Association of current income and reduction in income during the COVID-19 pandemic with anxiety and depression among non-healthcare workers.

BACKGROUND: Many workers experienced income reduction during the coronavirus disease 2019 (COVID-19) pandemic, which may link to adverse mental health. AIMS: This study aimed to examine the association of current income and reduction in income during COVID-19 with anxiety and depression levels among non-healthcare workers. METHODS: This is a multi-city cross-sectional study. We used standardized questionnaires to collect information. We regrouped the current income and income reduction during COVID-19 according to the tertile and median value of each specific city. Depression, Anxiety and Stress Scales-21 item short version (DASS-21) was used to assess anxiety and depression levels. We performed multinomial logistic regression to examine the association of current and reduced income with anxiety and depression. Path models were developed to outline the potential modification/indirect effect of subsidies from government. RESULTS: Large income reduction and low current income were significantly associated with more anxiety/depression symptoms. Path analysis showed that government subsidies could not significantly alleviate the impact of reduced income on anxiety/depression. CONCLUSION: Our findings showed that large income reduction and low current income were independently associated with anxiety/depression, while these symptoms may not be ameliorated by one-off government funds. This study suggests the need for long-term policies (e.g. developing sustained economic growth policies) to mitigate negative impacts of the COVID-19.

Compliance and attitudes of blood donors following transitioning from permanent to 12-month deferral of men who have sex with men in Hong Kong.

BACKGROUND AND OBJECTIVES: Blood safety hinges not just on the scientific rationale for deferral period but potential donors' compliance with the prevailing policy. This study aimed to investigate donors' awareness, attitudes and compliance with the two-phased policy implementation of time-limited deferral for men who have sex with men (MSM) in Hong Kong. MATERIALS AND METHODS: Three rounds of questionnaire survey were conducted between July 2017 and June 2019 covering the periods of pre-implementation (Round A), post-implementation without and with pre-donation questionnaire revision (Round B and C). Chi-square test and multivariable regression analysis were performed. RESULTS: Of 3085 donors recruited, 968, 1036 and 1081 completed the surveys in Round A, B and C, respectively. The non-compliance rate of MSM remained stable at 0·6% (3/497), 0·4% (2/551) and 0·5% (3/587) among male donors in Round A, B and C, respectively. Two MSM donors from Round C complying with the prevailing policy were identified. About two-thirds (60·7%) of respondents from Round B and C were unaware of the policy change. Overall, over 80% were either neutral or positive about the change. CONCLUSION: Our study showed a consistently low non-compliance rate of MSM over the three periods. The generally high level of acceptance of time-limited deferral among donors lends support to science-based policy development to protect blood safety. The identification of compliant MSM donors suggests that the 12-month deferral is effective and acceptable to MSM. With a deferral period far exceeding the window period, it is a step towards a more equitable policy.

Collaborate across silos: Perceived barriers to integration of care for the elderly from the perspectives of service providers.

PURPOSE: To examine the barriers that hinder collaboration between health care and social care services and to report recommendations for effective collaboration to meet the growing support and care needs of our ageing population. METHODS: Data for this qualitative study were obtained from interviews with 7 key informants (n = 42) and 22 focus groups (n = 117) consisting of service providers who were from the health care or social care sectors and supporting elderly patients with multiple chronic diseases or long-term care needs. Data collection was conducted from 2015 to 2016. The data were analysed using an inductive approach on the basis of thematic analysis. FINDINGS: Qualitative analysis reviewed a number of factors that play a significant role in setting up barriers at the operational level, including fragmentation and lack of sustainability of discharge programmes provided by non-governmental organisations, lack of capacity of homes for the elderly, limitation of time and resources, and variation of roles in supporting end-of-life care decisions between the medical and social sectors. Other barriers are those of communication to be found at the structural level and perceptual ones that exist between professionals. Of these, perceptual barriers affect attitudes and create mistrust and interprofessional stereotypes and a hierarchy between the health care and social care sectors. CONCLUSION: Health care and social care service providers recognise the need for collaborative work to enhance continuity of care and ageing in place; however, their efforts are hindered by the identified barriers that need to be dealt with in practical terms and by a change of policy.

Caregivers' Experience of End-of-Life Stage Elderly Patients: Longitudinal Qualitative Interview.

OBJECTIVES: This study seeks to provide an understanding of the changing experiences in caregivers of end-of-life patients in Hong Kong through exploring their caregiving journey. METHODS: Using longitudinal individual qualitative interviews, a total of 14 caregivers of community-dwelling elderly patients receiving end-of-life care were recruited between 2015 and 2016. A series of in-depth interviews and observations were conducted in 14 cases during the end-of-life journey. RESULTS: A thematic analysis revealed four sequential experiential stages, abbreviated as "CAPE" that caregivers confronted: Stage 1 Certainty, (1a) lack of certainty regarding the progression of decline at the end-stage of life (1b) feelings of despair as patients' function decreased; Stage 2 Ambivalence, (2a) feelings of ambivalence after decisions were made regarding EOL care, (2b) struggle over care responsibility within families; Stage 3 Perturbed, (3a) varied in quality of EOL care, (3b) depressed mood arisen from frequent exposure to the suffering of elderly patients; and Stage 4 Expectation, (4a) losing the caregiving role as patients showing signs of imminent death. CONCLUSIONS: These findings increase our understanding of caregivers' in-depth experience over time that arise within the structural context of end-of-life care. Our data highlights the need for end of life related knowledge and information, provision of a caring atmosphere and communication, and professional-led detachment in creating caregiving-friendly service in healthcare system, thus as to provide support and alleviate stress for caregivers with their critical responsibility and role during the course of end-of-life care.

What makes an optimal delivery for PrEP against HIV: A qualitative study in MSM.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is an effective means of HIV prevention for men who have sex with men (MSM), a key population whose engagement is crucial for achieving effective public health outcomes. An optimal service model would be important in planning the implementation of PrEP in places where such service has not been established. METHODS: A qualitative study was conducted to delineate the attributes of an optimal PrEP service model for MSM in Hong Kong, a city where no formal PrEP programs existed. Twenty purposively sampled MSM who were enrollees of two pilot PrEP projects participated in the semi-structured interviews promoting story-telling. The coded data were thematically analyzed following Grounded Theory approach, focusing on uncovering a typology of the essential attributes of an optimal PrEP service model, and the reasons for such preferences. RESULTS: Participating MSM were all ethnic Chinese and aged 26 to 52 years. All had received PrEP from pilot projects in conjunction with periodic screening of sexually transmitted infections (STI), HIV antibody, and plasma creatinine. Four major themes emerged as regards the attributes of a preferred PrEP service: (i) comprehensiveness of HIV/STI and safety monitoring; (ii) convenient unitary service; (iii) stigma-free PrEP access and protecting confidentiality; and (iv) affordable price. Whereas regular provision of PrEP was acceptable to MSM, unaffordability and related stigma were the anticipated challenges for potential service providers. CONCLUSIONS: The qualitative assessment of MSM's preference for PrEP service delivery has yielded important information on the many facets of a desirable service model.

Determinants of workplace safety towards SARS-Cov-2 and combating COVID-19 among non-healthcare workers in Hong Kong, Nanjing and Wuhan, China.

There has been no validated tool to assess workplace infection control towards SARS-Cov-2 in non-healthcare industries. In this first year survey during 07/2020-04/2021, 6684 workers were recruited from varied non-healthcare settings of Hong Kong, Nanjing and Wuhan of China and responded standard questionnaires containing information of prevention measures and policies implemented by companies and personal preventive behaviour towards infection control. All participants were randomly stratified into two sub-samples as training and validation sample. Workplace safety index towards SARS-Cov-2 (WSI-SC2) was developed and validated using exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). We identified 14 manifest variables in WSI-SC2, with three sub-indices named "Workplace infection control measures and prevention", "Company occupational safety and health management and commitment" and "Worker's personal preventive behavior and awareness towards infectious control". WSI-SC2 obtained a good internal consistency reliability (Cronbach's alpha coefficients ranged: 0.76-0.91), good composite reliability (composite reliability ranged: 0.70-0.95) and satisfactory fit of the model (GFI = 0.95; SRMR = 0.05; RMSEA = 0.07). We further performed stratified analysis according to cities, and the index remained stable. Workers with higher scores of WSI-SC2 were more likely to uptake COVID-19 test. This multi-city large study developed a novel and validated tool that could horizontally measure the workplace safety towards SARS-Cov-2 in non-healthcare workers.

Legal provisions for enforcing social distancing to guard against COVID-19: the case of Hong Kong.

The implementation of social distancing measures through legal regulations to contain an epidemiologic outbreak has received little research attention. We reviewed and synthesized data on epidemiology, mobility trends and enforcement activities in the first 5 months of the COVID-19 epidemic in Hong Kong to examine the effectiveness of the newly enacted social distancing regulations. Data collected showed reduced patronage of retail and recreational activities during the epidemic. The regulations' enforcement could be inferred from the increase in the number of inspections, verbal warnings given to operators of scheduled premises and to people in public gatherings, but which rarely led to prosecutions. In parallel, the number of reported COVID-19 cases became stabilized. Our analyses suggested that public compliance with social distancing regulations could be maintained through promotional efforts without enforcement by prosecution. The adverse impacts of prolonged social distancing on the economy and citizens' social and psychological well-being were, however, of concern.

A review of HIV pre-exposure prophylaxis (PrEP) programmes by delivery models in the Asia-Pacific through the healthcare accessibility framework.

INTRODUCTION: In the Asia-Pacific, pre-exposure prophylaxis (PrEP) is a newly introduced public health intervention for minimizing HIV transmission, the coverage of which has remained limited. The best delivery models and strategies for broadening access of the vulnerable communities are not fully known. This review identified PrEP programmes reported in the Asia-Pacific, which were classified by delivery models and assessed with a healthcare accessibility framework. METHODS: We performed a literature search on PubMed and Ovid MEDLINE using relevant search terms, manual searched grey literature by visiting relevant websites, examined reference lists and contacted authors for clarification of included PrEP programmes reported through July 2019. A structured table was used for data extraction and summarizing findings in accordance with the five constructs of approachability, acceptability, availability, affordability and appropriateness grounded in the conceptual framework of Healthcare Accessibility. RESULTS AND DISCUSSION: This literature search yielded a total of 1308 publications; 119 full texts and abstracts were screened, and 24 publications were included in the review. We identified 11 programmes implemented in seven cities/countries in the Asia-Pacific. A typology of four PrEP delivery models was delineated: (a) fee-based public service model; (b) fee-based community setting model; (c) free public service model; and (d) free community setting model. Overall, the free community setting model was most commonly adopted in the Asia-Pacific, with the strength to boost the capacity of facility and human resources, which enhanced "approachability", "availability" and "acceptability." The free public service model was characterized by components designed in improving "approachability," "availability" and "appropriateness," with attention on equity in accessing PrEP. Among free-based models, long-term affordability both to the government and PrEP users would need to be maximized to increase accessibility. Alongside the need for raising awareness, supportive environments and ensuring timely access were means for enabling the development of a sustainable PrEP service. CONCLUSION: PrEP programmes could be classified by delivery models through the five constructs of healthcare accessibility. While the coverage of PrEP remains limited in the Asia-Pacific, an evaluation of these models could benchmark best practices, which would in turn allow effective models to be designed.

The diagnostic and management challenge for concomitant fragility fractures of pelvis and hip - a Case series with literature review.

BACKGROUND: Fragility fractures of hip and pelvis in the elderly population are common. They do co-exist but are frequently missed and undertreated. METHODS AND RESULTS: 3 cases of concomitant fragility fractures of hip and pelvis were identified. Hip fractures were treated with cemented hemiarthroplasty or cephalomedullary nail fixation, while pelvic fractures were treated with percutaneous screw fixation in same general anesthesia session. Anti-osteoporotic treatments were offered. Subjects were followed up for 1 year. CONCLUSION: Surgical treatment of fragility hip and pelvic fractures improves fracture stability, achieves better pain relief and allows earlier mobilization. Anti-osteoporotic treatment is essential as secondary prevention in fragility fractures.

Delineation of chemsex patterns of men who have sex with men in association with their sexual networks and linkage to HIV prevention.

BACKGROUND: Previous studies have shown that men who have sex with men (MSM) and who engage in drug use in sexualized contexts (chemsex) were more likely to be HIV positive. Their social networks and adoption of HIV prevention measures have, however, not been fully investigated. We aim to compare the sexual behavior, HIV prevention efforts and social networks of MSM by the intensity and patterns of their drug use. METHODS: Data from respondents of a community-based, cross-sectional survey (PRiSM) conducted among MSM in Hong Kong in 2017 were collected retrospectively. Characteristics of MSM engaged and not engaged in chemsex were compared in logistic regressions, delineated by latent class analysis (LCA) and compared in multinominal logistic regression. FINDINGS: Of 4133 respondents, 3044 were sexually active with an HIV prevalence of 6.5%. The prevalence of chemsex engagement in the preceding 6 months was 12%, after excluding use of poppers or erectile dysfunction agents (EDA) alone. Four types of drug user were identified by LCA: Minimal (mainly poppers), low-threshold (mainly poppers and EDA), medium-threshold (mainly methamphetamine, GHB, poppers and EDA) and intense (extensive use of different types of drug). Medium-threshold and intense drug users were more likely to be HIV positive, be diagnosed with sexually transmitted infections, make gay friends through mobile apps and sex parties, and intend to take pre-exposure prophylaxis (PrEP). Medium-threshold drug users had a more influential role in their social network, as shown by their higher centrality in mobile apps network. CONCLUSION: Chemsex engagement in MSM is significantly associated with HIV infection in Hong Kong. The HIV transmission risk could however be offset by the inclination of MSM belonging to medium-threshold and intense drug users to take PrEP, should the intervention become accessible to the community. Further mobile apps could be a good channel to access MSM who are medium-threshold drug users.

Quality of Palliative and End-Of-Life Care in Hong Kong: Perspectives of Healthcare Providers.

BACKGROUND: In response to population aging, there is a need for health systems to focus on care for chronic disease, specifically palliative care, while focusing on people-centered care. The objective of this study is to explore the healthcare system enablers and barriers to the provision of quality palliative and end-of-life care from the perspective of healthcare professionals. MATERIALS AND METHODS: Using purposive sampling, fifteen focus group interviews and nine individual interviews involving 72 healthcare providers were conducted. Primary qualitative data were collected between May 2016 and July 2017. All recorded discussions were transcribed verbatim and analyzed. A thematic framework was developed. RESULTS: The provision of quality palliative and end-of-life care is influenced by the interaction and integration of nine sub-themes under four identified themes: (1) political context; (2) organization setting; (3) support to patients, caregivers, and family members, and (4) healthcare workers and the public. CONCLUSIONS: Integration of palliative and end-of-life care is an important pillar of healthcare service to improve quality of life by addressing patients' values, wishes and preference, and assist their family to handle challenges at the end stage of life. Further improvements to the service framework would be required, specifically in the political framework, multidisciplinary approach, and readiness and competence in healthcare workers and community. These were highlighted in our study as key components in service provision to ensure that patients can receive continuous and integrated care between hospitals and the community as well as dignified care at the end stage of life.

Three-dimensional-guided navigation percutaneous screw fixation of fragility fractures of the pelvis.

BACKGROUND: Three-dimensional (3D)-guided navigation percutaneous screw fixation of pelvi-acetabular fractures has been reported in patients with high-energy trauma. Its use in fragility fractures of the pelvis is expanding and its results are promising. METHODS: We report a series of 17 consecutive patients with fragility fractures of the pelvis treated with 3D-guided navigation percutaneous screw fixation from 2016 to 2017. Percutaneous screw trajectories were planned preoperatively for the majority of patients. Closed reduction was performed prior to fixation in grossly displaced fractures. RESULTS: The mean time to surgery was 8.6 ± 2.4 days, and the mean intraoperative blood loss was 94.1 ± 26.6 mL. One early surgical complication occurred involving an infected pelvic external fixator iliac pin track site, and there were no cases of neurological deficits after fixation. In total, 7 of the 14 patients had screw backout, and the mean backout distance was 8.3 ± 4.4 mm. Cortical perforation was seen in one patient involving an anterior column screw by 5.7 mm; 14 patients were followed up for a mean of 18.7 ± 2.8 months; 13 patients achieved complete fracture union, and 1 patient had a fracture non-union. Premorbid ambulatory function was restored in 8 of the 14 patients. The mean visual analogue scale for pain severity at follow-up was 0.36 ± 0.50. There were no cases of 30-day and 1-year mortality. CONCLUSION: 3D-guided navigation percutaneous screw fixation is a safe, precise, and effective surgical technique for managing fragility fractures of the pelvis.

Empowered to Serve: Implementing Community Stroke Outreach Using Peer Educators to Improve Readiness to Act Among Local Community Members.

The purpose of this project was to develop a community-based volunteer group of peer educators to provide stroke education to local residents aimed at increasing stroke awareness and action readiness using the American Heart Association and American Stroke Association's "Empowered to Serve" evidence-based curriculum. The "Don't Miss a Stroke" module addresses the recognition of stroke warning signs, actions to take during a stroke, and stroke prevention. A total of 16 volunteers were recruited and subsequently trained. Six volunteers organized community events during the initial 3 months of the project, reaching more than 300 community members. Most participants (84.9%) identified as female, with a mean age of 63 years. Analysis of variance revealed significant improvements in knowledge regarding stroke immediately after the class, which was present 1 month later (F2,144 = 4.832, P = .009). This approach to raising community awareness about stroke emergencies was effective and did not require significant financial investment. Easy access to the curriculum and availability of free printed materials minimized the overall program costs and enhanced the quality of the educational content.

Metabolism-based identification of a potent thrombin receptor antagonist.

The metabolism of our prototypical thrombin receptor antagonist 1, Ki = 2.7 nM, was studied and three major metabolites (2, 4, and 5) were found. The structures of the metabolites were verified independently by synthesis. Compound 4 was shown to be a potent antagonist of the thrombin receptor with a Ki = 11 nM. Additionally, compound 4 showed a 3-fold improvement in potency with respect to 1 in an agonist-induced ex-vivo platelet aggregation assay in cynomolgus monkeys after oral administration; this activity was sustained with 60% inhibition observed at 24 h post-dose. Compound 4 was highly active in functional assays and showed excellent oral bioavailability in rats and monkeys. Compound 4 showed a superior rat enzyme induction profile relative to compound 1, allowing it to replace compound 1 as a development candidate.

Knowledge, Attitudes, and Preferences of Advance Decisions, End-of-Life Care, and Place of Care and Death in Hong Kong. A Population-Based Telephone Survey of 1067 Adults.

OBJECTIVES: According to the 2015 Quality of Death Index published by the Intelligence Unit of the Economist, Hong Kong is ranked 22nd in terms of quality of palliative care in the world, behind many other major developed countries in Asia, including Taiwan, Singapore, Japan, and South Korea. The objectives of the present study were to describe the knowledge, attitude, and preferences of the general Hong Kong adult population across different age groups regarding end-of-life (EOL) care decisions, place of care and death, as well as advance directive (AD). METHODS: This was a population-based cross-sectional survey conducted by telephone. A total of 1067 adults over 30 years old were contacted through residential telephone lines using a random sampling method and were interviewed. Information on sociodemographic factors, general health status, chronic diseases, knowledge, attitude and preferences of advance decisions, EOL care, and place of death were collected. RESULTS: A total of 85.7% had not heard of AD, but 60.9% would prefer to make their own AD if legislated after explanation; and for those who did not prefer to have an AD, the predominant concern was the possible change of mind afterward. Adjusted logistic regression suggested that female participants were less willing to make an AD, whereas those with prior knowledge of do-not-attempt-cardiopulmonary-resuscitation significantly increased the chance of making an AD. In terms of life-sustaining treatments, a predominant 87.6% preferred to receive appropriate palliative care that gives comfort rather than to prolong life if being diagnosed to be terminally ill; 43% disagreed that doctors should generally try to keep patients alive for as long as possible; and 86.2% agreed that the patient's own wishes should determine what treatment he/she should receive. Adjusted logistic regression showed that palliative care was more preferred by age groups 50 years or above but was less preferred by those who did not care for their family members with chronic diseases. Regarding place of death, 31.2% of the participants would choose to die at home, and among those, 19.5% would still prefer to die at home even if they did not have sufficient support. Adjusted logistic regression showed a decreased trend for all older age groups from 40-49 years to 80+ years, as well as having poor self-rated health, to prefer to die at home. Being a female participant and having education level of tertiary or above, however, had higher preference for death at home. CONCLUSIONS: This is the first population-representative survey of the general Hong Kong adult population on the knowledge, attitude, and preferences of AD, EOL care, and place of care/death. The main implication of this study was that preferences to have autonomy over own EOL care, to receive palliative care, and to die at home were greater than the actual practice currently, highlighting the service gaps for better EOL care in the future.

Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents.

Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration.

Development of a high cell-density fed-batch bioprocess for the heterologous production of 6-deoxyerythronolide B in Escherichia coli.

A robust high cell-density fed-batch bioprocess was developed for the heterologous production of 6-deoxyerythronolide B (6-dEB), the macrocyclic core of the antibiotic erythromycin, with a recombinant Escherichia coli strain expressing the 6-deoxyerythronolide B synthase (DEBS) from Saccharopolyspora erythraea. Initial evaluation of the E. coli strain in a 5-l bioreactor with the addition of exogenous propionate for polyketide biosynthesis resulted in a maximum cell density of 30 g l(-1) (OD600 approximately 60) and the production of 700 mg l(-1) of 6-dEB. Retention of the two plasmids harboring the heterologous genes was maintained between 90 and 100% even in the absence of antibiotic selection. However, the accumulation of excess ammonia in the culture medium was found to significantly decrease the productivity of the cells. Through optimization of the medium composition and fermentation conditions, the maximum cell density was increased by two-fold, and a final titer of 1.1 g l(-1) of 6-dEB was achieved. This represents an 11-fold improvement compared to the highest reported titer of 100 mg l(-1) with E. coli as the production host.

Discovery and synthesis of a novel series of quinoline-based thrombin receptor (PAR-1) antagonists.

The design, synthesis, and SAR studies of a structurally novel series of highly potent thrombin receptor (PAR-1) antagonists are described. Compound 30 is a highly potent thrombin receptor antagonist (IC(50)=6.3 nM), a related compound 36 showing efficacy in a monkey ex vivo study.

Quantitative analysis of loading and extender acyltransferases of modular polyketide synthases.

The acyltransferase (AT) domains of modular polyketide synthases (PKSs) are the primary determinants of building block specificity in polyketide biosynthesis and are therefore attractive targets for protein engineering. Thus far, investigations into the fundamental biochemical properties of AT domains have been hampered by the inability to produce these enzymes as self-standing polypeptides. Here we describe an alternative, generally applicable strategy for overexpression and analysis of AT domains from modular PKSs as truncated didomain proteins (approximately 60 kDa). Recently, we reported the expression and reconstitution of the loading didomain of 6-deoxyerythronolide B synthase (Lau, J., Cane, D. E., and Khosla, C. (2000) Biochemistry 39, 10514-20). By replacing the AT domain of this protein with a methylmalonyl-CoA specific AT domain from module 6 of the 6-deoxyerythronolide B synthase, or alternatively a malonyl-CoA specific AT domain from module 2 of the rapamycin synthase, each of these extender unit AT domains could be overproduced and purified to homogeneity. Using acyl-CoA substrates as acyl group donors and N-acetylcysteamine as the thiol acceptor, we devised a steady-state kinetic assay to probe the properties of these three didomain proteins and selected mutants. Propionyl-CoA was the preferred substrate of the loading didomain, although acetyl- and butyryl-CoA were also accepted with approximately 40-fold-lower specificity. In contrast to the relatively relaxed specificity of the loading AT domain, the methylmalonyl- and malonyl-specific AT domains had high specificity (>1000-fold) toward their natural substrates. The acyl transfer reaction was inhibited by coenzyme A (CoASH) with both a competitive and a noncompetitive component. Use of an exogenous holo-acyl carrier protein (ACP) as an acceptor thiol did not increase the rate of acyl transfer relative to the reaction involving N-acetylcysteamine, suggesting that either the on-rate of the acyl group is rate-limiting or that the apo-ACP component of the didomain protein precludes effective docking of a second ACP onto the AT active site. Mutation of Trp-222 in the loading AT domain to an Arg residue that is universally conserved in all extender unit AT domains failed to enable the loading AT domain to accept methylmalonyl-CoA as an alternative substrate. In contrast, mutation of the equivalent Arg residue in an extender AT domain resulted in a protein with no activity. Together, these results provide a foundation for future structural and mechanistic investigations into the properties of AT domains of modular PKSs.