Polymethylmethacrylate (PMMA) also referred as (acrylic) bone cement is a non-degradable biomaterial that has been used in clinical orthopedic practice for several decades. PMMA can be used in a plain formulation, but is often used in an antibiotic-loaded formulation in (primary and revision) arthroplasty and in treatment of orthopedic infections as prosthetic joint infections (PJI) and chronic osteomyelitis. In treatment of PJIs antibiotic-loaded PMMA is often used as a carrier material for local antibiotic delivery in addition to treatment with systemic antibiotics. In this case, the antibiotic-loaded PMMA is often used as a spacer or as a bead chain. Since the introduction of PMMA as an antibiotic carrier there is a tremendous amount of scientific and clinical papers published, which studied numerous different aspects of antibiotic-loaded PMMA. This paper will review the research regarding basic principles of antibiotic-loaded PMMA as mechanism of action, antibiotic-release capacities, choice of antibiotics and influences on mechanical properties of PMMA. Subsequently, concerns regarding the application of antibiotic-loaded PMMA, biofilm formation, antibiotic resistance and local or systemic toxicity will be discussed. In addition to these subjects, the role of antibiotic loaded PMMA in clinical treatment of PJIs and chronic osteomyelitis is discussed in the final part of this paper. Bacterial infections are one of the most devastating complications in the field of orthopedic surgery. Especially infections related to implants e.g., cases of infection in total joint arthroplasty (TJA), or infections related orthopedic traumatology where implants are used for bone fixation are burdensome and difficult to treat. The infection rates vary based on the etiology of the infections, this review highlights the orthopedic prosthetic joint infections (PJIs) and trauma related chronic osteomyelitis. In cases of PJI the infection rates vary from <1% in primary total hip arthroplasty up to 10 to 14% in spine surgery or revision arthroplasty . In the The number of orthopedic implant surgeries is rising in the past years and is expected to increase in the upcoming years. Not solely the absolute numbers of PJIs are increasing, but also the relative infection rates are increasing . These nAs mentioned before, local antibiotic therapy is important in treatment of PJIs and chronic osteomyelitis. For the antibacterial effectiveness, it is important that the local antibiotic concentration exceed the minimal inhibitory concentrations (MIC) of the causative pathogens . DependiBone cement is used for almost 150 years since Gluck introduced it in 1870 for fixation of a total knee prosthesis . Back thIn the past decades, the optimization of antibiotic-loaded PMMA became an important research topic in the improvement of prophylaxis and treatment of PJIs . PMMA isin vitro studies showed that the pharmacokinetic release profiles of PMMA can be optimized by adjusting several properties of the PMMA. Since antibiotics are released by dissolution after contact with body fluids, an increase of the surface roughness and the porosity of the PMMA result in an increase of surface area, leading to an increased antibiotic release  release up to 93% of the added antibiotics  and achieve antibiotic concentrations up to seven times higher compared to normal PMMA beads  and the PROSTALAC® spacer . Some studies suggests that mobile spacers might even result in better infection treatment, although this is still under debate due to the absence of unequivocal evidence  and  joint mobility, which all favor the re-implantation of the definitive prosthesis during the second stage of PJI treatment, see l months . In contl months . In compl months . This isl months . Second-evidence . Disadvaevidence  and assoReduction of biofilms or prevention/inhibition of biofilm formation remains one of the major challenges in prevention and treatment of PJIs and chronic osteomyelitis. The phenomenon of biofilm formation is often termed “the race for the surface,” which was first described by Since bacteria in biofilm are protected by the biofilm layer they cause clinically relevant therapeutic and diagnostics challenges. The biofilm may cause difficulties in the microbiological diagnosis because the biofilm matrix can impede culturing of the bacteria, which can lead to false-negative cultures and missed diagnosis of infections. In order to prevent this there are many new developments in detaching the bacteria from their biofilm for better diagnosis .Therapeutic difficulties caused by biofilms are related to the decreased susceptibility for  antibiotics. The extracellular matrix of the biofilm causes an additional barrier resulting in decreased diffusion. In addition, substances of the matrix react with the antibiotics and thereby decrease the transport rates . Besidesin vitro studies showed that high local antibiotic concentrations inhibit, but not fully avoid, biofilm formation  antibiotics are the toxic side effects, especially cytotoxicity and systemic toxicity. Cytotoxicity after local antibiotic therapy is studied on cell survival and the capacity to recover of eukaryotic cells (like osteoblasts) in different ntamicin . For mosibiotics . AlthougAnother major concern in the application of antibiotic-loaded PMMA is the increase of bacterial antibiotic resistance. It is thought that after release of the majority of the antibiotics out of the antibiotic-loaded PMMA, the remaining antibiotics lead to sub-inhibitory concentrations, causing mutational antibiotic resistance . In addiWith the introduction of antibiotic-loaded PMMA around the 1970s and the specific gentamicin-loaded PMMA a few years later, the prevalence of PJIs decreased from around 5% to less than 1% . After sAntibiotic loaded PMMA spacers are used over two decades in two-stage PJI treatment with good clinical results. Different studies show that in treatment of infected THA as well in treatment of TKA, eradication rates of two-stage treatment are successful in 85 to 100% . HoweverAs PJIs and chronic osteomyelitis remain a substantial problem in orthopedic surgery, improvement of treatment of PJIs and chronic osteomyelitis with local antibiotic-loaded PMMA continues. Current research concepts are regarding surface modification and microencapsulation of specific antibiotics as e.g., rifampicin to enable biofilm breakdown and infection treatment by rifampicin loaded PMMA cement with good mechanical properties .In addition to development of antibiotic-loaded PMMA in prevention and treatment of PJIs, new carriers and coatings for controlled release of local antibacterial agents are important research topics for biofilm infections. Thereby, new carriers are interesting prophylactic opportunities for the uncemented prosthesis in TJA as well. These new strategies are based on adaptation of the surface of implants to prevent from infection, basic principles are (1) passive surface modification, (2) active surface modification and (3) local carriers/coatings, see In treatment of chronic osteomyelitis there is a tremendous increase in different biomaterials that might be suitable for local antibiotic delivery. In addition to local antibiotic delivery, these new biomaterials must have good bone defect filing capacities and should be biodegradable. Using these biodegradable local-antibiotic carriers enables the possibility for one-stage treatment of chronic osteomyelitis, which results in lower patient burden, less hospitalization and lower costs. In order to enable on-stage surgery these biomaterials must have proper biocompatibility to stimulate new bone formation and the must not have any toxic side effects on the surrounding tissues. Thereby they should have good biomechanical properties in order to prevent fractures or other mechanical failures after surgery. In the development of these biodegradable antibiotic-loaded biomaterials, different materials have been tested in pre-clinical and clinical studies. Examples of these materials are natural polymers like collagen and chitosan; synthetic polymers like polylactide; ceramics like calcium sulfates and calcium phosphates  and bioactive glasses . A recenTvV did the literature research, wrote the first draft, and finalized it to submitted version. JA and JG assisted with literature research, provided additional information, and reviewed the different versions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


As HIV/AIDS emerged in the 1980s as a new and seemingly overwhelming public health challenge, prisons were highlighted as an important location for the control of the epidemic. Yet, they often seemed unwilling or unable to adopt national guidelines. This article compares the policy decisions made by the prison services of the Republic of Ireland and England & Wales in response to HIV/AIDS in the 1980s and 1990s, bringing together the histories of penal policy and HIV/AIDS for the first time. It develops our understanding of contemporary policy history, and demonstrates the value of a comparative approach to both penal and health histories. Policy-making was shaped by both national and more localised traditions and trends, from attitudes to criminal justice and responses to HIV/AIDS at the national level, to the histories, structures, and staffing of prison services themselves. As HIV/AIDS emerged in the 1980s as a new and seemingly overwhelming public health challenge, prisons were singled out as a likely flash point for its spread and an important location for controlling the potential epidemic.3Policy making of this kind was a frequent focus of initial research into interpretations of HIV/AIDS.7Historians also pointed to the importance of ‘pre-history’. Policy making did not occur in a vacuum, but was clearly influenced by the traditions of particular policy areas and by pre-existing issues and tensions.A comparative analysis of HIV/AIDS policy-making for prisons in the 1980s and 1990s forms the focus of this article, which contrasts the Irish Prison Service and Her Majesty’s Prison Service of England & Wales (HMPS).Our analysis considers initial reactions to discoveries of HIV within prisons in both jurisdictions, following which segregation loomed large, before moving on to examine the 1990s and long-running issues of condom provision and addiction treatment. The comparison of the Republic of Ireland with England & Wales reveals that four interconnected factors were of particular importance in shaping HIV/AIDS policy. First, the histories and structures of these two prison systems, including the legacy of political prisoners and the extent of external scrutiny, were significant. Second is the level and nature of political attention granted to prisons and punishment. This changed for both jurisdictions in the 1990s, albeit in different ways, but in both cases one result was a less insular prison system which brought penal policy closer into line with national standards. Thirdly, the presence or absence of medical professionals within prisons and within policy making structures was key. This remained the case into the 1990s and beyond, although as the example of HMPS shows, a greater medical presence was not always to the benefit of policy implementation. Lastly, broader national responses to HIV/AIDS were influential, for both good and ill. What therefore characterised penal policy making in both jurisdictions is the weight of institutional pressures and structures, as well as the broader social and political context.There is a current revival of HIV/AIDS as a historical subject, but this has shown less interest to date in the policy analysis which marked the earlier historiography.14This article deals with very recent history, but the methodology of government archives, grey literature, official reports and news items is familiar to those who work on the history of policy. In one area, the use of oral history, some further comment is needed. This article draws upon interviews with 30 civil servants, prison staff, voluntary sector workers, probation officers, clinicians and former prisoners from both England and Ireland, conducted in 2016–17. It has also made use of earlier interviews, anonymised at the time, which were conducted by Virginia Berridge in the late 1980s and early 1990s for a study of HIV/AIDS policy making in the UK. Many of these informants have since died, including Dr Kilgour, then Director of the Prison Medical Service, and Len Curran, HMPS psychologist who played a leading role in the difficult task of developing research on HIV/AIDS in prisons in England & Wales.15This has prompted reflection on the differences between researching HIV/AIDS policy making in the 1990s and in 2017. The recent revival of historical interest in HIV/AIDS reflects its redefinition as ‘real history’, whereas before it was sometimes viewed as ‘slow journalism’. In the 1990s, archives were more difficult to come by, often handed over ‘under the counter’.The 1980s and particularly the 1990s have been seen as transformative decades for the Republic of Ireland. In the early 1980s, Ireland appeared to be an anomaly amongst developed Western nations thanks to its economic failings, its repressive sexual politics and ‘clerical interventionism’, and its religious and territorial conflicts. Paralleling patterns elsewhere, the 1960s and 1970s had been a period of modest but significant social change but were followed by a backlash in the 1980s, stimulated by the visit to Ireland of Pope John Paul II in 1979.20Irish penal history has focused upon the role of prisons in the ‘containment of political disorder’ before the establishment of the Free State and during the Troubles, and the widespread use of alternative institutions such as psychiatric hospitals and Magdalene laundries for holding socially deviant individuals. The former encouraged the isolation and secrecy of the Department of Justice, which retained tight control over all prison-related decisions, and spared little attention for the ‘ordinary’ prisoner. The latter saw exceptionally low numbers of people in the prisons of the Republic of Ireland throughout much of the twentieth century: well below a thousand in the 1960s and barely 2,000 by the early 1980s. The result, social scientists have argued, was stagnation in policy terms and a widespread lack of interest in prisons overall.In England & Wales, the prison service was much larger and had been growing since the 1950s. By the 1980s, the Home Office was responsible for over 100 establishments and tens of thousands of inmates, managed through its Prisons Board and reviewed by an independent inspector. Histories of the prison service of England & Wales have identified significant debate and change over the twentieth century, with interest in the rehabilitation of offenders keeping penal questions alive and maintaining the expansion and influence of its medical service.25In both jurisdictions, the 1990s have been identified as a point of intensification. Where once political prisoners had occupied the lion’s share of attention, the prisons of the Republic of Ireland began to face the new problems of overcrowding, drug use and violence. This, in combination with much greater public interest in matters of law and order, prompted the stirrings of a new approach to prison administration.and state provision for health and social care. Gay Health Action was formed in 1985 and worked to raise awareness and to share information, but as homosexual acts remained illegal until 1993, funding and working relationships with policy makers were all but impossible to obtain.Amidst this sits the HIV/AIDS crisis. The first diagnoses were made in the early 1980s amongst gay men in both jurisdictions, but national perceptions and responses to the looming epidemic soon diverged. Gay groups, voluntary organisations and specialist clinicians put pressure on the UK government to act. By 1986, a sense of crisis prompted national advertising campaigns, the formation of a special Cabinet Committee and a Social Services Select Committee Enquiry, plus funding for pilot needle exchange schemes and biomedical research, quickly followed by the creation of the National AIDS Trust to coordinate the rapidly expanding voluntary sector. Anxiety cooled in the later 1980s as treatments emerged and the numbers of those affected failed to fulfil the worst predictions, and by the 1990s challenges to the liberal consensus were emerging. In the Republic of Ireland, the activities of activist and voluntary groups were more muted and fragmentary. Work on HIV/AIDS in Ireland has highlighted the particularity of Ireland’s conservative political and cultural landscape and the impact of this upon sexual mores and laws Both jurisdictions were spurred into action by the discovery of HIV/AIDS within their prisons. For England & Wales, the death from an AIDS-related illness of the chaplain at Chelmsford prison, Gregory Richards, hit the headlines in early 1985 and led to an element of panic that chimed with the national atmosphere. For a brief period, the Prison Officers’ Association (POA) refused to allow any movement in or out of the prison, bringing home to the prison service the need for an urgent and decisive response to prevent similar episodes elsewhere.31British Medical Journal both showing interest. Added to this was the level of media coverage and public anxiety around HIV/AIDS, which was reaching fever pitch in 1985–86.HMPS benefited from the knowledge of Dr Kilgour, who had until 1983 worked for the WHO. He made the most of his contacts there in order to stay up to date with the latest information and guidance regarding HIV/AIDS, and to encourage the WHO to produce guidelines on AIDS in prisons that could then be used to advocate for change at home. HMPS also benefited from a large network of medical professionals in senior positions, through which information and policy could be disseminated. At the local level, some prison doctors were then willing and able to share knowledge and reassurances with discipline staff and management teams, although the efficacy of this would depend upon individual doctors and local relationships and structures.One of the first and most significant policy decisions in England & Wales, taken in late 1985, was to apply the Viral Infectivity Regulations (VIR) to prisoners with HIV/AIDS. These regulations had been developed only a short time earlier for hepatitis B, and were to be implemented at the discretion of medical staff. Prison doctors could recommend that prisoners with hepatitis or HIV/AIDS were housed separately from the general population, and excluded from sports activities or work involving sharp objects or food preparation. 36The discretionary and permissive nature of these policies left considerable scope for interpretation. As with the programme of education that had followed Revd Richards’ death, this approach depended upon the interventions and influence of individual doctors across the prison estate. The relative novelty of the VIR in 1985, in combination with the specific and heightened anxieties about HIV/AIDS at that moment and the reliance upon medical decisions and authority, meant that their implementation was unpredictable. Violence towards prisoners thought to be ‘AIDS carriers’ led to their separation from the general population in some instances, blurring the VIR with operational reasons to segregate inmates at risk.39Analyses of UK prison policy regarding HIV/AIDS have attributed the introduction and variable implementation of the VIR to the isolation of prison medicine from mainstream medicine, and the extent of local independence across the prison estate. These factors allowed prison policy to deviate from national policy by allowing segregation, and made the strict enforcement of blanket policies an alien and challenging proposition.In the Republic of Ireland, the events of 1985 and 1986 took a different path. A burgeoning heroin epidemic in Dublin had prompted an influx of young heroin addicted inmates, and where prisons had stood half-empty only a decade before, there was now increasingly severe overcrowding.44As was the case in Chelmsford prison, fears about how easily HIV/AIDS might spread prompted considerable concern amongst staff. But the reaction in policy terms was different, with the Irish prison service immediately introducing a national policy of segregation that was not wholly abandoned for ten years. There were several reasons for this. First, the prison service was following the lessons from its own history. The segregation of political prisoners from the general population of inmates was well-established. Blanket segregation in the name of good order was tried and tested, staff could easily implement it, and the Department of Justice was accustomed to ordering it. Secondly and connectedly, the decision-making process in the Republic relied on a small number of people, and no one with any medical expertise at all. A handful of civil servants and ministers were accustomed to taking all decisions, and in the case of HIV/AIDS this left policy-making susceptible to fears, rumours and pressure from the IPOA. This association was remembered as being ‘very well organised and very powerful, and had huge political influence’: one probation officer recalled that a particular Justice Minister would stop off at the prison officers’ drinking club on a regular basis, and other senior staff felt that ‘across the board, we have to keep the IPOA on side to do anything … prison management were unashamed: that’s our priority’.45In addition to this, expertise and interest in the Republic of Ireland regarding HIV/AIDS, and the activities of prisons, was limited. The state was involved less in matters of public health and social care than was the case in England & Wales, and a fractured and fractious medical profession had little experience in either genito-urinary medicine or addiction, two fields in which HIV/AIDS emerged most urgently. Spending on health care was extremely low compared to other EEC countries, and was facing cut after cut throughout the 1980s.A lack of external scrutiny and medical influence helped the policy of segregation to endure, but so, too, did the problems that the policy itself generated or intensified. Distress, mental illness and drug use were not uncommon, especially as time went by and current and former occupants of the separation unit died of AIDS-related illnesses in increasing numbers. Prisoners sometimes cut their arms in protest or desperation, prompting considerable anxiety amongst staff who feared contact with their blood, and in one memorable hostage situation an officer was held with a noose around his neck and threatened with a used syringe. Better facilities in the segregation unit, both perceived and actual, also created problems for reintegration.Policy for women with HIV/AIDS in Irish prisons changed fairly quickly. Around 1987, a Department of Justice working group advised that segregation should be gradually phased out, and recommended a plan for re-integration that would include staff and prisoner education and the adoption of new guidelines for managing prisoners with HIV/AIDS. These guidelines, with clear echoes of the VIR in England & Wales, stated that inmates known to have HIV/AIDS ‘may be placed on ordinary location in a single cell or accommodation shared with other inmates who are antibody positive’.Although policy and practice on segregation took years to resolve, the key policy issues in the 1990s centred upon reducing the risks of HIV infection from sex and injecting drug use. Neither prison service initially acknowledged that sex or drug-taking took place within its establishments, but by the late 1980s, advisory bodies were making recommendations that challenged this stance. Guidelines from the WHO and the Council of Europe stated that condoms should be provided to prisoners, that facilities for safer injecting should be made available, whether in the form of needle exchanges or disinfectant, and that methadone should be prescribed on a long-term basis as an alternative to heroin. With the exception of needle exchanges in prisons, these proposed policies were endorsed by various groups in England & Wales including the Advisory Council on the Misuse of Drugs, the Prison Reform Trust, the prison service AIDS Advisory Committee, set up in 1986 and comprising both prison staff and external HIV/AIDS experts, and the AIDS and Prisons Forum organised by the National AIDS Trust.Recommendations that condoms be made available to male prisoners prompted some debate in medical journals and campaigning amongst HIV/AIDS advocacy bodies in England & Wales, but the prison service steadfastly opposed the idea.Condoms for prisoners remained contentious throughout the 1990s. External recommendations and criticisms persisted, and one health worker recalled that there were ‘tactical games played at senior level, where people were trying to move the boundaries as much as possible’.60Ongoing calls to permit prisoners access to condoms reflected the readiness with which condoms had been accepted as a valuable public health measure across most of British society. They also reflected the continuing scrutiny of a variety of external bodies which kept up pressure on the prison service to reconsider its approach, and the growing numbers of health promotion workers, HIV/AIDS co-ordinators, and genito-urinary consultants who were beginning to work in prisons.Official opposition to condoms was maintained in the mid-1990s by the particularly staunch commitment of ministers and government to focus upon security and punishment in prisons, at the expense of efforts to achieve equivalence with community services. The gap between the prison medical service and the NHS mattered less here than the politicisation of criminal justice. However, criticisms from external bodies and internal concerns about the spread of infection and resultant legal action prompted penal policy makers to once again follow the path of a permissive policy that relied upon the decision making of its doctors. As with the VIR, the presence of senior medical staff within the prison service with some independence and authority made this possible, but also allowed for considerable variation in implementation. In some instances, doctors interpreted the guidance extremely narrowly; in others, they remained unaware of its existence.In the Republic of Ireland, there was virtually no discussion about changing policy to allow the provision of condoms to prisoners. It was mentioned within the Department of Justice in the aftermath of the first HIV diagnoses in Mountjoy and there was reportedly some caveated support, but it proved too controversial for the state to pay for and provide condoms when homosexuality remained entirely illegal and the sale of condoms to those at liberty was still restricted.66One Dublin-based addiction worker remarked that ‘everybody found it much easier to talk about drug use and injecting than safer sex’.As with the emergence of HIV/AIDS and the subsequent policy of segregation, the problem of drug use appeared to be firmly concentrated in the Mountjoy prison complex in Dublin, and new policies and practices were adopted there first. Prior to the mid-1990s, there had been very little by way of services or treatment for addiction in Mountjoy, other than advice from probation and welfare officers, chaplains and one or two addiction treatment services that were granted access to talk to inmates and encourage them to seek out their services.This also pointed towards the growing importance and influence of medical expertise within the Irish prison system in particular, as armed conflict on the island lessened and attention to more everyday matters of crime and punishment grew. Methadone was quietly introduced and prescribed to prisoners in the separation unit, ostensibly only during detoxification but in practice on a longer-term basis as well, and this continued in the new Medical Unit when it opened in 1993. In 1996, a new drug treatment programme was launched and a new GP with expertise in addiction and experience in prescribing long-term methadone was hired alongside agency nurses, also with knowledge and experience of community practice.75Policy and practice surrounding drug addiction in Irish prisons changed markedly.th, because they just test me to make their figures look good”’.Policy relating to harm minimisation in England & Wales changed less. Indeed, by the mid-1990s and the compromise over condoms, the issue of HIV/AIDS had faded. Rates of HIV/AIDS amongst prisoners and injecting drug users were comparatively low.The introduction of disinfecting tablets for cleaning injecting equipment also faced difficulties in England & Wales: despite repeated recommendations and a successful pilot in the late 1990s, it was not rolled out more widely for some time and continued to be beset with problems.Histories of HIV/AIDS are beginning to analyse the events of the 1980s and 1990s from new perspectives. The reactions of prisons provide a useful lens through which to reexamine policy making and its interpretation during those decades. Broadly characterised, prison policy in England does partly fit the model of a ‘liberal consensus’, but this is less true for prison policy in Ireland. However, in both cases the question of prison policy in relation to HIV/AIDS reflects the social conservatism with which the 1980s is often associated. Prison policy making also illustrates the importance of institutional structures, histories and knowledge as well as the broader canvas of social, cultural and political contexts onto which HIV/AIDS emerged. This is also demonstrated through the comparison here of two distinct jurisdictions, close in terms of geography and population flow but at a distance from one another in other respects. Differences in national responses to HIV/AIDS were important to prison policy making, but so too were localised concerns and preoccupations, the nature and extent of external scrutiny, and the presence and influence of a variety of experts within decision making circles, particularly medical professionals. This adds to our understanding of the history of prisons over this period, which has at times been over-simplified as an era of endless crisis caused by overcrowding and understaffing. The case of the Republic of Ireland also adds nuance to existing periodisations and characterisations of HIV/AIDS policy making, suggesting more muted and even covert activities over the 1980s and into the 1990s. There is undoubtedly scope for much more work on Irish reactions to, and experiences of, HIV/AIDS.Pre history was important here. When compared to national policies, penal policies in response to HIV/AIDS could appear excessive, as in the case of segregation, or insufficient, as with the availability of condoms. The long-standing isolation of the Irish Department of Justice, its preoccupation with security, and its relative inexperience with issues such as overcrowding, as well as the extent and geographical focus of its first encounter with HIV/AIDS, prompted the creation of the segregation unit for prisoners with HIV/AIDS. The absence of external expertise or scrutiny helped it to endure, with interested voluntary groups and individual experts few in number. The absence of medical professionals within the Irish penal system was also significant, as was the presence of senior medical staff on the other side of the Irish sea. Policies within HMPS were influenced by medical and other expert views, both internally and coming from external advisory bodies and committees. But, and to the detriment of implementation, they also relied heavily upon medical discretion. This indicates the impact of greater levels of local independence and less central control within HMPS than was the case for the Irish Prison Service.Policies in the Republic began to change as the prison service itself began to expand and open up over the 1990s. This was a period of change for the nation more broadly, with shifts in attitudes towards homosexuality and contraception that would go on to have an impact upon prisons. Also key was a lessening of sectarian conflict and greater criticism of national institutions such as the Church over this period: the Department of Justice was not immune from criticism, and was encouraged by this changing context to adjust its management and priorities for the prison system. HIV/AIDS became one such priority, and the involvement of new drug agencies and medical professionals in prisons helped to shift practices on the ground. Advice and recommendations from external bodies finally began to emerge, providing not only support for those within the service who wanted to make the case for change, but also the promise of further public scrutiny. The creation of the Irish Penal Reform Trust in 1994 was indicative of this new scrutiny. Changes in England & Wales were less marked, interrupted by the imposition of ‘tough on crime’ rhetoric from government and de-prioritised as targets focused on offender management rose and HIV/AIDS dropped down the agenda, but external scrutiny did not disappear. Furthermore, as the prison service negotiated partial privatisation and its new status as a purchaser of services, ever-closer union with the NHS and other external providers drew nearer. NHS staff as well as HIV/AIDS co-ordinators and drug agency workers were to be found inside prisons in greater numbers, bringing with them the policies and standards of the wider community. HIV/AIDS therefore coincided with a lessening of the isolation of prison services, acting as one amongst many reminders that prison walls were not impermeable. In the Republic of Ireland, this was particularly pronounced, as the secrecy surrounding the prison system as a whole began to subside, but it was apparent in England & Wales as well. As stronger links were forged between prisons and social care providers, including health services and voluntary bodies, penal policy moved closer towards parity with national policy as the new century approached.


The European patent for intravenous trastuzumab lapsed in 2017, and this stimulated research into a number of trastuzumab biosimilars. Quality assessment of their development and clinical results might enable establishment of a clinical hierarchy of these agents. This editorial will underline the key points for consideration when determining such an evaluation. Unfortunately, it is not uniformly available for routine use owing to its prohibitively high cost. With financial contingencies following the economic crisis together with rapidly increasing healthcare costs, even the richest countries are exploring ways to reduce their healthcare expenditures. In 2017, the patent for intravenous trastuzumab (Herceptin) expired across Europe, which stimulated the development of numerous trastuzumab biosimilar agents . For trastuzumab exposure, large variability in the AUC(0-t) is observed up to cycle 5, beyond which the values become stable and homogeneous over time.14 Therefore, a large randomised study aimed at comparing the activities should also perform a PK assessment in patients receiving iterative administration.The development of a biosimilar drug requires the collation of extensive pre-clinical comparability studies to demonstrate similar structural, physicochemical, and functional biological characteristics with the referent medical product.10 The strength of the statistical demonstration of equivalence is a key parameter in the quality of this comparability exercise.15 The approach recommended by regulatory authorities for deriving equivalence margins relies on preserving the reference treatment effect, estimated using a meta-analysis focusing on major studies. These recommendations posit a 50–60% preservation of the reference treatment effect from the average effect, or from the lower boundary of the 95% confidence interval. Variable margins of equivalence using different ranges of confidence were pre-specified to define equivalence , or assessment at neoadjuvant setting using pathological complete response (pCR). The neoadjuvant setting is a more homogeneous population, meaning fewer uncertainty factors. In contrast, efficacy at the metastatic setting could be impacted by previous treatment exposures, including chemotherapy and anti-HER2-targeted agents, and by tumour burden or the type of metastatic sites involved. The neoadjuvant setting selects patients with localised disease who are naïve to any anticancer therapy. Moreover, the neoadjuvant setting allows the use of pCR, which is a better efficacy assessment criterion and is related to survival outcome.18 ORR for metastatic lesions is not related to survival outcomes, and has not been used for the basis of any drug registration in breast cancer.19 Considering these points, the neoadjuvant setting is considered to be an important area for development in HER2-positive breast cancer.20 If a hierarchy based on clinical assessment could be developed for trastuzumab biosimilar candidates, then the agents with a favourable clinical assessment using pCR after neoadjuvant therapy might appear at the top of such classification  at cycle 5 is relevant, because a key PK parameter to consider is a Ctrough value higher than the threshold of biological activity. Whereas investigators of other biosimilar competitors have studied this PK in an ancillary sub-study of a unique randomised clinical trial,4 the development of PF-05280014 has now involved a dedicated randomised trial to evaluate PK non-inferiority with Herceptin.A single clinical study, in either the metastatic or the neoadjuvant setting, is usually sufficient to prove the equivalent efficacy of a biosimilar drug. CPT-6 was previously assessed in studies using both settings, but this was due to small changes in the production process that required duplication of all the comparability exercises .8 The 47% and 50% pCR rates achieved by PF-05280014 and Herceptin, respectively, provide a stratified difference for pCR of –2.81% (95% CI –16.58%/10.96%) based on investigator assessment. These differences and the 95% CI values are in line with the reported values provided by other biosimilar competitors in the same setting (Table 5 Thus, our neoadjuvant-based pCR assessment demonstrates comparable efficacy and provides complementary data supporting the success of this biosimilar candidate in the competition for market access.The neoadjuvant trial reported in the study by Lammers et al. has provided supplementary clinical data demonstrating comparable efficacy, based on pCR results.Several trastuzumab biosimilar candidates have already obtained authorisation for routine use in Europe, and a few of them might be in use within months. The next step will be to assess the impact in terms of cost savings resulting from the implementation of these biosimilars in these countries. To this day, debate over the cost decrease prospects for trastuzumab with the use of biosimilars is still at a speculative stage; further developments in the ongoing year are awaited with great interest.


Delayed antimicrobial therapy is an independent risk factor for mortality and prolonged organ dysfunction in sepsis. Barriers to timely antibiotic administration include lack of situational awareness about medication status and inconsistent communication with ordering clinicians.The specific aim of this project was to achieve antibiotic administration within 60 minutes of order for ≥ 70% of suspected sepsis episodes in pediatric intensive care unit patients.In the 55-bed pediatric intensive care unit of an academic referral center, a standardized workflow to decrease antibiotic administration time for patients with suspected sepsis was iteratively implemented from 2012 to 2017. An electronic orderset (phase 1) and best practice alert for “stat” antibiotic ordering (phase 2) were combined with a scripted multidisciplinary bedside “sepsis huddle” (phase 3). Subsequently, a bedside, 1-touch electronic notification button was introduced (phase 4), which triggered automated phone alerts to the clinical team until antibiotic administration was complete (Fig. There was a progressive decrease in time from antibiotic order to administration from phase 1 through 4 Table . This imCombining automated, timed reminders with a multidisciplinary huddle improved situational awareness about challenges to timely antibiotic delivery and decreased time to administration for critically ill children with suspected sepsis. Follow-up work includes integrating the 1-touch notification process into an automated sepsis recognition algorithm.


In this study, the numerical investigation of the detectability of concrete aggregate segregation in circular concrete-filled steel tubulars (CCFST) based on piezoelectric lead zirconate titanate (PZT) measurement is performed. The stress wave propagation in the concrete core of circular CCFST excited with a surface-mounted PZT actuator is studied with multi-scale and multi-physical field coupling analysis. The piezoelectric effect of PZT patches and its coupling effect with CFSTs are considered. Numerical concrete modeling technology is employed to construct the concrete core composed of randomly distributed aggregates with and without aggregate segregation at different levels, mortar, and an interfacial transition zone (ITZ). The effects of the random distribution of elliptical aggregates, aggregate segregation, and the existence of ITZ in the concrete core on the wave fields in the cross-section and the corresponding voltage response of the embedded PZT sensor are discussed. An evaluation index based on wavelet packet analysis on the output voltage response is defined, and its sensitivity to concrete aggregate segregation is systematically investigated. The multi-scale and multi-physics coupling simulation results indicate that concrete aggregate segregation in the concrete core of CFST members can be efficiently detected based on the stress wave measurement with a PZT sensor. Equation (5) shows the governing equations of the piezoelectric coupling system in the form of the generalized matrices and vectors.dC] is the damping matrix, [dK] stands for the dielectric matrix components, and [zK] is the electromechanical coupling matrix components. When the PZT patch is employed as an actuator, {F} = {0} and {Q} = {Q(t)}. Similarly, when the PZT patch is employed as a sensor, {F} = {F(t)} and {Q} = {0} [After establishing the multi-scale models of CCFST based on the random aggregate generation program, finite element meshing is performed with the multi-physical analysis software COMSOL as a solver. The dynamic equation of piezoelectric ceramics and the circuit state equation are described in Equations (3) and (4) ,13,31: and (7) are the basic requirements for mesh size and integration time step. As shown in F(t) and F0 correspond to the pulse force signal and its amplitude, f is the signal frequency, and t stands for the time variable in seconds. Here, F0 is set to 10−7 N, and the signal frequency f takes the value of 100 kHz.In this section, the stress wave propagation process in the cross-section of CCFST excited by the PZT actuator is investigated. As mentioned above, the multi-physical coupling models at the meso scale are composed of aggregates, ITZ, mortar, steel plates, and PZT patches. In order to reduce the computational cost, a horizontal pulse force signal is applied at the outer surface of the steel plate to simulate the vibration of the PZT actuator, since the planner dimension of the PZT patch is much smaller when compared with the whole cross-section of the CCFST and the high linearity properties of the PZT material. The pulse force signal adopted in this section is described in Equation (8):According to the material properties listed in −5 s. As shown in Three different CCFST members with normally distributed aggregates are constructed to further discuss the effect caused by the random distribution of aggregates. As discussed above, the effect of the random distribution of elliptical aggregates on stress wave propagation in the CCFST with the identical quantity and gradation of aggregates is limited. In engineering practice, aggregates may not be uniformly distributed during the casting of the concrete core, resulting in concrete aggregate segregation. Unlike the three samples with randomly distributed aggregates as presented in −5 s. At the same time instant, the wave fields of the other three CCFST members with different aggregates segregation scenarios are shown in It can be observed from The ITZ plays critical roles in the mechanical behavior of concrete materials. Here, further investigation on the effect of IZT on the stress wave propagation of CCFST members is carried out with the help of numerical concrete modeling technology at the meso scale. The stress wave field snapshots corresponding to the CCFST with normally distributed aggregates with and without ITZ are presented in In this study, each ITZ is located at the outer of the corresponding aggregate and has the shape of an ellipse, and its long and short axes are 1.1 times those of its corresponding aggregates, respectively. However, the stress wave field and propagation pattern of the two models with and without the consideration of IZT are almost identical. Hence, numerical simulations show that the influence of the IZT on the stress wave propagation is very limited. It is reasonable to omit ITZ in the finite element (FE) modeling of CCFST members for stress wave propagation numerical simulation analysis for the purpose of improving computation efficiency.It can be seen from V(t) and V0 correspond to voltage excitation and its amplitude, and f(t), f0, and f1 stand for the frequency of the voltage signal at the time instant t, the initial frequency, and final frequency, respectively. Here, V0 takes the value of 10 V, and the time duration T equals to 0.001 s. f0 and f1 are set to 20 kHz and 40 kHz, respectively.The previous studies performed by the authors show that the PZT sensor measurement embedded in CFST members excited with a sweep frequency signal is sensitive to the interface debonding defect due to its wide frequency band . Hence, Numerical simulation on the stress wave propagation and the response of the embedded PZT sensor is carried out with the PZT-CCFST coupling models, considering the piezoelectric effect of PZT materials and the coupling effects between PZT patches and the CCFST member.For comparison, wavelet packet analysis on the output voltage signal of the embedded PZT sensor in CCFST members with a concrete core modeled with different aggregates segregation is carried out, and the corresponding wavelet packet energies are determined to describe the effect of aggregate segregation in this section.N signal sets N-level wavelet packet [I = 1, 2, ..., 2N, j = 1, 2, ..., M. M stands for the number of samples within the frequency band k. E is the wavelet packet energy value of voltage signals from the PZT sensor embedded in the concrete core with different aggregates distribution and segregation. Emax stands for the wavelet packet energy of the voltage signal of the PZT sensor corresponding to the concrete core established with three-graded random aggregates, which is taken as the reference value in the comparative analysis. In this study, N is set to 3.Each original voltage signal of a PZT sensor can be expressed as a summation of 2t packet ,33. ThenBefore investigating the effect of aggregates segregation in the concrete core on the voltage response of the PZT sensor embedded in CFST members, the dynamic response of the PZT sensor in three CCFST members with fully-graded and normally distributed aggregates is analyzed first. For the purpose of assessing the influence of aggregates segregation on the evaluation index, the voltage response of the embedded PZT sensor under the sweep frequency excitation is simulated. Here, the three numerical concrete models with different aggregates segregation scenarios shown in In this section, the difference in the output voltage of the PZT sensor embedded in numerical concrete core models with and without considering the ITZ is investigated. In this study, for the purpose of investigating the detectability of aggregates segregation in the inaccessible concrete core of CCFST members, multi-physical and multi-scale coupling numerical models composed of a surface-mounted PZT actuator, a CCFST component with a meso-scale numerical concrete core, and an embedded PZT sensor are established at first. With the help of random aggregates generation and a packing program, a concrete core is decomposed as the combination of three-graded elliptical aggregates, mortar, and the ITZ. The stress wave propagation process and the stress wave fields are comparatively discussed. The influence of meso-scale structure variation in the concrete core on the stress wave fields and the output voltage of the embedded PZT sensor are investigated in detail. The major conclusions can be made as follows:The numerical concrete modeling approach based on random aggregate generation and the packing method is employed to model the meso-scale structure of the concrete core in CCFST members, which is composed of elliptical aggregates with different dimensions and distribution, mortar, the ITZ. The numerical concrete modeling approach provides an efficient way to investigate the effect of meso-scale structure variation of the concrete core and aggregates segregation in the concrete core on the stress wave propagation as well as the voltage response of embedded PZT sensor measurement in the cross-section of CCFST members.The initiation and propagation process of stress waves in CCFSTs modeled with fully-graded random aggregate samples with normal distribution are investigated at first via the multi-scale and multi-physical fields coupling FE models. The results indicate that the stress wave velocity is not significantly affected while changing the distribution pattern of three-graded elliptical aggregates samples without aggregates segregation. Besides, the existence of ITZ also poses a limited influence on stress wave propagation. However, the stress wave fields are obviously influenced by the aggregates segregation of the concrete core in CCFST members.The time–history voltage signal of the embedded PZT sensor and the corresponding evaluation index NWPEV based on wavelet packet analysis are sensitive to the aggregates segregation of the concrete core of CCFST members. The evaluation index NWPEV consistently drops with the level increment of aggregates segregation. In contrast to aggregates segregation, the influence of the existence of ITZ and the randomness distribution of fully-graded aggregates without segregation is not obvious. The effect of aggregates segregation on the stress wave propagation in the cross-section of CCFST members and the time–history voltage response of embedded PZT sensor is dominant.The findings imply that aggregates segregation, as a typical early age defect in the concrete core of CCFST members, can be identified efficiently by using the stress wave propagation measurement from PZT sensors. The early age aggregate segregation detection is very important and meaningful, because countermeasures can be carried out to handle the defect before the hardening of the concrete core. The feasibility of the proposed PZT-based concrete aggregate segregation detection approach for CCFST members is verified numerically in this study by taking advantage of the convenience of modeling the aggregates segregation in numerical concrete models. However, based on the findings from the numerical simulation results in this study, experimental study on the feasibility of the proposed aggregates segregation detection technique for CCFST members can be carried out in the follow-up studies, where the preparation of the concrete core in CCFST members with desired aggregates segregation scenarios will be a challenging task. In order to model the real distribution of aggregates in concrete, scanning electron microscopy (SEM) photographs technology is helpful.


Atypical manifestations, such as elevated serum immunoglobulin-G4 (IgG4) and extra-pulmonary IgG4 positive plasmacyte infiltration, have been described in patients with eosinophilic granulomatosis with polyangiitis (EGPA), such complicated situation might not be readily differentiated from IgG4-related disease.Here, we report an interesting and rare case of EGPA in a 41 year-old male with negative anti-neutrophil cytoplasmic antibodies (ANCAs), which showed abundant pulmonary IgG4-positive plasma cells infiltration and markedly elevated serum IgG4 levels without extra-pulmonary lesions of IgG4-related disease. The clinical characteristics hesitated us whether the diagnosis as EGPA overlapping with IgG4-related lung disease should be concluded because of the absence of storiform fibrosis and obliterative phlebitis with lymphoplasmacytic infiltration. The patient’s systemic symptoms, pulmonary lesions, blood eosinophils count / percentage, and serum IgG4 levels were significantly improved with immunosuppressive therapy.We consider that the overlapping pathogenesis exists in the disease course of EGPA and IgG4-related disease, which may lead to interaction during the course of the diseases. And the utilization of diagnostic criteria for IgG4-related lung disease with the careful differentiation is needed in such cases. Eosinophilic granulomatosis with polyangiitis(EGPA), previously called Churg-Straus syndrome, is a rare systematic disorder histopathologically characterized with eosinophilic infiltration, extravascular granulomas and necrotizing vasculitis predominantly affecting small to medium-sized vessels . Recent A 41-year-old Chinese male was admitted to our hospital because of a 3-year history of recurrent productive cough and new onset of recurrent hemoptysis and fever for 6 months. Three years ago, the patient had been admitted to the local hospital because of cough and expectoration, and the chest computed tomography (CT) scan revealed bilateral lower lung infection. Not much improvement of respiratory symptoms had been observed, although treatments of anti-infection and anti-tuberculosis had been administrated in turn. Besides, the patient suffered a new onset of intermittent symmetric pain of limb joints, swelling of the upper eyelid, and erythematous maculopapular rash on the dorsal surfaces of the metacarpophalangeal joint, bilateral elbow joint, and proximal interphalangeal joint. Both lower limbs developed a livedo reticularis appearance after standing for approximate 5 min. Six months before admission, the patient experienced hemoptysis and developed a fever with maximum temperature of 38.5 °C. The frequency of redness and swelling of upper eyelids increased with and left and right eyelids alternated once a week. The new soybean-sized subcutaneous nodules with tenderness were found on the bilateral finger pulp. High potency anti-infection, anti-tuberculosis and anti-fungus treatment were given but demonstrated ineffectiveness with accelerated cough and expectoration. The patient had a 3-year history of sinusitis and family history of asthma. And he had no previous history of smoking and drinking.9/L), and markedly increased eosinophil count and percentage , erythrocyte sedimentation rate (99 mm/h) and C-reactive protein (167 mg/L). Further laboratory studies showed increased levels of serum IgG (30.8 g/L) and highly elevated levels of serum IgG4 (24.5 g/L). Tests for IgE levels, complement system, Anti-nuclear antibody, anti-extractable nuclear antigen antibody, dermatomyositis-associated antibodies, myeloperoxidase-ANCA, proteinase-3-ANCA, anti-cardiolipin antibody, anti-cyclic citrullinated peptide antibody and rheumatoid factor were all normal. The ultrasounds of parotid gland, submandibular gland, thyroid, heart were all normal. Pulmonary function tests showed severe mixed pulmonary ventilation dysfunction, moderate pulmonary diffusion function,negative bronchodilation test. And the diurnal variation of peak expiratory flow (PEF) was more than 10% and the value of fractional exhaled nitric oxide was also high (26 ppb). A chest CT scan revealed diffuse ground-glass opacities in both lungs and patches with increased density and blurred edges  medication to relieve shortness of breath before admission and during hospitalization. Furthermore, the percentage of blood eosinophil was 11.7%, which was more than 10%. The patient also had a 3-year history of sinusitis, which was also confirmed by CT scan of sinuses. The chest CT scan showed non-fixed pulmonary infiltration, with multiple patches in both lungs and ground-glass opacities. Moreover, the skin biopsy showed enriched eosinophil infiltration in the vessels and interstitial spaces of the dermis. Therefore, the patient was diagnosed as EGPA with following diagnostic basis: asthma, peripheral blood eosinophilia (>10%), paranasal sinusitis, transient pulmonary infiltration and eosinophil infiltration of the skin.There are no commonly accepted diagnostic criteria for EGPA. And the classification criteria for EGPA defined by American College of Rheumatology (ACR) was widely used by clinician . It is c9/L, 0.40%), and serum IgG4 level (16.6 g/L). After discharge, treatment of oral methylprednisolone with 35 mg/d and intravenous cyclophosphamide (0.4 g per 2 week) were both administrated. One month later, cough, expectoration, maculopapular rash, subcutaneous nodules, reticulated blemishes were all completely disappeared. Gastrocnemius tenderness was also reduced. The follow-up laboratory tests showed further decreased eosinophils count and percentage  and serum IgG4 level (7.41 g/L). The follow-up thoracic CT scan showed that bilateral lung lesions were also significantly improved was started and followed by oral methylprednisolone (40 mg/d). Seven days later, respiratory symptoms, like cough and expectoration, were improved. Hemoptysis, fever, redness and swelling of eyelid and polyarthralgia were all completely disappeared. The follow-up laboratory tests showed reduced eosinophils count and percentage clinical manifestation with typical diffuse/localized swelling or masses in single/multiple organs; (2)elevated serum IgG4 concentrations(>1.35 g/L); (3) characteristic histopathological examination showing significant lymphocytes and plasmacytes infiltrate, fibrosis and enriched infiltration of IgG4+ plasmacytes with ratio of IgG4+ to IgG+ cells >40% and >10 IgG4+ plasma cells per high-power field . DefinitIn recent years, elevation of serum IgG4 level and/or IgG4+ plasma cells infiltrate were found in multiple lung diseases, such as pulmonary malignancy, granulomatosis with polyangiitis, EGPA, interstitial pneumonias, multicentric castleman’s disease . A high Up-regulated responses of T helper (Th) 2 cell and T regulatory (Treg) cells and their cytokines (interleukin (IL)-4, IL-5, IL-13, IL-10 and transforming growth factor beta 1) play a key role in the pathogenesis of IgG4-RD.  EGPA is In summary, giving a diagnosis of IgG4-RD may be challenging in such cases and requires a comprehensive consideration with clinical symptoms, laboratory examinations and histopathologic studies. We gave the patient the diagnosis of EPGA complicated with probable IgG4-RD eventually. Fortunately, recommended first-line therapy for EPGA and IgG4-RD are both immunosuppressive therapy with glucocorticoids , 20. In In conclusion, it is the first report showing markedly elevated serum IgG4 levels and abundant infiltration of IgG4 positive plasma cells in the lung tissue simultaneously in patient with EGPA, which strongly suggest us that EGPA and IgG4-RD may share an overlapped pathogenesis in local and systemic IgG4 response. We consider that EGPA and IgG4-RD may intersect in the course of disease and, in some extent, the development of one disease can influence the onset of another disease. Further studies should be required to investigate the potential mechanism.


Clinical features of all the participants were collected and analyzed statistically. Eighty-seven patients (20%) with eosinophilia were found. As compared to those with a normal range of blood eosinophil count, male predominance, longer disease duration, increased prevalence of dacryoadenitis, sialadenitis, lymphadenopathy, and skin rash, higher IgG4-RD responder index, more organ involvement and higher levels of serum IgG4  was found in patients with eosinophilia. There was no significant difference in the incidence of allergic disease between the two groups. Peripheral eosinophil counts were positively correlated with disease duration, the number of involved organs, IgG4-RD responder index, and serum IgG4. Higher recurrence rate during follow-up period was found in patients with eosinophilia . IgG4-RD patients with eosinophilia exhibited different clinical patterns from patients without. Eosinophilia appeared independent of allergies in IgG4-RD.It has been reported that patients with IgG4-related disease (IgG4-RD) showed an elevated incidence of eosinophilia. We aim to explore the clinical patterns of IgG4-RD patients with and without eosinophilia. Four hundred and twenty-five IgG4-RD patients referred to Peking Union Medical College Hospital were enrolled. Blood eosinophil count higher than 0.5 × 10 In response to a variety of stimuli, mature peripheral blood eosinophils are recruited into the tissue, where they modulate immune responses through multiple mechanisms. Eosinophils secrete a series of cytokines capable of promoting T cell expansion, and T helper type 1 (Th1)/2 (Th2) polarization2. Eosinophilia is defined as an elevation of eosinophils in the bloodstream. Many diseases are associated with eosinophilia, including parasitic diseases, allergy, autoimmune diseases, malignancy, primary hypereosinophilic syndrome3.Eosinophils are terminally differentiated cells of the myeloid lineage implicated in the pathogenesis of numerous inflammatory processes4. The pathogenesis of IgG4-RD remains poorly understood.Immunoglobulin G4-related disease (IgG4-RD) is an increasingly recognized chronic fibroinflammatory disorder with multiple organ involvement, including salivary glands, lacrimal glands, pancreas, retroperitoneum, kidneys, lymph nodes, lungs, and liver among others. IgG4-RD is pathologically characterized by IgG4-positive lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis11. This eosinophilia appeared inherent to the IgG4-RD rather than atopic disease11. Some patients with high eosinophils as the first manifestation were finally confirmed to be IgG4-RD14. Eosinophils also infiltrate in the involved tissues, which is generally mild to moderate but can be remarkable in some cases15. Eosinophilic angiocentric fibrosis was recently described as a form of IgG4-related systemic disease16. In 2010, Sah et al. reported a similar clinical profile in type 1 autoimmune pancreatitis patients with and without peripheral eosinophilia11. In 2014, Della-Torre et al. reported that there was a positive correlation between eosinophil count and serum IgG410. In 2017, Culver et al. revealed that eosinophil count was positively correlated with both serum IgE and serum IgG4. However, there was no statistical difference in serum IgG4 levels between IgG4-RD patients with and without eosinophilia7.Recently, eosinophilia had been reported to be associated with IgG4-RD to varying degrees (11–38%)In this study, we investigated the prevalence of eosinophilia in IgG4-RD patients in the largest prospective IgG4-RD cohort in China, and report here for the first time that patients with eosinophilia presented with significantly different clinical patterns in comparison to those with normal peripheral eosinophil count.9 per L), 134 patients (32%) showed peripheral blood eosinophil ratio more than 5%. The eosinophil count higher than 1500 cells per μL were recorded in 13 (3%) patients.Among 425 patients in this cohort, the median blood eosinophil count was 210 cells per μL  and with longer disease duration  , submandibular sialadenitis , lymphadenopathy  and skin rash   Fig. , as wellCorrelation analysis revealed that peripheral eosinophil counts were positively correlated with disease duration, numbers of organs involved, and IgG4-RD RI Table . BesidesIn the overall 425 patients, 46 patients (10.8%) were untreated and under observation, 110 patients (25.9%) received glucocorticoids monotherapy (GC mono), 60 patients (14.1%) received immunosuppressants monotherapy (IM mono), 208 patients (48.9%) received combination therapy with GC and IM, 1 patient (0.2%) chose traditional Chinese medicine treatment. Treatment options displayed no significant difference between the two groups.P = 0.096]  and 89.7% (52/58), respectively (P = 0.526).Remission rates were evaluated six months after initiating remission induction treatment with GC or GC combined IM. It seemed that patients with eosinophilia tend to have a lower remission rate, but the difference was not statistically significant  Fig. . IgG4-RDP = 0.034]  displayed a trend of higher recurrence rate than patients with blood eosinophil count range from 500 to 1500 cells per μL, but the difference was not significant . A lower proportion of patients with eosinophilia had a blood IgG4 level reaching the normal range at the 3rd, 6th, 12th-month follow-up , and patients with eosinophilia showed a higher relapse rate than patients without eosinophilia  Fig. . The meaP < 0.001). Comparing patients with different treatment choices, we found that glucocorticoid-based therapy seemed to be more conducive to peripheral blood eosinophil counts declination  in 92.6% 50/54), 80.9% (38/47) and 83% (35/42) at the 3rd, 6th, 12th-month follow-up, respectively. While three patients without eosinophilia at baseline assessment developed eosinophilia during follow-up, and these patients showed no signs of disease relapse Fig. . The tre, 80.9%  is a fibroinflammatory disease with systemic involvement. The pathogenesis of IgG4-RD remains mostly unknown. Many studies have described blood and tissue eosinophilia in patients with IgG4-RDet al.17, patients were divided into four groups, Group 4 was male-dominated, characterized by classic Mikulicz syndrome with systemic involvement, showing the highest serum IgG4 levels, but they did not give the comparison of blood eosinophil counts among groups. We previously revealed that systemic IgG4-RD patients with dacryoadenitis and sialadenitis (IgG4-DS) and internal organs involvement had higher serum IgG4 levels and a higher rate of eosinophilia than patients with only IgG4-DS18. Patients with only IgG4-DS are more likely to ignore the disease, thus delay the diagnosis and treatment until systemic symptoms occurred, this could be speculated by longer disease duration at diagnosis in patients with eosinophilia. When we independently analyzed the organ involvement number apart from lacrimal glands, salivary glands, and lymph nodes, there was no significant difference between the two groups.In this study, based on the largest cohort of IgG4-RD patients in China, we report that 20% of patients had eosinophilia. Patients with and without eosinophilia showed different clinical patterns in terms of organ involvement and laboratory findings. Patients with eosinophilia seemed to have a higher disease burden as indicated by elevated serum IgG, IgG4, ESR, and more organs involved, and higher IgG4-RD RI score. As in an IgG4-RD grouping analysis which reported by Wallace 19. However, there was no statistically significant difference in the incidence of allergic disease between patients with and without eosinophilia, indicating that eosinophilia is independent of allergies in IgG4-RD patients, which was consistent with the results reported by Della-Torre et al.10 and Sah et al.11. Wallace et al.20 have found that elevated eosinophil count in the baseline was an independent predictor of disease relapse; also, our previous study showed eosinophilia was a risk factor for remission induction failure21. Here, we confirmed that IgG4-RD patients with peripheral eosinophilia were more liable to disease relapse.Allergic disorders are common causes of reactive eosinophilia26, and this may be responsible for eosinophilia in IgG4-RD19. Otherwise, activated eosinophils release cytokines2, which can promote the production of IgG427. Although it remains unclear that IgG4 plays a pathogenic or protective role in IgG4-RD28, these indicate that eosinophils participate in the pathogenesis of IgG4-RD.We found here that peripheral eosinophil counts in IgG4-RD patients were positively correlated with serum IgG4 and disease burden. In addition, serum IgG4 level at 12 months was also positively correlated with the blood eosinophil count at 12 months. IgG4-RD exhibited activated Th2 responsee higher eosinophil count30.Both CRP and ESR are used to predict inflammatory conditions. ESR level can be affected by factors other than inflammation, such as levels of serum fibrinogen and immunoglobulins. We believe that the difference of ESR levels between the two groups was mainly due to the different distribution of serum IgG and IgG4, as patients with eosinophilia had higher serum IgG, IgG4, while with a similar level of CRP compared to patients with normal eosinophil counts. Patients with eosinophilia showed male predominance, as reported that peripheral blood eosinophil count is skewed according to gender, males usually hav2, and the latter was reported to participate in the pathogenesis of fibrosis. Fibrosis occurred in the affected organs of advanced IgG4-RD patients. We found that peripheral eosinophil counts in IgG4-RD patients were positively correlated to treatment-free disease duration; patients with eosinophilia showed longer disease duration. These indicate that eosinophilia may occur in the advanced stage of IgG4-RD, and may participate in the fibrosis of affected tissues.Activation of eosinophils led to the production of transforming growth factor (TGF)-βTo date, several treatment approaches, including glucocorticoids, myelosuppressive drugs, leukotriene antagonists, tyrosine kinase inhibitors, IFN-α, and anti-IL-5 antibodies, have been described for eosinophilia. Although the role of eosinophilia in the pathogenesis of IgG4-RD is debatable, we found that IgG4-RD patients with peripheral eosinophilia tend to be more liable to disease relapse, this raises the possibility of anti-eosinophil therapy such as monoclonal antibody to IL-5 for IgG4-RD patients with recurrent disease.et al.31, the diagnosis of idiopathic HES need to rule out IgG4-RD, the differential diagnosis between IgG4-RD and myeloid or lymphocytic variant HES need careful consideration of clinical and laboratory manifestation.Our study has some limitations. This is a single-center study, which may cause bias in interpreting results. Only two patients with eosinophilia had done bone marrow biopsy at baseline and showed elevated bone marrow eosinophils. No further tests for the myeloid or lymphocytic variant hypereosinophilic syndrome (HES) had performed. As proposed by Chen In conclusion, peripheral eosinophilia was associated with a different clinical pattern of IgG4-RD. Eosinophil may play an important role in the development of IgG4-RD, especially in patients with longer disease duration and probably pronounced fibrotic lesion. Our findings paved the way for identifying the role of eosinophils in the pathogenesis of IgG4-RD.32. Fifty-one patients who had a history of other rheumatic diseases, infectious diseases, or malignancies, which may cause eosinophilia, were excluded. As of August 2018, 425 newly diagnosed IgG4-RD patients were enrolled in this study.A multidisciplinary collaborative prospective cohort study of IgG4-RD and Mimicry patients has been conducted in Peking Union Medical College Hospital  since January 2011, registered on ClinicalTrials.gov (ID: NCT01670695). Patients were diagnosed with IgG4-RD according to the 2011 comprehensive diagnostic criteria for IgG4-RD9 per L). We divided the patients into two groups according to whether there was eosinophilia. According to the Allergy Definition of the European Society for Allergy and Clinical Immunology33: (1) a history of clinical allergic diseases; (2) a positive skin test or an increase in serum allergen-specific IgE, while satisfying the definition of both as an allergy. Patients with newly diagnosed IgG4-RD were classified as allergic and non-allergic. All patients visited the doctors regularly at 1st and every 3 to 6 months intervals follow up.Eosinophilia in the peripheral blood was defined as eosinophil count greater than 500 per μL , liver and renal function tests, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum immunoglobulin levels, IgG subclasses, and total IgE levels were collected. Organ involvements were defined by physical examination and imaging findings, including computed tomography (CT), or magnetic resonance imaging (MRI), or Positron Emission Tomography/Computed Tomography (PET-CT). Disease activity was assessed by the IgG4-RD responder index (RI)21. Briefly, the initial 6th -months of treatment was defined as the remission induction stage, and remission was defined as fulfilling each of the following after 6-month treatment: (1) ≥50% decline in the IgG4-RD RI; (2) GC tapered to maintenance dose (prednisone ≤10 mg/day); and (3) no relapse during GC tapering (within 6 months). Clinical symptoms recurred, or imaging findings worsened with or without IgG4 level increased were considered as disease relapse in patients who had a follow-up period of 3 months or longer.Disease remission and relapse were described as beforet-test or the appropriate non-parametrical test, depending on normal or non-normal data distribution. Categorical variables were expressed as percentages, and χ2-test was used for comparisons. Fisher’s exact test was used when one or more expected frequencies were less than 5. Correlation between two continuous non-normal variables was analyzed using Spearman’s rank correlation. Univariate logistic regression was used to predict risk factors for eosinophilia at 12 months follow-up. Statistical analysis was performed by SPSS version 24.0 and Graphpad Prism version 7.0. A P-value < 0.05 was considered statistically significant.Continuous variables are described in mean and standard deviation (SD) or median and interquartile range (IQR) according to the data distribution. Comparisons between the two groups were performed using Student’s This study complied with the Declaration of Helsinki and was approved by the Human and Animal Ethics Review Committees of PUMCH, China . Informed consent was obtained from all individual participants included in the study.


Sepsis in neonates and infants remains a major cause of death despite a decline in child mortality and morbidity over the last decades. A key factor in further reducing poor clinical outcomes is the optimal use of antibiotics in sepsis management. Developmental changes such as maturation of organ function and capacity of drug metabolizing enzymes can affect the pharmacokinetic profile and therefore the antibiotic exposure and response in neonates and infants. Optimal antibiotic treatment of sepsis in neonates and young infants is dependent on several key components such as the determination of treatment phase, the administered dose and the resulted drug exposure and microbiological response. During the initial phase of suspected sepsis, the primary focus of empirical treatment is to assure efficacy. Once bacterial infection as the cause of sepsis is confirmed the focus shifts toward a targeted treatment, ensuring an optimal balance between efficacy and safety. Interpretation of antibiotic exposure and microbiological response in neonates and infants is multifaceted. The response or treatment effect can be determined by the microbiological parameters (MIC) together with the characteristics of the pathogen (time- or concentration dependent). The antibiotic response is influenced by the properties of the causative pathogen and the unique characteristics of the vulnerable patient population such as reduced humoral response or reduced skin barrier function. Therapeutic drug monitoring (TDM) of antibiotics may be used to increase effectiveness while maximizing safety and minimizing the toxicity, but requires expertise in different fields and requires collaborations between physicians, lab technicians, and quantitative clinical pharmacologists. Understanding these clinical, pharmacological, and microbiological components and their underlying relationship can provide a scientific basic for proper antibiotic use and reduction of antibiotic resistance in neonates and infants. This highlights the necessity of a close multidisciplinary collaboration between physicians, pharmacists, clinical pharmacologists and microbiologist to assure the optimal utilization of antibiotics in neonates and young infants. Despite a decline in child mortality during the last decades, close to 6 million children died before the age of 5 years in 2015 with almost half of these patients dying during the neonatal period . In 2015The diagnosis of sepsis in neonates and infants is complex, and a complete discussion on clinical decision-making about initiations of antibiotics is beyond the scope of this review . Early aStreptococcus and Escherichia coli account for most episodes of EONS, whereas Klebsiella is the most common organism in low and middle income countries , which reflects the timing of onset of symptoms, type and virulence of organism and associated pathogenesis . First, ountries , 14. Risnization , 15, 16.nization . Second,settings . Currentountries .In the first 2 years of life, maturational processes affect drug clearance and make antibiotic dosing more challenging, compared to older infants where dosing is mainly adjusted by body weight and renal function. Most of the current dosing guidelines for antibiotic treatment are simply extrapolated from adult studies and it has been reported that dosing recommendations across intensive care units and international guidelines are highly variable and inconsistent . We reviIn a clinical setting, there is generally no time to wait for the result from microbiologic samples when there is suspected sepsis. Antibiotic treatment can therefore be viewed as having two phases, namely an initial, empirical treatment phase followed by a targeted treatment phase once a causative pathogen is confirmed Figure . Both phIn the 1 hours to days of treatment, the primary focus is to deliver effective treatment. During this earliest stage mortality is directly related to the effects of the life-threatening infection and managing toxicity is less central. As the causative organism generally remains unknown, selection of the antibiotic regimen needs to take into account the overall epidemiology of sepsis in the age group of the patient .in vitro tests and are applied to an entire population. Initial antibiotic doses should be targeting the “worst-case” minimal inhibitory concentrations, captured by the phrase “go hard and go home”  and pharmacodynamic, microbiological characteristics (PD). In order to understand optimal and individualized dosing of antibiotic treatment, one should be aware of the drug related processes in the human body and their influences on each other Figure .A drug can have several formulations and can be administered through various routes, intravenous and oral being the most frequently used Figure . HoweverThe relationship between dose and drug exposure is governed by pharmacokinetics, defined by the kinetic processes abbreviated as ADME, which defines the absorption, distribution, metabolism, and excretion of a drug Figure . Due to Pharmacodynamic (PD) and microbiological aspects focus on the effects of a given drug on the pathogen and body Figure . In ordeUnderstanding the PK of antibiotics is necessary but not sufficient for optimizing and individualizing dosing strategies. It is essential to also understand characteristics and dynamics of the target (pathogen) as well . The groAn increase in MICs, which is the result of decreasing susceptibility of a pathogen in a population, must in many cases be accompanied by dose adjustments to ensure effective exposure and maximize the effect. Recent changes to the interpretation of the so-called intermediate breakpoint as representing susceptibility for which successful treatment outcomes are likely with adjustments of the dosing regimen reflect this .With a limited pipeline of new antibiotics, relying on proper use and understanding the link between antibiotic exposure (PK) and microbiological response  is a key issue concerning dosing optimization of the presently available antibiotics .et al. noticed the time dependent properties of penicillin, and realized that penicillins are best administered as continuous infusions, whereas a concentration dependent agent is better given as an intravenous bolus to achieve high maximum concentrations  and a microbiological parameter (e.g. MIC) . Antibiotrations , 41.Cmax/MIC). Depending on the antibiotic class, different ratios apply , the dose should be increased from 5 to 7.5 mg/kg in neonates   Beta-lacin vitro setting, where the conditions are dissimilar from those at the site of infection in the in vivo situation. Better understanding of population-specific MICs is demanded to guide empiric antibiotic treatment . Since there are several population PK models published for antimicrobial agents, researchers should assess new data or use existing data to extend and improve existing population PK models . In. In57). K models , 58. PhaK models .In contrast to the MIC, which reflects the susceptibility of a pathogen at only one time point, bacterial kill-curves can offer more detailed information about the killing activity as a function over time and might even be used to identify the presence of resistant subpopulations , 61. BacFurthermore, in recent decades novel non-invasive techniques have provided information about the process of target site distribution. Microdialysis provides direct measurement of concentrations of unbound antibiotics at the site of action when the site of infection is not the bloodstream , 62. MeaThere are still numerous challenges to overcome the burden of sepsis in neonates and infants, of which the lack of implementation of optimized, individualized dosing recommendations can be considered as remarkably important. Key components for optimal antibiotic treatment of sepsis in neonates and infants are indicated as treatment phase, dose, drug exposure and microbiological response. During the first days of treatment the focus lies on establishing an effective dose, thereafter the balance is shifting toward ensuring a safe and effective treatment. In neonates and young infants, drug exposure is affected by developmental changes such as maturation of organ function and metabolizing enzymes, which requires dosing adjustments. The response or treatment effect can be determined by the microbiological parameters (MIC) together with the pathogen characteristics (time- or concentration dependent). Understanding these clinical, pharmacological and microbiological components and their underlying relationship might provide a basis for proper antibiotic use and reduction of antibiotic resistance. This also illustrates the necessity of a close multidisciplinary collaboration between physicians, pharmacists, pharmacometricians, clinical pharmacologists and microbiologists to assure optimal utilization of antibiotics in neonates and infants.TvD, JB, and MP drafted the concept of the review. TvD wrote the first draft of the manuscript and generated tables and figures. JB contributed to the sections considering infectious diseases. JvdA and MP contributed to the clinical pharmacology section. All authors critically revised the manuscript, and approved the final version before submission.MP has a part-time employment with the consulting company Certara, USA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.