Achieving self-sufficiency in skin allograft: A Singapore experience.

AIM: This paper describes how Singapore achieved skin allograft self-sufficiency in 2017 by adopting 5 key strategies in 2012. BACKGROUND: Singapore General Hospital (SGH) established its own allograft recovery programme in 1998 but was still dependent on overseas allograft procurement. KEY STRATEGIES: RESULTS: The allograft recovery programme expanded from 4 to all 20 institutions. Donor referrals increased by 42.9% from 35 in 2014 to over 50 currently. Donor numbers increased by 210%, rising from 4.5 per year before 2015 to an average of 14 per year from 2015 to 2022. The total allografts recovered increased by 223%, climbing from 13,000 to 42,000 annually. Cryopreservation was adopted, extending shelf life to 5.5 years and doubling storage capacity to more than 140,000 cm2 in 2022. CONCLUSION: Singapore achieved skin allograft self-sufficiency with no overseas procurement since 2017.

A Qualitative Study on the Implementation of the National Action Plan on Antimicrobial Resistance in Singapore.

Antimicrobial resistance (AMR) is a global public health threat that affects humans, animals, and the environment across the One Health spectrum. Singapore launched its own National Strategic Action Plan (NSAP) on AMR in 2017 with the aim of tackling the growing threat of AMR in Singapore through coordinated approaches. However, little is known about the implementation of the NSAP. In this study, we analysed the implementation of the NSAP with guidance from an AMR governance framework. We conducted in-depth interviews with 20 participants across the One Health spectrum. The interviews were transcribed verbatim and analysed thematically. Overall, the implementation of activities against AMR was more advanced with respect to human health compared to other sectors such as (1) AMR and antimicrobial use (AMU) surveillance systems in hospitals; (2) the hospital antimicrobial stewardship (AMS) service and legislation to optimise AMU; (3) the national children and adults vaccination programme for IPC; (4) multiple avenues for education and awareness for both professionals and public; and (5) extensive research and collaboration networks with many sources of funding. Areas that were lacking presented problems including (1) an incomplete surveillance system for AMR and AMU across all sectors; (2) the need for better AMS and legislation in some sectors; (3) insufficient innovation in education for sustained behavioural modification; and (4) the need for more open research collaborations and the translation of research into policy outcomes. Improvements in these areas will enhance the overall implementation of the NSAP through a more holistic One Health approach.

A Qualitative Study on the Policy Process and Development of the National Action Plan on Antimicrobial Resistance in Singapore.

The global public health threat of antimicrobial resistance (AMR) has been accelerated by many interrelated factors spanning across One Health-human health, animal health, and the environment. Singapore launched its own National Strategic Action Plan (NSAP) on AMR in November 2017 with the aim of tackling the growing threat of AMR in Singapore through coordinated approaches. However, little is known about the policy process and development of the NSAP in Singapore. In this study, we analysed these aspects using an AMR governance framework. In-depth interviews were conducted with 20 participants across the One Health spectrum. The interviews were transcribed verbatim and analysed thematically. Areas that were well executed included (1) good coordination across various agencies, (2) a dedicated office to coordinate the work on the NSAP, and (3) a high level of governmental support. Areas that were lacking included (1) a lack of participation from certain sectors, (2) insufficient awareness around the AMR issue, (3) constraints in information sharing, and (4) a lack of ideal indicators to track the progress in addressing AMR. Improvements in these areas will provide a more holistic One Health engagement in support of the effective planning and implementation of the NSAP.

Human Umbilical Cord Lining-Derived Epithelial Cells: A Potential Source of Non-Native Epithelial Cells That Accelerate Healing in a Porcine Cutaneous Wound Model.

Human umbilical cord lining epithelial cells [CLECs) are naïve in nature and can be ethically recovered from cords that are routinely discarded. The success of using oral mucosal epithelial cells for cornea defects hints at the feasibility of treating cutaneous wounds using non-native CLECs. Herein, we characterized CLECs using flow cytometry (FC) and skin organotypic cultures in direct comparison with skin keratinocytes (KCs). This was followed by wound healing study to compare the effects of CLEC application and the traditional use of human skin allografts (HSGs) in a porcine wound model. While CLECs were found to express all the epidermal cell markers probed, the major difference between CLECs and KCs lies in the level of expression (in FC analysis) as well as in the location of expression (of the epithelium in organotypic cultures) of some of the basal cell markers probed. On the pig wounds, CLEC application promoted accelerated healing with no adverse reaction compared to HSG use. Though CLECs, like HSGs, elicited high levels of local and systemic immune responses in the animals during the first week, these effects were tapered off more quickly in the CLEC-treated group. Overall, the in vivo porcine data point to the potential of CLECs as a non-native and safe source of cells to treat cutaneous wounds.

A Qualitative Study on the Design and Implementation of the National Action Plan on Antimicrobial Resistance in the Philippines.

Antimicrobial resistance (AMR) is a global public health threat that warrants urgent attention. Countries developed their national action plans (NAPs) following the launch of the Global Action Plan on AMR in 2015. The development and implementation of NAPs are often complicated due to the multifaceted nature of AMR, and studies analyzing these aspects are lacking. We analyzed the development and implementation of the Philippine NAP on AMR with guidance from an AMR governance framework. We conducted in-depth interviews with 37 participants across the One Health spectrum. The interviews were transcribed verbatim and were analyzed thematically, adopting an interpretative approach. The enabling factors for NAP implementation include (1) a high level of governmental support and involvement of relevant stakeholders, (2) the development of policies to support improved responses in infection prevention and control and antimicrobial stewardship, and (3) better engagement and advocacy by professional associations and civil society groups. The challenges include (1) a lack of resources and regulatory capacity, (2) insufficient impetus for AMR research and surveillance, and (3) limited One Health engagement. Although there has been considerable progress for human health, strengthening the involvement and representation of the animal health and environment sectors in the AMR scene must be undertaken. Developing well-defined roles within policies will be paramount to the strong implementation of AMR strategies.

Adiabatic Waveforms from Extreme-Mass-Ratio Inspirals: An Analytical Approach.

Scientific analysis for the gravitational wave detector LISA will require theoretical waveforms from extreme-mass-ratio inspirals (EMRIs) that extensively cover all possible orbital and spin configurations around astrophysical Kerr black holes. However, on-the-fly calculations of these waveforms have not yet overcome the high dimensionality of the parameter space. To confront this challenge, we present a user-ready EMRI waveform model for generic (eccentric and inclined) orbits in Kerr spacetime, using an analytical self-force approach. Our model accurately covers all EMRIs with arbitrary inclination and black hole spin, up to modest eccentricity (≲0.3) and separation (≳2-10 M from the last stable orbit). In that regime, our waveforms are accurate at the leading "adiabatic" order, and they approximately capture transient self-force resonances that significantly impact the gravitational wave phase. The model fills an urgent need for extensive waveforms in ongoing data-analysis studies, and its individual components will continue to be useful in future science-adequate waveforms.

The effect of mission duration on LISA science objectives.

The science objectives of the LISA mission have been defined under the implicit assumption of a 4-years continuous data stream. Based on the performance of LISA Pathfinder, it is now expected that LISA will have a duty cycle of ≈ 0.75 , which would reduce the effective span of usable data to 3 years. This paper reports the results of a study by the LISA Science Group, which was charged with assessing the additional science return of increasing the mission lifetime. We explore various observational scenarios to assess the impact of mission duration on the main science objectives of the mission. We find that the science investigations most affected by mission duration concern the search for seed black holes at cosmic dawn, as well as the study of stellar-origin black holes and of their formation channels via multi-band and multi-messenger observations. We conclude that an extension to 6 years of mission operations is recommended.

Challenges in the management of extensive aplasia cutis congenita.

Aplasia cutis congenita (ACC) is a rare group of congenital disorders characterised by focal or widespread absence of skin, predominantly affecting the scalp. A Malay female infant was born at 37 weeks with extensive ACC, affecting 37% of total body surface area, including her scalp and trunk. There is no consensus on the management of ACC given the rarity and variable presentation. A multi-disciplinary team comprising neonatologists, paediatric dermatologists, plastic surgeons and medical laboratory scientists at the skin bank, employed a more aggressive surgical approach with the aim of avoiding potentially catastrophic morbidity, including sagittal sinus haemorrhage and brain herniation. Out of several surgical options, the team used a staged artificial dermal matrix (Integra) and cultured epithelial autograft application, followed by regular wound dressing, and eventually allowed the child to achieve complete epithelialisation of her trunk, and most of scalp before she was discharged from hospital.

Intraperitoneally Delivered Umbilical Cord Lining Mesenchymal Stromal Cells Improve Survival and Kidney Function in Murine Lupus via Myeloid Pathway Targeting.

To determine the therapeutic efficacy of human umbilical cord lining mesenchymal stromal cells (CL-MSCs) (US Patent number 9,737,568) in lupus-prone MRL/lpr (Faslpr) mice and elucidate its working mechanisms. A total of 4 doses of (20-25) × 106 cells/kg of CL-MSCs was given to 16-week-old female Faslpr mice by intraperitoneal injection. Three subsequent doses were given on 17 weeks, 18 weeks, and 22 weeks, respectively. Six-week-old Faslpr mice were used as disease pre-onset controls. Mice were monitored for 10 weeks. Mouse kidney function was evaluated by examining complement component 3 (C3) deposition, urinary albumin-to-creatinine ratio (ACR), and lupus nephritis (LN) activity and chronicity. Working mechanisms were elucidated by flow cytometry, Luminex/ELISA (detection of anti-dsDNA and isotype antibodies), and RNA sequencing. CL-MSCs improved mice survival and kidney function by reducing LN activity and chronicity and lymphocyte infiltration over 10 weeks. CL-MSCs also reduced urinary ACR, renal complement C3 deposition, anti-dsDNA, and isotype antibodies that include IgA, IgG1, IgG2a, IgG2b, and IgM. Immune and cytokine profiling demonstrated that CL-MSCs dampened inflammation by suppressing splenic neutrophils and monocytes/macrophages, reducing plasma IL-6, IL-12, and CXCL1 and stabilizing plasma interferon-γ and TNF-α. RNA sequencing further showed that CL-MSCs mediated immunomodulation via concerted action of pro-proinflammatory cytokine-induced chemokines and production of nitric oxide in macrophages. CL-MSCs may provide a novel myeloid (neutrophils and monocytes/macrophages)-targeting therapy for SLE.

Keratin-Alginate Sponges Support Healing of Partial-Thickness Burns.

Deep partial-thickness burns damage most of the dermis and can cause severe pain, scarring, and mortality if left untreated. This study serves to evaluate the effectiveness of crosslinked keratin-alginate composite sponges as dermal substitutes for deep partial-thickness burns. Crosslinked keratin-alginate sponges were tested for the ability to support human dermal fibroblasts in vitro and to support the closure and healing of partial-thickness burn wounds in Sus scrofa pigs. Keratin-alginate composite sponges supported the enhanced proliferation of human dermal fibroblasts compared to alginate-only sponges and exhibited decreased contraction in vitro when compared to keratin only sponges. As dermal substitutes in vivo, the sponges supported the expression of keratin 14, alpha-smooth muscle actin, and collagen IV within wound sites, comparable to collagen sponges. Keratin-alginate composite sponges supported the regeneration of basement membranes in the wounds more than in collagen-treated wounds and non-grafted controls, suggesting the subsequent development of pathological scar tissues may be minimized. Results from this study indicate that crosslinked keratin-alginate sponges are suitable alternative dermal substitutes for clinical applications in wound healing and skin regeneration.

Exciting Modes due to the Aberration of Gravitational Waves: Measurability for Extreme-Mass-Ratio Inspirals.

Gravitational waves from a source moving relative to us can suffer from special-relativistic effects such as aberration. The required velocities for these to be significant are on the order of 1000 km s^{-1}. This value corresponds to the velocity dispersion that one finds in clusters of galaxies. Hence, we expect a large number of gravitational-wave sources to have such effects imprinted in their signals. In particular, the signal from a moving source will have its higher modes excited, i.e., (3,3) and beyond. We derive expressions describing this effect and study its measurability for the specific case of a circular, nonspinning extreme-mass-ratio inspiral. We find that the excitation of higher modes by a peculiar velocity of 1000 km s^{-1} is detectable for such inspirals with signal-to-noise ratios of ≳20. Using a Fisher matrix analysis, we show that the velocity of the source can be measured to a precision of just a few percent for a signal-to-noise ratio of 100. If the motion of the source is ignored, parameter estimates could be biased, e.g., the estimated masses of the components through a Doppler shift. Conversely, by including this effect in waveform models, we could measure the velocity dispersion of clusters of galaxies at distances inaccessible to light.

An analysis of national action plans on antimicrobial resistance in Southeast Asia using a governance framework approach.

The complex problem of antimicrobial resistance (AMR) is spread across human health, animal health, and the environment. The Global Action Plan (GAP) on AMR and context-specific national action plans (NAPs) were developed to combat this problem. To date, there is no systematic content analysis of NAPs from countries of the Association of Southeast Asia Nations (ASEAN). As the validity periods of most NAPs are ending, an analysis now will provide an opportunity to improve subsequent iterations of these NAPs. We analysed the current NAPs of ten ASEAN countries. We explored their objective alignment with GAP and performed content analysis using an AMR governance framework. Themes were broadly classified under five governance areas: policy design, implementation tools, monitoring and evaluation, sustainability, and One Health engagement. We identified policy priorities, useful features of NAPs, and specific areas that should be strengthened, including accountability, sustained engagement, equity, behavioural economics, sustainability plans and transparency, international collaboration, as well as integration of the environmental sector. Enhancement of these areas and adoption of best practices will drive improved policy formulation and its translation into effective implementation.

Health systems resilience in managing the COVID-19 pandemic: lessons from 28 countries.

Health systems resilience is key to learning lessons from country responses to crises such as coronavirus disease 2019 (COVID-19). In this perspective, we review COVID-19 responses in 28 countries using a new health systems resilience framework. Through a combination of literature review, national government submissions and interviews with experts, we conducted a comparative analysis of national responses. We report on domains addressing governance and financing, health workforce, medical products and technologies, public health functions, health service delivery and community engagement to prevent and mitigate the spread of COVID-19. We then synthesize four salient elements that underlie highly effective national responses and offer recommendations toward strengthening health systems resilience globally.

Rapid Generation of Fully Relativistic Extreme-Mass-Ratio-Inspiral Waveform Templates for LISA Data Analysis.

The future space mission LISA will observe a wealth of gravitational-wave sources at millihertz frequencies. Of these, the extreme-mass-ratio inspirals of compact objects into massive black holes are the only sources that combine the challenges of strong-field complexity with that of long-lived signals. Such signals are found and characterized by comparing them against a large number of accurate waveform templates during data analysis, but the rapid generation of templates is hindered by computing the ∼10^{3}-10^{5} harmonic modes in a fully relativistic waveform. We use order-reduction and deep-learning techniques to derive a global fit for the ≈4000 modes in the special case of an eccentric Schwarzschild orbit, and implement the fit in a complete waveform framework with hardware acceleration. Our high-fidelity waveforms can be generated in under 1 s, and achieve a mismatch of ≲5×10^{-4} against reference waveforms that take ≳10^{4} times longer. This marks the first time that analysis-length waveforms with full harmonic content can be produced on timescales useful for direct implementation in LISA analysis algorithms.

The use of negative-pressure wound therapy over a cultured epithelial autograft for full-thickness wounds secondary to purpura fulminans in an infant.

Purpura fulminans is a serious condition that can result in severe morbidity in the pediatric population. Although autologous skin grafts remain the gold standard for the coverage of partial- to full-thickness wounds, they have several limitations in pediatric patients, including the lack of planar donor sites, the risk of hemodynamic instability, and the limited graft thickness. In Singapore, an in-house skin culture laboratory has been available since 2005 for the use of cultured epithelial autografts (CEAs), especially in burn wounds. However, due to the fragility of CEAs, negative-pressure wound therapy (NPWT) dressings have been rarely used with CEAs. With several modifications, we report a successful case of NPWT applied over a CEA in an infant who sustained 30% total body surface area full-thickness wounds over the anterior abdomen, flank, and upper thigh secondary to purpura fulminans. We also describe the advantages of using NPWT dressing over a CEA, particularly in pediatric patients.