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Introduction More than 70% of new HIV infections in Asia occurred in eight countries in 2020: Cambodia, China, India, Indonesia, Myanmar, Nepal, Thailand, and Vietnam—with a rising incidence among men who have sex with men (MSM). The World Health Organization (WHO) recommends pre-exposure prophylaxis (PrEP) for those at risk of acquiring HIV, yet wide-scale implementation of PrEP, on a daily or event-driven basis, has been limited in Asia. Methods The Optima HIV model was applied to examine the impact of scaling-up PrEP over five-years to cover an additional 15% of MSM compared with baseline coverage, a target deemed feasible by regional experts. Based on behavioral survey data, we assume that covering 15% of higher-risk MSM will cover 30% of all sexual acts in this group. Scenarios to compare the impact of generic-brand daily dosing of PrEP with generic event-driven dosing (15 days a month) were modelled from the start of 2022 to the end of 2026. Cost-effectiveness of generic versus branded PrEP was also assessed for China, the only country with an active patent for branded, higher cost PrEP. The impact on new HIV infections among the entire population and cost per HIV-related disability-adjusted life year (DALY) averted were estimated from the beginning of 2022 to the end of 2031 and from 2022 to 2051. Results If PrEP were scaled-up to cover an additional 15% of MSM engaging in higher-risk behavior from the beginning of 2022 to the end of 2026 in the eight Asian countries considered, an additional 100,000 (66,000–130,000) HIV infections (17%) and 300,000 (198,000–390,000) HIV-related DALYs (3%) could be averted over the 2022 to 2031 period. The estimated cost per HIV-related DALY averted from 2022 to 2031 ranged from US$600 for event-driven generic PrEP in Indonesia to US$34,400 for daily branded PrEP in Thailand. Over a longer timeframe from 2022 to 2051, the cost per HIV-related DALY averted could be reduced to US$100–US$12,700. Conclusion PrEP is a critical tool to further reduce HIV incidence in highly concentrated epidemics. Implementing PrEP in Asia may be cost-effective in settings with increasing HIV prevalence among MSM and if PrEP drug costs can be reduced, PrEP could be more cost-effective over longer timeframes.

Summary Background To move towards ending AIDS by 2030, HIV resources should be allocated cost-effectively. We used the Optima HIV model to estimate how global HIV resources could be retargeted for greatest epidemiological effect and how many additional new infections could be averted by 2030. Methods We collated standard data used in country modelling exercises (including demographic, epidemiological, behavioural, programmatic, and expenditure data) from Jan 1, 2000, to Dec 31, 2015 for 44 countries, capturing 80% of people living with HIV worldwide. These data were used to parameterise separate subnational and national models within the Optima HIV framework. To estimate optimal resource allocation at subnational, national, regional, and global levels, we used an adaptive stochastic descent optimisation algorithm in combination with the epidemic models and cost functions for each programme in each country. Optimal allocation analyses were done with international HIV funds remaining the same to each country and by redistributing these funds between countries. Findings Without additional funding, if countries were to optimally allocate their HIV resources from 2016 to 2030, we estimate that an additional 7·4 million (uncertainty range 3·9 million–14·0 million) new infections could be averted, representing a 26% (uncertainty range 13–50%) incidence reduction. Redistribution of international funds between countries could avert a further 1·9 million infections, which represents a 33% (uncertainty range 20–58%) incidence reduction overall. To reduce HIV incidence by 90% relative to 2010, we estimate that more than a three-fold increase of current annual funds will be necessary until 2030. The most common priorities for optimal resource reallocation are to scale up treatment and prevention programmes targeting key populations at greatest risk in each setting. Prioritisation of other HIV programmes depends on the epidemiology and cost-effectiveness of service delivery in each setting as well as resource availability. Interpretation Further reductions in global HIV incidence are possible through improved targeting of international and national HIV resources. Funding World Bank and Australian NHMRC.

Australia remains the only developed country to have endemic levels of trachoma (a prevalence of 5% or greater among children) in some regions. Endemic trachoma in Australia is found predominantly in remote and very remote Aboriginal communities. The Australian Government funds the National Trachoma Surveillance and Reporting Unit to collate, analyse and report trachoma prevalence data and document trachoma control strategies in Australia through an annual surveillance report. This report presents data collected in 2013. Data are collected from Aboriginal and Torres Strait Island communities designated at-risk for endemic trachoma within New South Wales, the Northern Territory, South Australia and Western Australia. The World Health Organization grading criteria were used to diagnose cases of trachoma in Aboriginal children, with jurisdictions focusing screening activities on the 5-9 years age group; but some children in the 1-4 and 10-14 years age groups were also screened. The prevalence of trachoma within a community was used to guide treatment strategies as a public health response. Aboriginal adults aged 40 years or over were screened for trichiasis. Screening coverage for the estimated population of children aged 5-9 years and adults aged 40 years or over in at-risk communities required to be screened in 2013 was 84% and 30%, respectively. There was a 4% prevalence of trachoma among children aged 5-9 years who were screened. Of communities screened, 50% were found to have no cases of active trachoma and 33% were found to have endemic levels of trachoma. Treatment was required in 75 at-risk communities screened. Treatment coverage for active cases and their contacts varied between jurisdictions from 79% to 100%. Trichiasis prevalence was 1% within the screened communities.

Background Estimated global new HIV infections among people who inject drugs (PWID) remained stable over the 2010–2015 period and the target of a 50% reduction over this period was missed. To achieve the 2020 UNAIDS target of reducing adult HIV infections by 75% compared to 2010, accelerated action in scaling up HIV programs for PWID is required. In a context of diminishing external support to HIV programs in countries where most HIV-affected PWID live, it is essential that available resources are allocated and used as efficiently as possible. Methods Allocative and implementation efficiency analysis methods were applied. Optima, a dynamic, population-based HIV model with an integrated program and economic analysis framework was applied in eight countries in Eastern Europe and Central Asia (EECA). Mathematical analyses established optimized allocations of resources. An implementation efficiency analysis focused on examining technical efficiency, unit costs, and heterogeneity of service delivery models and practices. Results Findings from the latest reported data revealed that countries allocated between 4% (Bulgaria) and 40% (Georgia) of total HIV resources to programs targeting PWID — with a median of 13% for the eight countries. When distributing the same amount of HIV funding optimally, between 9% and 25% of available HIV resources would be allocated to PWID programs with a median allocation of 16% and, in addition, antiretroviral therapy would be scaled up including for PWID. As a result of optimized allocations, new HIV infections are projected to decline by 3–28% and AIDS-related deaths by 7–53% in the eight countries. Implementation efficiencies identified involve potential reductions in drug procurement costs, service delivery models, and practices and scale of service delivery influencing cost and outcome. A high level of implementation efficiency was associated with high volumes of PWID clients accessing a drug harm reduction facility. Conclusion A combination of optimized allocation of resources, improved implementation efficiency and increased investment of non-HIV resources is required to enhance coverage and improve outcomes of programs for PWID. Increasing efficiency of HIV programs for PWID is a key step towards avoiding implicit rationing and ensuring transparent allocation of resources where and how they would have the largest impact on the health of PWID, and thereby ensuring that funding spent on PWID becomes a global best buy in public health.

Background: Detention of people who use drugs into compulsory drug detention centres (CDDCs) is common throughout East and Southeast Asia. Evidence-based pharmacological therapies for treating substance use disorders, such as opioid agonist treatments with methadone, are generally unavailable in these settings. We used a unique opportunity where CDDCs coexisted with voluntary drug treatment centres (VTCs) providing methadone in Malaysia to compare the timing and occurrence of opioid relapse (measured using urine drug testing) in individuals transitioning from CDDCs versus methadone maintenance in VTCs. Methods: We did a parallel, two-arm, prospective observational study of opioid-dependent individuals aged 18 years and older who were treated in Malaysia in the Klang Valley in two settings: CDDCs and VTCs. We used sequential sampling to recruit individuals. Assessed individuals in CDDCs were required to participate in services such as counselling sessions and manual labour. Assessed individuals in VTCs could voluntarily access many of the components available in CDDCs, in addition to methadone therapy. We undertook urinary drug tests and behavioural interviews to assess individuals at baseline and at 1, 3, 6, 9, and 12 months post-release. The primary outcome was time to opioid relapse post-release in the community confirmed by urinary drug testing in individuals who had undergone baseline interviewing and at least one urine drug test (our analytic sample). Relapse rates between the groups were compared using time-to-event methods. This study is registered at ClinicalTrials.gov (NCT02698098). Findings: Between July 17, 2012, and August 21, 2014, we screened 168 CDDC attendees and 113 VTC inpatients; of these, 89 from CDDCs and 95 from VTCs were included in our analytic sample. The baseline characteristics of the two groups were similar. In unadjusted analyses, CDDC participants had significantly more rapid relapse to opioid use post-release compared with VTC participants (median time to relapse 31 days [IQR 26–32] vs 352 days [256–unestimable], log rank test, p

Australia remains the only developed country to have endemic levels of trachoma (a prevalence of 5% or greater among children) in some regions. Endemic trachoma in Australia is found predominantly in remote and very remote Aboriginal communities. The Australian Government funds a National Trachoma Surveillance and Reporting Unit to collate, analyse and report trachoma prevalence data and document trachoma control strategies in Australia through an annual surveillance report. This report presents data collected in 2012. Data are collected from Aboriginal and Torres Strait communities designated as at-risk for endemic trachoma in the Northern Territory, Queensland, South Australia and Western Australia. The World Health Organization grading criteria were used to diagnose cases of trachoma in Aboriginal children with jurisdictions focusing screening activities on the 5-9 years age group; however, some children in the 1-4 and 10-14 years age groups were also screened. The prevalence of trachoma within a community was used to guide treatment strategies as a public health response. Aboriginal adults aged 40 years or older were screened for trichiasis. Community screening coverage of the designated at-risk communities was 96%. Screening coverage of the estimated population of children aged 5-9 years and adults aged 40 years or older in at-risk communities was 71% and 31%, respectively. Trachoma prevalence among children aged 5-9 years who were screened was 4%. Of communities screened, 63% were found to have no cases of active trachoma and 25% were found to have endemic levels of trachoma. Treatment was required in 87 at-risk communities screened. Treatment coverage of active cases and their contacts varied from 79%-97% between jurisdictions. Trichiasis prevalence was 2% within the screened communities.

To be eligible to donate blood, potential donors must meet certain eligibility criteria to ensure safety to the donor and to the blood supply. In Australia, there is no reliable estimate of the size of the donor-eligible population. This study uses a refinement to a published method to determine the population prevalence of donor-exclusion factors and subsequently estimates the size of the potential donor pool in Australia.A total of 70 donor-exclusion factors (in addition to age) were identified. The donor-eligible population was estimated by subtracting the prevalence of the exclusion factors from the total population. Prevalence of the donor-exclusion factors was adjusted for age, deferral period, and overlap of multiple conditions. Overlap was adjusted by extending a published random-probability model according to known association of epidemiologic data on overlapping conditions.The most prevalent (deferral period-adjusted) donor-exclusion factor among the 16- to 80-year-old Australian population was variant Creutzfeldt-Jakob disease-related travel risk (6.8%) followed by upper respiratory tract infections (6.4%). After exclusion of all factors, and accounting for overlapping factors, 62% of 16- to 80-year-olds or 47.3% of the total population were donor eligible in Australia.We developed a refined method for estimating the size of the donor-eligible population. Applying this method to Australia, we estimate that approximately 10.7 million people (62% of the 16- to 80-year-olds) were eligible to donate blood in Australia in 2012.

Using a predonation screening questionnaire, potential blood donors are screened for medical or behavioral factors associated with an increased risk for transfusion-transmissible infection. After disclosure of these risks, potential donors are deferred from donating. Understanding the degree of failure to disclose full and truthful information (termed noncompliance) is important to determine and minimize residual risk. This study estimates the prevalence of, and likely reasons for, noncompliance among Australian donors with the deferrals for injecting drug use, sex with an injecting drug user, male-to-male sex, sex worker activity or contact, and sex with a partner from a high-HIV-prevalence country.An anonymous, online survey of a nationally representative sample of Australian blood donors was conducted. Prevalence of noncompliance with deferrable risk categories was estimated. Factors associated with noncompliance were determined using unadjusted and adjusted odds ratios.Of 98,044 invited donors, 30,790 donors completed the survey. The estimated prevalence of overall noncompliance (i.e., to at least one screening question) was 1.65% (95% confidence interval CI, 1.51%-1.8%). Noncompliance with individual deferrals ranged from 0.05% (sex work) to 0.54% (sex with an injecting drug user). The prevalences of the disclosed exclusionary risk behaviors were three to 14 times lower than their estimated prevalence in the general population.The prevalence of noncompliance is relatively low but our estimate is likely to be a lower bound. The selected high-risk behaviors were substantially less common in blood donors compared to the general population suggesting that self-deferral is effective. Nevertheless, a focus on further minimization should improve the blood safety.

Introduction : It is increasingly important to prioritize the most cost-effective HIV interventions. We sought to summarize the evidence on which types of interventions provide the best value for money in regions with concentrated HIV epidemics. Methods : We conducted a systematic review of peer-reviewed and grey literature reporting measurements of cost-effectiveness or cost-benefit for HIV/AIDS interventions in Asia and Eastern Europe. We also collated HIV/AIDS spending assessment data from case-study countries in the region. Results : We identified 91 studies for inclusion, 47 of which were from peer-reviewed journals. Generally, in concentrated settings, prevention of mother-to-child transmission programmes and prevention programmes targeting people who inject drugs and sex workers had lower incremental cost-effectiveness ratios than programmes aimed at the general population. The few studies evaluating programmes targeting men who have sex with men indicate moderate cost-effectiveness. Collation of prevention programme spending data from 12 countries in the region (none of which had generalized epidemics) indicated that resources for the general population/non-targeted was greater than 30% for eight countries and greater than 50% for five countries. Conclusions : There is a misalignment between national spending on HIV/AIDS responses and the most affected populations across the region. In concentrated epidemics, scarce funding should be directed more towards most-at-risk populations. Reaching consensus on general principles of cost-effectiveness of programmes by epidemic settings is difficult due to inconsistent evaluation approaches. Adopting a standard costing, impact evaluation, benefits calculation, analysis and reporting framework would enable cross comparisons and improve HIV resource prioritization and allocation. Keywords: HIV; cost-benefit analyses; programme evaluation; systematic review; concentrated epidemics; Asia; Eastern Europe; cost-effectiveness. To access the supplementary material to this article please see Supplementary Files in the column to the right (under Article Tools). (Published: 25 February 2014) Citation: Craig AP et al. Journal of the International AIDS Society 2014, 17 :18822 http://www.jiasociety.org/index.php/jias/article/view/18822 | http://dx.doi.org/10.7448/IAS.17.1.18822

Endemic trachoma continues to exist in remote Aboriginal communities in Australia. The National Trachoma Surveillance and Reporting Unit, established in 2006, is responsible for the collation, analysis and reporting of trachoma prevalence data and the documentation of trachoma control strategies in Australia. Data were collected from Aboriginal communities designated at-risk for endemic trachoma (defined as prevalence of 5% or greater among children) within the Northern Territory, South Australia and Western Australia. This report presents data collected in 2010. Aboriginal children aged 1-14 years were screened using the World Health Organization grading criteria to diagnose and classify individual cases of trachoma. Aboriginal adults aged 40 years or older were screened for trichiasis. Community screening coverage of the designated at-risk communities was 60% in 2010. Screening coverage of the estimated population of children aged 1-14 years and of adults aged 40 years or older in at-risk communities was 11.5% and 5%, respectively. Trachoma prevalence among children aged 1-14 years who were screened was 11%. Of the communities screened, 36% were found to have no cases of active trachoma and 55% were found to have endemic levels of trachoma. Treatment coverage of active cases and their contacts varied between jurisdictions from 64% to 90%. Trichiasis prevalence was 4% within the screened communities.

Routine monitoring of trends in transfusion-transmissible infections (TTIs) is essential to maintaining and improving transfusion safety. Although periodic studies have been published there is no comprehensive trend analysis for TTIs in Australian donors. This study determined recent trends in TTIs for which testing is conducted in Australia and described key attributes of infected blood donors.This is a retrospective analysis using data on donation testing for TTIs (2005-2010) from the national blood service donor database and data on postdonation interviews with TTI-positive donors (2008-2010) from a risk factor database incorporating responses to standardized interview questions. The study measured the prevalence and incidence of TTIs in Australia and assessed their time trends. Multivariate analysis of time trends was conducted using Poisson regression models.Overall, the prevalence and incidence of TTIs in 2005 to 2010 remained low and steady. The prevalence of hepatitis C virus decreased (rate ratio [RR], 0.93; 95% confidence interval [CI], 0.89-0.97) and the prevalence of active syphilis increased (RR, 1.51; 95% CI, 1.15-1.99) significantly during the study period. Prevalence of TTIs among Australian blood donors was substantially lower than that in the general population and no unique risk factors were identified in test-positive blood donors when compared with the general population.Both the prevalence and the incidence of TTIs in Australian blood donors remained low, with a steady or declining trend for most infections except active syphilis. The lower prevalence of TTIs in blood donors compared with the general population reflects the effectiveness of donor education and donor selection measures in Australia.

FCDI (fast Ca²⁺-dependent inactivation) is a mechanism that limits Ca²⁺ entry through Ca²⁺ channels, including CRAC (Ca²⁺ release-activated Ca²⁺) channels. This phenomenon occurs when the Ca²⁺ concentration rises beyond a certain level in the vicinity of the intracellular mouth of the channel pore. In CRAC channels, several regions of the pore-forming protein Orai1, and STIM1 (stromal interaction molecule 1), the sarcoplasmic/endoplasmic reticulum Ca²⁺ sensor that communicates the Ca²⁺ load of the intracellular stores to Orai1, have been shown to regulate fast Ca²⁺-dependent inactivation. Although significant advances in unravelling the mechanisms of CRAC channel gating have occurred, the mechanisms regulating fast Ca²⁺-dependent inactivation in this channel are not well understood. We have identified that a pore mutation, E106D Orai1, changes the kinetics and voltage dependence of the ICRAC (CRAC current), and the selectivity of the Ca²⁺-binding site that regulates fast Ca²⁺-dependent inactivation, whereas the V102I and E190Q mutants when expressed at appropriate ratios with STIM1 have fast Ca²⁺-dependent inactivation similar to that of WT (wild-type) Orai1. Unexpectedly, the E106D mutation also changes the pH dependence of ICRAC. Unlike WT ICRAC, E106D-mediated current is not inhibited at low pH, but instead the block of Na⁺ permeation through the E106D Orai1 pore by Ca²⁺ is diminished. These results suggest that Glu¹⁰⁶ inside the CRAC channel pore is involved in co-ordinating the Ca²⁺-binding site that mediates fast Ca²⁺-dependent inactivation.

Beliefs regarding the origins of the universe and life differ substantially between groups of people and are often particularly associated with religious worldviews. It is important to understand factors associated with evolution and creationism beliefs and unacceptance of scientific evidence for evolution. An internet-based survey was conducted to elicit information from people who self-identify as Christians, atheists, agnostics and other belief systems, as well as by geographical location and other demographic variables, on acceptance of evolution or creationism, certainty with which each position is believed, and reasons for rejecting the alternative. It was found that almost 60% of Christians believe in creationism and less than 10% believe in natural evolution. Worldwide, these proportions were relatively consistent across all locations except for in Europe. Among European Christians the majority of Christians believe in a form of evolution. It was found that the vast majority (87%) of Christians are 'absolutely certain' about their beliefs, compared with the minority of atheists and agnostics claiming 'absolute certainty'. Generally, reasons Christians did not accept evolution were based not on evidence but on religious doctrine. In contrast, the most common reason for not accepting the existence of a god by atheists who supported evolution was the lack of evidence. Innovative strategies may be required to communicate evolutionary science effectively to non-European Christians.

To understand age-specific sexual mixing patterns of men who have sex with men in Australia, for behavioral insight, and to determine which age groups are at greatest risk of acquiring HIV in the future.Diagnoses data based on Australia's HIV surveillance system are analyzed with a mathematical sexual transmission model to estimate the age-mixing patterns of sexual partnerships amongst men who have sex with men. The degree of assortativity and the relative rate of partner acquisition across different age groups are estimated.Although there are some differences between age groups, sexual mixing is primarily assortative for men of all ages, between completely random partner acquisition and fully assortative mixing, with greatest assortativity among middle-aged men. Men aged 25-34 years were shown to have the greatest level of sexual partner acquisition. There is little evidence to support disassortative mixing on average across the population.Although there is a tendency for partners of a similar age to be chosen and the average age of HIV-infected people in Australia is relatively old, suggesting that the epidemic may eventually age out depending on death rates, there seems to be sufficient cross-age mixing and high sexual mixing in younger age groups to sustain the HIV epidemic over the medium to long term.

Introduction : Despite recent and robust economic growth across the Asia-Pacific region, the majority of low- and middle-income countries in the region remain dependent on some donor support for HIV programmes. We describe the availability of bilateral and multilateral official development assistance (ODA) for HIV programmes in the region. Methods : The donor countries considered in this analysis are Australia, Canada, Denmark, France, Germany, Netherlands, Norway, Sweden, the United Kingdom and the United States. To estimate bilateral and multilateral ODA financing for HIV programmes in the Asia-Pacific region between 2004 and 2013, we obtained funding data from the Organisation for Economic Co-operation and Development Creditor Reporting System database. Where possible, we checked these amounts against the funding data available from government aid agencies. Estimates of multilateral ODA financing for HIV/AIDS were based on the country allocations announcement by the Global Fund to Fight AIDS, Tuberculosis and Malaria (the Global Fund) for the period 2014 to 2016. Results : Countries in the Asia-Pacific region receive the largest share of aid for HIV from the Global Fund. Bilateral funding for HIV in the region has been relatively stable over the last decade and is projected to remain below 10% of the worldwide response to the epidemic. Bilateral donors continue to prioritize ODA for HIV to other regions, particularly sub-Saharan Africa; Australia is an exception in prioritizing the Asia-Pacific region, but the United States is the bilateral donor providing the greatest amount of assistance in the region. Funding from the Global Fund has increased consistently since 2005, reaching a total of US$1.2 billion for the Asia-Pacific region from 2014 to 2016. Conclusions : Even with Global Fund allocations, countries in the Asia-Pacific region will not have enough resources to meet their epidemiological targets. Prevention funding is particularly vulnerable and requires greater domestic leadership and coordination. Bilateral donors are still crucially important in the response to HIV throughout the Asia-Pacific region. Keywords: HIV; bilateral; multilateral; funding; Asia; Pacific. (Published: 16 November 2015) Citation: Stuart RM et al. Journal of the International AIDS Society 2015, 18 :20004 http://www.jiasociety.org/index.php/jias/article/view/20004 | http://dx.doi.org/10.7448/IAS.18.1.20004

BackgroundShared injecting apparatus during drug use is the premier risk factor for hepatitis C virus (HCV) transmission.AimsTo estimate the per-event probability of HCV infection during a sharing event, and the transmission probability of HCV from contaminated injecting apparatus.MethodsEstimates were obtained using a maximum likelihood method with estimated IDU and sharing events obtained from behavioural data.SettingsCohort study in multiple correction centres in New South Wales, Australia.ParticipantsSubjects (N = 500) with a lifetime history of injecting drug use (IDU) who were followed up between 2005 and 2012. During follow-up, interviews for risk behaviours were taken and blood sampling (HCV-antibody and RNA testing) was performed.MeasurementsSelf-reported frequencies of injecting drugs and sharing events, as well as other risk behaviours and details on the nature of injecting events.FindingsThe best estimate of the per-event probability of infection was 0.57% (CI: 0.32-1.05%). A sensitivity analysis on the likely effect of under-reporting of sharing of the injecting apparatus indicated that the per event infection probability may be as low as 0.17% (95% CI: 0.11%-0.25%). The transmission probability was similarly shown to range up to 6%, dependent on the presumed prevalence of the virus in injecting equipment.ConclusionsThe transmission probability of HCV during a sharing event is small. Hence, strategies to reduce the frequency and sharing of injecting equipment are required, as well as interventions focused on decreasing the per event risk.

Calmodulin (CaM)-dependent myosin light chain kinase (MLCK) plays a key role in activation of smooth muscle contraction. A soybean isoform of CaM, SCaM-4 (77% identical to human CaM) fails to activate MLCK, whereas SCaM-1 (90.5% identical to human CaM) is as effective as CaM. We exploited this difference to gain insights into the structural requirements in CaM for activation of MLCK. A chimera (domain I of SCaM-4 and domains II-IV of SCaM-1) behaved like SCaM4, and analysis of site-specific mutants of SCaM-1 indicated that K30E and G40D mutations were responsible for the reduction in activation of MLCK. Competition experiments showed that SCaM-4 binds to the CaM-binding site of MLCK with high affinity. Replacement of CaM in skinned smooth muscle by exogenous CaM or SCaM-1, but not SCaM-4, restored Ca(2+)-dependent contraction. K30E/M36I/G40D SCaM-1 was a poor activator of contraction, but site-specific mutants, K30E, M36I and G40D, each restored Ca(2+)-induced contraction to CaM-depleted skinned smooth muscle, consistent with their capacity to activate MLCK. Interpretation of these results in light of the high-resolution structures of (Ca(2+))(4)-CaM, free and complexed with the CaM-binding domain of MLCK, indicates that a surface domain containing Lys(30) and Gly(40) and residues from the C-terminal domain is created upon binding to MLCK, formation of which is required for activation of MLCK. Interactions between this activation domain and a region of MLCK distinct from the known CaM-binding domain are required for removal of the autoinhibitory domain from the active site, i.e., activation of MLCK, or this domain may be required to stabilize the conformation of (Ca(2+))(4)-CaM necessary for MLCK activation.