The need for sexual health clinics, their future role, and contribution to public health

Keywords: clinics, health services, public health, STIs, STDs, sexually transmitted diseases, sexually transmitted infections, sexual health, sexual health clinics.

Specialised sexual health clinics (SHCs) are a key part of the public health response to rising rates of sexually transmitted infections (STIs) and ongoing needs for HIV prevention in many nations. Since the early 2000s, reported gonorrhoea and syphilis cases have reached historically high levels in some nations.^1–3 In the US, rates of gonorrhoea increased by 45%, syphilis increased by 52%, and chlamydia decreased by 1.2% from 2016 to 2020.³ In Australia, gonorrhoea notifications increased by 97%, syphilis by 146%, and chlamydia by 21% from 2014 to 2018, with the highest number of cases seen in New South Wales (NSW), Australia.² A 2020 NSW STI surveillance report showed that gonorrhoea has increased by 29%, syphilis has increased by 9%, and chlamydia has decreased by 5% from 2016 to 2020.⁴ In the Netherlands, chlamydia infections increased by roughly 14%, gonorrhoea and syphilis each by 52% from 2015 to 2019.^1,5 Sexually transmitted disease (STD) surveillance data during 2020 are likely underreported due to the coronavirus disease 2019 (COVID-19) pandemic and need to be interpreted with caution.⁶ The resulting economic, public health and individual health ramifications of such high STI burdens are significant. STIs are estimated to have cost the US nearly $16 billion in healthcare costs in 2018 alone.⁷ Preliminary data for 2020 show the burden of some STIs – syphilis in particular – will be even higher, even taking into consideration decreased testing and reporting during the COVID-19 pandemic.^8–10 STIs can result in long-term individual health consequences. For example, neuro-, ocular or otologic syphilis can lead to stroke, irreversible blindness, or hearing loss. Congenital syphilis has increased 279% since 2015 in the US, and there were nearly 2100 cases of congenital syphilis in 2020, resulting in almost 140 stillbirths or infant deaths.^11,12 Many of the initial monkeypox cases in the ongoing outbreak in 2022 in non-endemic countries was first identified in SHCs, and SHCs have been an integral part of evaluating patients with symptoms and providing post-exposure prophylaxis for contacts.^13–15 At the population level, circulation of STI pathogens can lead to the emergence and onward transmission of drug-resistant strains.

Specialised SHCs in many high-income nations provide specialised care to diagnose and treat STIs, including potential complications from these infections. In some areas, SHCs also provide services to meet broader sexual health needs of specific populations, such as men who have sex with men (MSM) and transgender persons. Despite the critical role SHCs play in addressing increasing rates of STIs, limited staffing and funding resources have reduced the number of SHCs and the services they provide. The COVID-19 pandemic has further put a strain on STI services as public health personnel and resources have been diverted towards the COVID-19 response.¹⁶ The impact of the COVID-19 pandemic on rates of STIs in upcoming years might be severe. We strongly believe specialised SHCs should be prioritised as a critical and fundamental part of the public health system. This manuscript discusses the rationale for sustaining and expanding the network of SHCs, their future role in the community, the need for a strong infrastructure to support SHCs and describes some innovative programs developed in different countries to serve priority populations. Although we focus on SHCs in high-income nations, any country with an established public health infrastructure can benefit from specialised SHCs to meet the needs of their population.

Despite increasing healthcare coverage in the US, SHCs remain a critical healthcare resource that is valued by patients. A survey of 326 local health departments in 2018 reported that specialised SHCs were the primary provider of STI services in 41% of jurisdictions.¹⁷ The Affordable Care Act (ACA) led to the expansion of Medicaid (a program that provides health insurance for low-income Americans) in 39 states (including the District of Columbia), and established a system of subsidised health insurance exchanges through the country, improving access to care for many Americans. However, disparities in insurance coverage and healthcare access across racial/ethnic groups still exist. In Rhode Island, where the ACA led to >95% of the state’s population being insured, 40% of patients who presented in a publicly funded SHC for services in 2015 were uninsured.¹⁸ A study in Baltimore, Maryland, found that the proportion of all STIs diagnosed at publicly funded SHCs was largely unchanged 3 years after ACA implementation, demonstrating that the increased access to primary medical care facilitated by the ACA had little impact on demand for SHC services.¹⁹ For patients who are uninsured or underinsured, SHCs help address a gap in healthcare access by providing free or low-cost care. Although SHCs are particularly important for patients who are uninsured or underinsured, the clinics are also widely used by insured patients. A survey of >4000 patients seeking care at 26 SHCs in a large metropolitan area in the US from 2018 to 2019 indicated 53% had health insurance and 50% reported having a usual place for medical care.²⁰ Studies involving SHCs in New York City (NYC), San Francisco and Rhode Island have also found that a substantial proportion (38–60%) of patients were insured.^18,21,22

Demand for SHC services among persons who could choose to seek care elsewhere is not confined to the US, and is widespread in nations with universal, publicly funded health care. In NSW, Australia, where testing and treatment for HIV and other STIs are usually managed by general practitioners, the annual proportion of HIV and STIs diagnosed at publicly funded SHCs increased from 2010 to 2014; up to 40% of infectious syphilis and gonorrhoea cases and 30% of HIV cases were diagnosed in specialised SHCs.²³ This is similar in the Netherlands, where aggregated national data show that about 30% of STI diagnoses are made in SHCs. The total number of gonorrhoea diagnoses made at all SHCs in the Netherlands increased by 11% and syphilis by 17% from 2018 to 2019, even though many patients have a primary care provider.¹ This is in stark contrast to the situation in Amsterdam where 70% of STI diagnoses are made at the Amsterdam SHC. The number of gonorrhoea cases rose by 1% and syphilis cases by 27% from 2018 to 2019 at the Amsterdam SHC. Table 1 details the number and percentage of HIV/STI cases diagnosed and managed in specialised SHCs in various cities in 2019, supporting the conclusion that many people prefer to be evaluated for STIs in these specific clinic settings.²⁴

Table 1.  Number and percentage of HIV/STI cases diagnosed and/or treated in sexual health clinics in 2019 by city.

There are many reasons patients may prefer specialised SHCs for STI care. The clinics employ specialised medical, nursing, public health and allied health staff who are highly skilled across domains of sexual health- related care, trained in cultural sensitivity, and often come from the priority populations they serve.²⁰ Patients can sometimes remain anonymous, are comfortable with the privacy provisions of SHCs, and often prefer to seek care at venues with reduced real or perceived stigma around sexual health and STI or HIV prevention.^18,22 Although different models of SHCs exist, the clinics are typically organised to minimise barriers to accessing care, often through self-referral with a convenient walk-in component.^20,25 Although STI screening and management might be available in other settings, staff in these locations often have limited ability to assess sexual risk, provide risk-reduction counselling, perform point-of-care tests, or provide a full menu of sexual health services (e.g. family planning, HIV pre-exposure prophylaxis [PrEP]). In some instances, primary care providers may not be familiar with some critical components of sexual health care (e.g. PrEP, extra-genital STI testing) or STI treatment guidelines.²⁶

SHCs provide clinical and prevention services to persons at high risk of STI acquisition and for those who may not have access to other healthcare services. In some settings, these clinics are the primary source of sexual health care, especially for racial and ethnic minorities, migrant populations, adolescents, bisexual and other MSM, transgender and gender-diverse people, sex workers, and people with multiple partners or history of an STI and/or HIV.^1,20,27 These communities might be at higher risk of STIs and benefit seeing staff highly skilled at sexual health-related care, but may also prefer visiting specialised SHCs due to stigma and inequities in other medical settings.^20,28,29

SHCs disproportionately serve men at high risk for bacterial STIs, and in many areas, are widely used by MSM and other sexual and gender minorities.^1,23,30–32 In the US, from 2010 to 2018, the number of MSM visiting 14 SHCs in five large urban cities increased by 44%, with the greatest increase among MSM aged ≥25 years,³¹ and in 40 SHCs, the majority of gonorrhoea and HIV infections were diagnosed in MSM.³⁰ The number of visits to SHCs in the Netherlands increased by 10% among MSM from 2018 to 2019, and 96% of syphilis infections diagnosed at SHCs were among MSM. In NSW, the majority of early syphilis and gonorrhoea cases diagnosed at publicly funded SHCs from 2010 to 2014 were among gay and bisexual men.²³ Publicly funded SHCs are also an important place for STI care for transgender persons, with a 10% increase in the number of visits to SHCs by transgender persons from 2015 to 2019 in the Netherlands and a more than two-fold increase in the US from 2010 to 2018.^1,31,33 In many high-income nations, SHCs have specialised in the care of sexual minority men and transgender persons, with providers and staff well versed in medical issues related to these communities.

SHCs also play a critical role in addressing racial disparities. In 40 SHCs in the US, >50% of patients were African American, and in four cities, >80% were African American.³⁰ The highest rates of new HIV diagnoses in the US occur among Black and Hispanic/Latino MSM.^34,35 SHCs are uniquely poised to serve these men. In Australia, access to publicly funded SHCs among priority populations, including Aboriginal and Torres Strait Islander people, who are disproportionately affected by STIs, increased by >30% from 2004 to 2011.³⁶ Social determinants of health influence disparities in STD rates among racial and ethnic minorities and these communities often need to rely on free or low-cost public health services found in SHCs for sexual health-related care.^29,37

SHCs frequently provide specialised medical care that is not widely available in other settings, including care for complicated cases of STIs. For example, SHCs are well versed in the diagnosis and management of neurosyphilis or drug-resistant STIs, which is usually not within the scope of general practitioners. Some STI treatments, such as injectable penicillin G benzathine, are not easily obtained in community settings.³⁸ These medications, along with common oral antibiotics used to treat STIs, are routinely provided in SHCs and are often available on-site, possibly resulting in timelier treatment.^20,39 Extra-genital testing for gonorrhoea and chlamydia, point-of-care testing for STIs, and access to specialised techniques and laboratory equipment such as Gram stains, darkfield microscopy for syphilis, and Neisseria gonorrhoeae culture are standard diagnostic components of many SHCs, but typically not available elsewhere.

The importance of SHCs extends well beyond the medical care they provide. Table 2 details some of the services provided in SHCs. One such area involves education and training. Staff educate medical, nursing and allied health trainees on topics related to sexual health and provide consultation to community health providers for specific STI-related cases. Many SHCs in the US closely work with the National Network of Sexually Transmitted Disease Clinical Prevention Training Centres to support training for clinical providers and other health professionals in STI management and care.⁴⁰ SHCs serve as research sites for new diagnostic tests and treatments, including therapies for increasingly recognised pathogens and multi-drug-resistant organisms.^41–47 SHCs have played an important role in the evaluation of point-of-care tests, extra-genital testing, self-collected specimens, resistance-guided anti-microbial therapy and therapies to advance the clinical care and management of patients with STIs.^46,48–50 Indeed, in the absence of such clinics, it is difficult to imagine how a study could enrol an adequate number of people with STIs to evaluate a new diagnostic test or treatment. Even with the current network of SHCs, the research capacity of many nations – including the US – is insufficient to conduct the number of studies needed to simultaneously confront the challenges of rising rates of syphilis, antimicrobial-resistant N. gonorrhoeae, Mycoplasma genitalium, and bacterial vaginosis. This would also include studies related to health services and implementation science, which greatly contribute to the application and understanding of STI and HIV prevention management in real world settings.^51–55

Table 2.  Examples of services provided at specialised SHCs in different jurisdictions.

Sentinel surveillance for STIs and HIV is a critical public health function incorporated into many SHCs. Sentinel surveillance involves the ongoing and systematic collection of case data from a sample of providers (in this case, SHCs) to identify trends in STIs in the larger population. For example, the US Gonococcal Isolate Surveillance Project (GISP), Strengthening the US Response to Resistant Gonorrhoea (SURRG), the Australian Gonococcal Surveillance Program and the Dutch Gonokokken Resistentie tegen Antibiotica Surveillance (GRAS) all monitor antibiotic resistance trends in N. gonorrhoeae culture isolates, predominately from SHC patient specimens, to inform treatment recommendations and programmatic planning.^56–59 In the US, the Netherlands, and Australia, many SHCs contribute to sentinel surveillance efforts to characterise STI and HIV epidemiology at the national level.^{1,31,35,56,60} Apart from surveillance of the more traditional STIs, SHCs play a vital role in surveillance of less well-known sexually transmissible pathogens, such as extensively drug-resistant Shigella sonnei and monkeypox virus.^13–15,61 SHCs are also often connected with broader public health surveillance efforts such as case investigation and partner services, which integrate public health data collection with the provision of vital services, such as linkage to PrEP and to HIV care for patients with newly diagnosed HIV infection or those who have fallen out of care.^54,62,63

There is a need to build, improve, and support the clinical infrastructure of SHCs. With rising rates of STIs, it will be important to expand services in SHCs, but also embrace opportunities for greater efficiency. These services will need to reflect priority populations for that community, those most needing of STI services and judicious use of resources. It will be critical for local and federal governments to allocate resources and funding to support SHCs.

Selective de-medicalisation of sexual health services and greater use of e-health technology can increase STI/HIV testing, treatment, and prevention services while minimising costs. For example, the use of computer-assisted self-administration interviews for sexual history taking has been shown to accurately identify patients eligible for STI/HIV testing-only visits without a clinician evaluation, streamlining clinic flow.^64,65 Self-obtained specimens for testing gonorrhoea and chlamydia and ‘express visits’ for routine asymptomatic screening can be widely implemented to increase efficiency, reduce long-term costs and reduce visit lengths.^66–72 Twenty-one percent of visits to specialised SHCs in the US were express STI or HIV testing-only visits, suggesting a large proportion of asymptomatic screenings can be accomplished without lengthy face-to-face consultation and in some areas, the need to see a clinician.³⁰

Lean service delivery models for high throughput and low barrier clinics for HIV/STI testing have been initiated to address increased volume and demand. Examples include Umbrella health and 56 Dean Street, part of the National Health Service in the United Kingdom, which provide walk-in, rapid STI screening service for asymptomatic individuals.^73,74 Standing orders for STI/HIV testing and/or treatment as used in NSW, Seattle and other cities can be implemented to expand the role of disease intervention specialists (DIS) (public health workers who provide partner services) and registered nurses within SHCs to help relieve clinician time if allowed by state or federal law.^75–77 In Amsterdam and Thailand, Key Population-Led Health Services engage certified community health workers to provide tailored and accessible sexual health and HIV prevention services.^78–80 At-home specimen STI and HIV testing and utilising telehealth are other means to expand sexual health services by SHCs.^81–84 These modalities not only help offset the burden of clinical visits, but are convenient, acceptable, and increase access to sexual health care and HIV prevention for patients with limited access to healthcare services due to stigma, privacy/confidentiality concerns, or the absence of locally accessible care.^85,86 Service expansion to meet the numbers of individuals needing sexual health care might be integrated within SHCs themselves, without the need for a clinician at every appointment or can be integrated within separate facilities to expand the network of services in a given area that then connect with SHCs as the central part of STI treatment, complex STI management and HIV prevention.

With greater efficiency, specialised SHCs should ideally focus on high-priority populations and expand services to meet the needs of those populations. Potential areas for service expansion include mental health and substance abuse treatment, HCV testing and treatment, and expanded services for gender-diverse populations. Many examples exist of successful service expansion.

Some of the ways specialised SHCs should focus on priority populations include innovative services to address co-morbid conditions associated with STIs and HIV. In Amsterdam, a SHC implemented syndemic-based interventions such as help-seeking advice on mental health screening and peer-led counselling hours around chemsex and smartphone dating application addiction⁸⁷ (Dr. Henry de Vries, pers. comm., July 2022). In NYC, SHCs incorporated behavioural health and substance use counselling, and in Baltimore, Maryland, staff successfully linked patients to substance use disorder treatment services in the community.^88–91 SHCs in Baltimore, Maryland, also offer free rapid hepatitis C virus (HCV) testing with linkage and outreach support to specialty HCV care.⁹² SHCs in NYC provide patients with same-day contraception initiation, with linkage to ongoing family planning as some patients may need or prefer SHCs for contraceptive care.⁹³ As many countries are facing a syndemic of HIV, other STIs, viral hepatitis, substance use and untreated mental health conditions, integration of services within SHCs or referrals to appropriate care providers can improve the care of individuals with relation to STIs and/or HIV.

In some SHCs, services focus on increasing engagement of specific priority populations who might not engage in healthcare elsewhere. Although many SHCs have not traditionally focused on the care of transgender, gender non-conforming and non-binary patients (TGNCNB), they have the capacity to do so and should ideally be able to provide services that reduce stigma and improve health.^31,33,94 For example, health disparities exist for TGNCNB and some specialised SHCs have implemented services such as the provision of hormone therapy to engage these communities and integrate STI and HIV prevention.^31,33,94,95 Other models include dedicated SHCs for groups with high rates of STIs, such as a specialised clinic for sex workers or transgender sex workers in Europe.^96,97 Although this might be best for local community needs in some settings, in other locations, SHCs focus on incorporating appropriate language and programs that are responsive to culturally specific needs and sensitivities.⁹⁸ For example, SHCs in NYC have external facilitator-led trainings on serving lesbian, gay, bisexual and queer/questioning and TGNCNB patients (Dr. Preeti Pathela, pers. comm., July 2022). Increasing access to care for populations disproportionately affected by STIs and/or HIV is a way to address disparities and improve overall health.

Although the majority of services offered in SHCs in high-income nations focus on management of STIs and prevention of HIV, some locations have been able to focus on other sexual health priorities and needs. Not only are some clinics able to expand services to address co-morbid conditions as mentioned above, different clinic structures or access to health care as changed priorities of SHCs in a jurisdiction. For example, in the US, the majority of patients visit SHCs for STI/HIV diagnosis and STI treatment.^20,31 In NSW and the Netherlands, where most routine STI and HIV testing is implemented in primary care, SHCs prioritise complicated cases and populations, but still remain focused on STI and HIV prevention and control. In the most recent outbreak of monkeypox disease, SHCs in many parts of the world have been at the forefront of patient care and management.

National strategies, such as the National HIV/AIDS Strategy for the US and the Ending the HIV Epidemic (EHE) can in part be achieved by utilising SHCs for PrEP, post-exposure prophylaxis (PEP), and initiation of antiretroviral treatment.^99,100 Staff in SHCs see a large number of individuals who would benefit from HIV prevention methods, such as MSM with a history of early syphilis or rectal gonorrhoea and patients seeking PrEP.^101,102 This would alleviate the ‘purview paradox’, or the notion that antiretroviral therapy for HIV prevention is not within the clinical domain of either HIV specialists or primary care providers.¹⁰³ PrEP referrals can be incorporated into case investigation and partner services given the potential for a seamless integration of SHC and STI/HIV surveillance activities.¹⁰⁴

SHC clinics have implemented a variety of models for providing PrEP. Some SHCs provide ongoing PrEP care, some initiate PrEP and then refer patients to other providers to continue the intervention, and others refer interested patients to another source of care, sometimes using patient navigators to help ensure linkage to care.¹⁰⁵ Models that refer patients to other clinics for ongoing PrEP have met variable results. In NYC and Chicago, 11% and 29% of those that offered intensive navigation or a warm hand-off from the SHC to an outside PrEP provider received a PrEP prescription, respectively.^53,106 In general, SHCs that provide ongoing PrEP care seem to enjoy greater success, though they also require more resources. A SHC in Seattle provided ongoing PrEP care to almost 1400 patients over 6 years using a de-medicalised model that task shifts most patient follow up to DIS.¹⁰⁷ In both the Netherlands and NSW, patients were initiated on PrEP and attended trimonthly PrEP visits within SHCs in pilot startup and rapid access programs. At the end of 2019, >2700 individuals (98% MSM) had an initial PrEP visit at SHCs in the Netherlands.¹ In NSW, >3500 MSM were initiated on PREP in 2016, 47% of which were seen at SHCs.¹⁰⁸ SHCs should strive not only to provide expert clinical care for STI patients, they are also ideal settings for HIV prevention.¹⁰⁹

For people with HIV (PWH), service integration of STI and HIV care may be beneficial for some patients or settings to promote multidisciplinary holistic sexual health. Over the years, STI- and HIV-related medical care has diverged. SHCs focus on STI treatment and prevention whereas HIV care is managed by infectious disease physicians or other HIV specialists and in countries like Australia, within primary care. However, SHCs may be a valuable resource to improve HIV care outcomes, especially for priority populations who might not seek care elsewhere.¹¹⁰ An early intervention of medical treatment and counselling was implemented for PWH attending Baltimore STD clinics, and the clinics continue to provide Ryan White HIV/AIDS Program (a source of federal funding for HIV care in the US) primary care services for PWH.¹¹¹ Although re-linkage services to HIV care might be helpful for some, interventions within SHCs to provide antiretroviral therapy and primary medical care might be best in some settings.

Some jurisdictions use SHCs to lead and activate key aspects of their broader HIV prevention and care strategies. One such innovative model, the MAX clinic, is a model of HIV care that is based on walk-in, incentivised, low barrier care with intensive psychosocial support for those patients who do not engage in the traditional healthcare model, and is housed within the SHC in Seattle.¹¹² Another program in Amsterdam, the HIV Transmission Elimination in Amsterdam initiative, combines various innovative interventions to prevent transmission of the virus by promoting prevention, earlier HIV testing and immediate treatment of infections, especially among populations with high prevalence of HIV.¹¹³ Similarly, the NSW HIV strategy guides prevention, testing, and care activity to priority populations, with a focus on SHCs to drive implementation in partnership with community organisations and academics.¹¹⁴ These targeted approaches place these programs within SHCs on the frontline of the global fight against HIV.

With the rising rates of STIs in many parts of the world, the threat of untreatable pathogens due to antibiotic resistance, and the need for clinical care to address complicated disease, we need to mobilise resources to support a stronger clinical infrastructure of specialised SHCs. However, the availability of SHCs and services offered in these clinics have been limited by lack of resources and funding in many countries. In the US, from 2008 to 2009, 69% of SHC programs experienced funding cuts and at least 10% of specialised SHCs closed.⁷⁵ A study of local health departments in the US in 2018 showed one-third do not have, or are not aware of, a primary referral point for safety-net STI services.^17,115 More recently, public health activities focused on the COVID-19 pandemic response diverted resources and personnel from SHCs. In April 2020, in NYC, seven of eight SHCs closed, with one clinic remaining open for limited and emergency services only;¹¹⁶ as of May 2022, four of the eight clinics were open. In the US, ≥60% of SHCs reported reduced capacity to screen or treat STIs, and 96% of programs reporting staff reassignment to COVID-19 work in April 2020.^117,118

Funding cuts are not limited to the US. Ninety-five percent of 20 Australian public SHCs surveyed reported delays in molecular STI testing and 70% of these clinics experienced staffing reductions due to reassignment of staff to assist in the COVID-19 response.⁹ The number of visits to SHCs in the Netherlands was reduced by about 80% during the lockdown period, and routine HIV/STI testing was temporarily suspended at the STI clinic of the Public Health Service of Amsterdam.^119,120 Despite an increase in telehealth visits to maintain STD-related care, shortage of STI treatment medications, diagnostic kits, and laboratory supplies and delays in testing have hampered testing and management.^9,121–124 The service disruptions in sexual health has potential detrimental effects on HIV and STI incidence in communities, the extent of which is not yet fully clear. Sexual health services need to be expanded to manage a rise in STI/HIV transmission resulting from the period of diminished testing and treatment coincident with the COVID-19 epidemic, especially given increases in reported bacterial STIs even prior to widespread COVID-19 mitigation measures and stay-at-home orders and the 2022 monkeypox outbreak.⁸

There is a need to increase the number of SHCs, expand services and increase funding resources. Ideally, a network of SHCs would best serve a community. In one way, this can be accomplished with larger central locations and smaller satellite clinics to reach an expanded geographic area. Services would be tailored to high-throughput, convenient STI/HIV screening and treatment with a focus on engaging those at highest risk of STI/HIV acquisition in the local community and fluctuating priorities to meet the needs of current sexually related public health goals. Flexibility will be key to implement new models of care to engage priority populations. Incorporating technology and home testing for STI screening and HIV prevention will be important as STI rates continue to increase, to meet the numbers of individuals who might need care.

Specialised SHCs are a key component of sexual health care in many places in the world. We need to strengthen, support, and expand SHCs if we are going to address the escalating problem of increasing STIs and their complications. The services provided in SHCs will need to evolve to meet the needs of the populations they serve in the context of limited resources. Focusing on priority populations and implementing innovative programs for STI and HIV screening, prevention and management can help deliver sexual health care to those who need it the most.

The data that support this study are not available.

MSR owns stock in Gilead and Merck. LAB has received research support, unrelated to this work, from Hologic, SpeeDx and Nabriva, and received consulting fees from Nabriva. For the remaining authors, no conflicts of interest are declared.

This publication was supported by NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, NIA, NIGMS, NIDDK of the National Institutes of Health under award number, AI027757.

All authors provided substantial contributions to the conception of the work, either drafted or revised the work critically for important intellectual content and approved the final version to be published. The submitted manuscript is an original contribution not previously published.