related quality of life among cohort of Malaysian patients: a discussion on methodological approach.

BACKGROUND: Health-related quality of life (HRQoL) is increasingly recognized as an important outcome and as a complement to traditional biological end points of diseases such as mortality. Unless there is a complete cure available for HIV/AIDS, development and implementation of a reliable and valid cross cultural quality of life measure is necessary to assess not only the physical and medical needs of HIV/AIDS people, but their psychological, social, environmental, and spiritual areas of life. METHODS: A qualitative exploration of HIV/AIDS patients' understanding, perceptions and expectations will be carried out with the help of semi structured interview guide by in depth interviews, while quantitative assessment of patient reported adverse drug reactions and their impact on health related quality of life will be carried out by using data collection tool comprising patient demographics, SF-12, Naranjo scale, and a clinical data sheet. RESULTS/OUTCOMES: The findings may serve as baseline QOL data of people living with HIV/AIDS in Malaysia and also a source data to aid construction of management plan to improve HIV/AIDS patients' QOL. It will also provide basic information about HIV/AIDS patients' perceptions, expectations and believes towards HIV/AIDS and its treatment which may help in designing strategies to enhance patients' awareness which in turn can help in addressing issues related to compliance and adherence.

Is forced migration a barrier to treatment success? Similar HIV treatment outcomes among refugees and a surrounding host community in Kuala Lumpur, Malaysia.

In response to an absence of studies among refugees and host communities accessing highly active antiretroviral therapy (HAART) in urban settings, our objective was to compare adherence and virological outcomes among clients attending a public clinic in Kuala Lumpur, Malaysia. A cross-sectional survey was conducted among adult clients (≥18 years). Data sources included a structured questionnaire that measured self-reported adherence, a pharmacy-based measure of HAART prescription refills over the previous 24 months, and HIV viral loads. The primary outcome was unsuppressed viral load (≥40 copies/mL). Among a sample of 153 refugees and 148 host community clients, refugees were younger (median age 35 [interquartile range, IQR 31, 39] vs 40 years [IQR 35, 48], p < 0.001), more likely to be female (36 vs 21 %, p = 0.004), and to have been on HAART for less time (61 [IQR 35, 108] vs 153 weeks [IQR 63, 298]; p < 0.001). Among all clients, similar proportions of refugee and host clients were <95 % adherent to pharmacy refills (26 vs 34 %, p = 0.15). When restricting to clients on treatment for ≥25 weeks, similar proportions from each group were not virologically suppressed (19 % of refugees vs 16 % of host clients, p = 0.54). Refugee status was not independently associated with the outcome (adjusted odds ratio, aOR = 1.28, 95 % CI 0.52, 3.14). Overall, the proportions of refugee and host community clients with unsuppressed viral loads and sub-optimal adherence were similar, supporting the idea that refugees in protracted asylum situations are able to sustain good treatment outcomes and should explicitly be included in the HIV strategic plans of host countries with a view to expanding access in accordance with national guidelines for HAART.

Assessment of Gender Differences in Letters of Recommendation for Physical Therapy Residency Applications.

INTRODUCTION: Letters of recommendation (LOR) are an integral component of physical therapy residency applications. Identifying the influence of applicant and writer gender in LOR will help identify whether potential implicit gender bias exists in physical therapy residency application processes. REVIEW OF LITERATURE: Several medical and surgical residency education programs have reported positive, neutral, or negative LOR female gender bias among applicants and writers. Little research exists on gender differences in LOR to physical therapy education programs or physical therapy residency programs. SUBJECTS: Seven hundred sixty-eight LOR were analyzed from 256 applications to 3 physical therapy residency programs (neurologic, orthopaedic, sports) at one institution from 2014 to 2020. METHODS: Thematic categories were developed to identify themes in a sample of LOR. Associations between writer and applicant gender were analyzed using summary statistics, word counts, thematic and psycholinguistic extraction, and rule-based and deep learning Natural Language Processing . RESULTS: No significant difference in LOR word counts were found based on writer or applicant gender. Increased word counts were seen in sports residency LOR compared with the orthopaedic residency. Thematic analysis showed LOR gender differences with male applicants receiving more positive generalized recommendations and female applicants receiving more comments regarding interpersonal relationship skills. No thematic or psycholinguistic gender differences were seen by LOR writer. Male applicants were 1.9 times more likely to select all male LOR writers, whereas female applicants were 2.1 times more likely to choose all female LOR writers. DISCUSSION AND CONCLUSION: Gender differences in LORs for physical therapy residencies were found using a comprehensive Natural Language Processing approach that identified both a positive recommendation male applicant gender bias and a positive interpersonal relationship skill female applicant gender bias. Applicants were not harmed nor helped by selecting LOR writers of the opposite gender. Admissions committees and LOR writers should be mindful of potential implicit gender biases in LOR submitted to physical therapy residency programs.

Gender-based Language Differences in Letters of Recommendation.

Gender stereotyping is the practice of assigning or ascribing specific characteristics, differences, or identities to a person solely based on their gender. Biased conceptions of gender can create barriers to equality and need to be proactively identified and addressed. In biomedical education, letters of recommendation (LOR) are considered an important source for evaluating candidates' past performance. Because LOR is subjective and has no standard formatting requirements for the writer, potential language bias can be introduced. Natural language processing (NLP) offers a promising solution to detect language bias in LOR through automatic extraction of sensitive language and identification of letters with strong biases. In our study, we developed, evaluated, and deployed four NLP different methods (sublanguage analysis, dictionary-based approach, rule-based approach, and deep learning approach) for the extraction of psycholinguistics and thematic characteristics in LORs from three different physical therapy residency programs (Neurologic, Orthopaedic, and Sport) at Mayo Clinic. The evaluation statistics suggest that both MedTaggerIE model and Bidirectional Encoder Representations from Transformers model achieved moderate-high performance across eight different thematic categories. Through the pilot demonstration study, we learned that male writers were more likely to use the words 'intelligence', 'exceptional', and 'pursue' and male applicants were more likely to have the words 'strength', 'interpersonal skills', 'conversations', and 'pursue' in their letters of recommendation. Thematic analysis suggested that male and female writers have significant differences in expressing doubt, motivation, and recommendation. Findings derived from the study needed to be carefully interpreted based on the context of the study setting, residency programs, and data. A follow-up demonstration study is needed to further evaluate and interpret the findings.

Factors affecting chemical-based purification of DNA from Saccharomyces cerevisiae.

Extraction of high molecular weight chromosomal DNA from yeast cells is a procedure that is performed frequently for experiments involving polymerase chain reaction (PCR), Southern blotting and other DNA analysis techniques. We have investigated several parameters affecting DNA yield and quality, using a simple chemical-based purification procedure that was modelled on alkaline lysis methods developed for bacterial cells. The three major steps of the procedure, cell lysis, protein removal and DNA precipitation, were optimized by testing the impacts of several chemicals, including sodium dodecyl sulphate (SDS), sodium hydroxide, Tris buffer, sodium acetate and potassium acetate. Other parameters, such as the effect of elevated temperatures on cell lysis, were also investigated. A rapid, optimized protocol was derived for the purification of DNA from small cell cultures that can be readily digested with restriction enzymes and used as a template for PCR. Average yield was calculated to be approximately 1.7 µg DNA/10(8) cells, which is similar to the theoretical maximum amount obtainable from haploid yeast cells.

HIV-1 drug resistance mutations among antiretroviral-naive HIV-1-infected patients in Asia: results from the TREAT Asia Studies to Evaluate Resistance-Monitoring Study.

Of 682 antiretroviral-naïve patients initiating antiretroviral therapy in a prospective, multicenter human immunodeficiency virus type 1 (HIV-1) drug resistance monitoring study involving 8 sites in Hong Kong, Malaysia, and Thailand, the prevalence of patients with ≥1 drug resistance mutation was 13.8%. Primary HIV drug resistance is emerging after rapid scaling-up of antiretroviral therapy use in Asia.

Prevalence of and risk factors for lipodystrophy among HIV-infected patients receiving combined antiretroviral treatment in the Asia-Pacific region: results from the TREAT Asia HIV Observational Database (TAHOD).

The prevalence of and risk factors for lipodystrophy (LD) among patients receiving combined antiretroviral treatment (cART) in the Asia-Pacific region are largely unknown. LD diagnosis was based on the adverse event definition from the US NIH Division of AIDS (2004 version), and only cases with a severity grade of ≥ 3 were included. TAHOD patients who had recently commenced cART with ≥ 3 drugs after 1996 from sites which had ever reported LD were included in the analysis. Covariates for the forward multivariate logistic regression model included demographic variables, CDC disease classification, baseline CD4 and viral load, hepatitis B/C virus co-infection, and regimen and duration of cART. LD was diagnosed in 217 (10.5%) of 2072 patients. The median duration of cART was 3.8 (interquartile range, 2.2-5.3) years [stavudine, 2.0 (1.0-3.5) years; zidovudine, 1.8 (0.6-3.9) years; and protease inhibitors (PI), 2.6 (1.3-4.5) years]. In the multivariate model, factors independently associated with LD included use of stavudine (≤ 2 years vs. no experience: OR 25.46, p<0.001, > 2 years vs. no experience: OR 14.92, p<0.001), use of PI (> 2.6 years vs. no experience: OR 0.26, p<0.001), and total duration of cART (> vs. ≤ 3.8 years: OR 4.84, p<0.001). The use of stavudine was strongly associated with LD in our cohort. Stavudine-sparing cART strategies are warranted to prevent the occurrence of LD in the Asia-Pacific region.

Trends in CD4 counts in HIV-infected patients with HIV viral load monitoring while on combination antiretroviral treatment: results from The TREAT Asia HIV Observational Database.

BACKGROUND: The aim of this study was to examine the relationship between trends in CD4 counts (slope) and HIV viral load (VL) after initiation of combination antiretroviral treatment (cART) in Asian patients in The TREAT Asia HIV Observational Database (TAHOD). METHODS: Treatment-naive HIV-infected patients who started cART with three or more and had three or more CD4 count and HIV VL tests were included. CD4 count slopes were expressed as changes of cells per microliter per year. Predictors of CD4 count slopes from 6 months after initiation were assessed by random-effects linear regression models. RESULTS: A total of 1676 patients (74% male) were included. The median time on cART was 4.2 years (IQR 2.5-5.8 years). In the final model, CD4 count slope was associated with age, concurrent HIV VL and CD4 count, disease stage, hepatitis B or C co-infection, and time since cART initiation. CD4 count continues to increase with HIV VL up to 20,000 copies/mL during 6-12 months after cART initiation. However, the HIV VL has to be controlled below 5,000, 4,000 and 500 copies/mL for the CD4 count slope to remain above 20 cells/microliter per year during 12-18, 18-24, and beyond 24 months after cART initiation. CONCLUSIONS: After cART initiation, CD4 counts continued to increase even when the concurrent HIV VL was detectable. However, HIV VL needed to be controlled at a lower level to maintain a positive CD4 count slope when cART continues. The effect on long-term outcomes through the possible development of HIV drug resistance remains uncertain.

Short-term clinical disease progression in HIV-infected patients receiving combination antiretroviral therapy: results from the TREAT Asia HIV observational database.

OBJECTIVE: The aim of our study was to develop, on the basis of simple clinical data, predictive short-term risk equations for AIDS or death in Asian patients infected with human immunodeficiency virus (HIV) who were included in the TREAT Asia HIV Observational Database. METHODS: Inclusion criteria were highly active antiretroviral therapy initiation and completion of required laboratory tests. Predictors of short-term AIDS or death were assessed using Poisson regression. Three different models were developed: a clinical model, a CD4 cell count model, and a CD4 cell count and HIV RNA level model. We separated patients into low-risk, high-risk, and very high-risk groups according to the key risk factors identified. RESULTS: In the clinical model, patients with severe anemia or a body mass index (BMI; calculated as the weight in kilograms divided by the square of the height in meters)

Risk and prognostic significance of tuberculosis in patients from The TREAT Asia HIV Observational Database.

BACKGROUND: To assess the risk and the prognostic significance of tuberculosis (TB) diagnosis in patients from The TREAT Asia HIV Observational Database, a multi-centre prospective cohort of HIV-infected patients receiving HIV care in the Asia-Pacific region. METHODS: The risk of TB diagnosis after recruitment was assessed in patients with prospective follow-up. TB diagnosis was fitted as a time-dependent variable in assessing overall survival. RESULTS: At baseline, 22% of patients were diagnosed with TB. TB incidence was 1.98 per 100 person-years during follow up, with predictors including younger age, lower recent CD4 count, duration of antiretroviral treatment, and living in high TB burden countries. Among 3279 patients during 6968 person-years, 142 died (2.04 per 100 person-years). Compared to patients with CDC category A or B illness only, mortality was marginally higher in patients with single Non-TB AIDS defining illness (ADI), or TB only (adjusted HR 1.35, p = 0.173) and highest in patients with multiple non-TB AIDS or both TB and other ADI (adjusted HR 2.21, p < 0.001). CONCLUSION: The risk of TB diagnosis was associated with increasing immunodeficiency and partly reduced by antiretroviral treatment. The prognosis of developing TB appeared to be similar to that following a diagnosis of other non-TB ADI.

Facilitators and Barriers Affecting Adherence Among People Living With HIV/AIDS: A Qualitative Perspective.

BACKGROUND: It is widely accepted that for HIV-positive persons on highly active antiretroviral treatment, high levels of adherence to treatment regimens are essential for promoting viral suppression and preventing drug resistance. OBJECTIVES: This qualitative study examines factors affecting the adherence to HIV/AIDS treatment among patients with HIV/AIDS at a local hospital in Malaysia. METHODS: The data from purposefully selected patients were collected by in-depth interviews using a pretested interview guide. Saturation was reached at the 13th interview. All interviews were audio-taped and transcribed verbatim for analysis using thematic content analysis. RESULTS: Fear and stigma of perceived negative image of HIV diagnosis, lack of disease understating, poor support from the community, and perceived severity or the treatment side effects were among the reasons of nonadherence. Appropriate education and motivation from the doctors and reduction in pill burden were suggested to improve adherence. CONCLUSION: Educational interventions, self-management, and peer and community supports were among the factors suggested to improve adherence. This necessitates uncovering efficient ways to boost doctor-patient communication and recognizing the role of support group for the social and psychological well-being of the patients.

The Balance Between Metalloproteinases and TIMPs: Critical Regulator of Microvascular Endothelial Cell Function in Health and Disease.

Endothelial cells (EC), especially the microvascular EC (MVEC), have critical functions in health and disease. For example, healthy MVEC provide a barrier between the fluid and protein found within the blood, and the surrounding tissue. Following tissue injury or infection, the microvascular barrier is often disrupted due to activation and dysfunction of the MVEC. Multiple mechanisms promote MVEC activation and dysfunction, including stimulation by cytokines, mechanical interaction with activated leukocytes, and exposure to harmful leukocyte-derived molecules, which collectively result in a loss of MVEC barrier function. However, MVEC activation is also critical to facilitate recruitment of inflammatory cells, such as neutrophils (PMNs) and monocytes, into the injured or infected tissue. Metalloproteinases, including the matrix metalloproteinases (MMPs) and the closely related, a disintegrin and metalloproteinases (ADAMs), have been implicated in regulating both MVEC barrier function, through cleavage of adherens and tight junctions proteins between adjacent MVEC and through degradation of the extracellular matrix, as well as PMN-MVEC interaction, through shedding of cell surface PMN receptors. Moreover, the tissue inhibitors of metalloproteinases (TIMPs), which collectively inhibit most MMPs and ADAMs, are critical regulators of MVEC activation and dysfunction through their ability to inhibit metalloproteinases and thereby promote MVEC stability. However, TIMPs have been also found to modulate MVEC function through metalloproteinase-independent mechanisms, such as regulation of vascular endothelial growth factor signaling. This chapter is focused on examining the role of the metalloproteinases and TIMPs in regulation of MVEC function in both health and disease.

Physician Decisions to Defer Antiretroviral Therapy in Key Populations: Implications for Reducing Human Immunodeficiency Virus Incidence and Mortality in Malaysia.

BACKGROUND: Antiretroviral therapy (ART) is recommended for all people living with human immunodeficiency virus (HIV), yet physician attitudes and prescribing behaviors toward members of key risk populations may limit ART access and undermine treatment as prevention strategies. METHODS: Physicians in Malaysia (N = 214) who prescribe antiretroviral therapy (ART) responded in an Internet-based survey to hypothetical clinical scenarios of HIV patients, varying by key risk population and CD4+ T-cell count, on whether they would initiate or defer ART compared with a control patient with sexually acquired HIV. RESULTS: The proportion of physicians who would defer ART in patients with advanced HIV (CD4 = 17 cells/µL) was significantly higher (P < .0001) for 4 key populations, including people who inject drugs ([PWID] 45.3%) or consume alcohol (42.1%), released prisoners (35.0%), and those lacking social support (26.6%), compared with a control patient (4.2%). People who inject drugs with advanced HIV (CD4 = 17 cells/µL) were 19-fold (adjusted odds ratio [AOR] = 18.9; 95% confidence interval [CI], 9.8-36.5) more likely to have ART deferred compared with the control. This effect was partially mitigated for PWID receiving methadone (AOR = 2.9; 95% CI, 1.5-5.7). At the highest CD4+ T-cell count (CD4 = 470 cells/µL), sex workers (AOR = 0.55; 95% CI, .44-.70) and patients with an HIV-uninfected sexual partner (AOR = 0.43; 95% CI, .34-.57) were significantly less likely to have ART deferred. CONCLUSIONS: Physicians who prescribe antiretroviral therapy in Malaysia may defer ART in some key populations including PWID and released prisoners, regardless of CD4+ T-cell count, which may help to explain very low rates of ART coverage among PWID in Malaysia. Reducing HIV incidence and mortality in Malaysia, where HIV is concentrated in PWID and other key populations, requires clinician-level interventions and monitoring physician adherence to international evidence-based treatment guidelines.

A comparison of assays for accurate copy number measurement of the low-affinity Fc gamma receptor genes FCGR3A and FCGR3B.

The FCGR3 locus encoding the low affinity activating receptor FcγRIII, plays a vital role in immunity triggered by cellular effector and regulatory functions. Copy number of the genes FCGR3A and FCGR3B has previously been reported to affect susceptibility to several autoimmune diseases and chronic inflammatory conditions. However, such genetic association studies often yield inconsistent results; hence require assays that are robust with low error rate. We investigated the accuracy and efficiency in estimating FCGR3 CNV by comparing Sequenom MassARRAY and paralogue ratio test-restriction enzyme digest variant ratio (PRT-REDVR). In addition, since many genetic association studies of FCGR3B CNV were carried out using real-time quantitative PCR, we have also included the evaluation of that method's performance in estimating the multi-allelic CNV of FCGR3B. The qPCR assay exhibited a considerably broader distribution of signal intensity, potentially introducing error in estimation of copy number and higher false positive rates. Both Sequenom and PRT-REDVR showed lesser systematic bias, but Sequenom skewed towards copy number normal (CN = 2). The discrepancy between Sequenom and PRT-REDVR might be attributed either to batch effects noise in individual measurements. Our study suggests that PRT-REDVR is more robust and accurate in genotyping the CNV of FCGR3, but highlights the needs of multiple independent assays for extensive validation when performing a genetic association study with multi-allelic CNVs.

Antibiotic management of complicated intra-abdominal infections in adults: The Asian perspective.

Regional epidemiological data and resistance profiles are essential for selecting appropriate antibiotic therapy for intra-abdominal infections (IAIs). However, such information may not be readily available in many areas of Asia and current international guidelines on antibiotic therapy for IAIs are for Western countries, with the most recent guidance for the Asian region dating from 2007. Therefore, the Asian Consensus Taskforce on Complicated Intra-Abdominal Infections (ACT-cIAI) was convened to develop updated recommendations for antibiotic management of complicated IAIs (cIAIs) in Asia. This review article is based on a thorough literature review of Asian and international publications related to clinical management, epidemiology, microbiology, and bacterial resistance patterns in cIAIs, combined with the expert consensus of the Taskforce members. The microbiological profiles of IAIs in the Asian region are outlined and compared with Western data, and the latest available data on antimicrobial resistance in key pathogens causing IAIs in Asia is presented. From this information, antimicrobial therapies suitable for treating cIAIs in patients in Asian settings are proposed in the hope that guidance relevant to Asian practices will prove beneficial to local physicians managing IAIs.