Spread of community-acquired meticillin-resistant Staphylococcus aureus skin and soft-tissue infection within a family: implications for antibiotic therapy and prevention.

Outbreaks or clusters of community-acquired meticillin-resistant Staphylococcus aureus (CA-MRSA) within families have been reported. We describe a family cluster of CA-MRSA skin and soft-tissue infection where CA-MRSA was suspected because of recurrent infections which failed to respond to flucloxacillin. While the prevalence of CA-MRSA is low worldwide, CA-MRSA should be considered in certain circumstances depending on clinical presentation and risk assessment. Surveillance cultures of family contacts of patients with MRSA should be considered to help establish the prevalence of CA-MRSA and to inform the optimal choice of empiric antibiotic treatment

Ultraviolet disinfection robots to improve hospital cleaning: Real promise or just a gimmick?

The global COVID-19 pandemic due to the novel coronavirus SARS-CoV-2 has challenged the availability of traditional surface disinfectants. It has also stimulated the production of ultraviolet-disinfection robots by companies and institutions. These robots are increasingly advocated as a simple solution for the immediate disinfection of rooms and spaces of all surfaces in one process and as such they seem attractive to hospital management, also because of automation and apparent cost savings by reducing cleaning staff. Yet, there true potential in the hospital setting needs to be carefully evaluated. Presently, disinfection robots do not replace routine (manual) cleaning but may complement it. Further design adjustments of hospitals and devices are needed to overcome the issue of shadowing and free the movement of robots in the hospital environment. They might in the future provide validated, reproducible and documented disinfection processes. Further technical developments and clinical trials in a variety of hospitals are warranted to overcome the current limitations and to find ways to integrate this novel technology in to the hospitals of to-day and the future

Memory Th1 Cells Are Protective in Invasive Staphylococcus aureus Infection

Mechanisms of protective immunity to Staphylococcus aureus infection in humans remain elusive. While the importance of cellular immunity has been shown in mice, T cell responses in humans have not been characterised. Using a murine model of recurrent S. aureus peritonitis, we demonstrated that prior exposure to S. aureus enhanced IFNγ responses upon subsequent infection, while adoptive transfer of S. aureus antigen-specific Th1 cells was protective in naïve mice. Translating these findings, we found that S. aureus antigen-specific Th1 cells were also significantly expanded during human S. aureus bloodstream infection (BSI). These Th1 cells were CD45RO+, indicative of a memory phenotype. Thus, exposure to S. aureus induces memory Th1 cells in mice and humans, identifying Th1 cells as potential S. aureus vaccine targets. Consequently, we developed a model vaccine comprising staphylococcal clumping factor A, which we demonstrate to be an effective human T cell antigen, combined with the Th1-driving adjuvant CpG. This novel Th1-inducing vaccine conferred significant protection during S. aureus infection in mice. This study notably advances our understanding of S. aureus cellular immunity, and demonstrates for the first time that a correlate of S. aureus protective immunity identified in mice may be relevant in humans

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Hospital Resource Utilisation by Patients with Community-Acquired Pneumonia.

Little data is available on the resource utilisation of patients admitted with Community-Acquired Pneumonia (CAP) in Ireland. A retrospective review of 50 randomly-selected patients admitted to Beaumont Hospital with CAP was undertaken. The mean length of stay of patients with CAP was 12 days (+/- 16 days). All patients were emergency admissions, all had a chest x-ray, a C-reactive protein blood test, and occupied a public bed at some point during admission. Common antimicrobial therapies were intravenous (IV) amoxicillin/clavulanic acid and oral clarithromycin; 60% received physiotherapy. The estimated mean cost of CAP per patient was €14,802.17. Costs arising from admission to hospital with CAP are substantial, but efforts can be undertaken to ensure that resources are used efficiently to improve patient care such as discharge planning and fewer in-hospital ward transfers

Patient demographics.

<p>^a Healthcare-associated infections were defined as (i) index positive blood culture collected ≥48hrs after hospital admission, and no signs or symptoms of the infection noted at time of admission; OR (ii) index positive blood culture collected <48hrs after hospital admission if any of the following criteria are met: received intravenous therapy in an ambulatory setting in the 30 days before onset of BSI, attended a hospital clinic or haemodialysis in the 30 days before onset of BSI, hospitalised in an acute care hospital for ≥ 2 days in the 90 days prior to onset of BSI, resident of nursing home or long-term care facility.</p><p>^b<i>Staphylococcus aureus</i> bacteraemia was defined as uncomplicated if all of the following criteria were met: exclusion of endocarditis; no evidence of metastatic infection; absence of implanted prostheses; follow-up blood cultures at 2–4 days culture-negative for <i>S</i>. <i>aureus</i>; defervescence within 72 h of initiating effective therapy. Percentages shown are of entire <i>S</i>. <i>aureus</i> BSI population.</p><p>^† Three patients had chronic diabetic foot ulcers as a source of their <i>S</i>. <i>aureus</i> BSI, and in all cases the contiguous underlying bone was also found to be infected.</p><p>MRSA = methicillin-resistant <i>Staphylococcus aureus</i>. NA = not applicable. BSI = bloodstream infection.</p><p>Data are displayed as median (interquartile range) and number (percentage). <i>P</i> values are calculated by Mann-Whitney and Fisher’s exact test respectively.</p

Vaccine-induced type 1 immunity protects against <i>S</i>. <i>aureus</i> infection.

<p>Mice were vaccinated with CpG (50μg/mouse), ClfA (1μg/mouse), or CpG+ClfA via s.c. injection on d 0, 14 and 28. On d 63 mice were challenged with <i>S</i>. <i>aureus</i> (5x10⁸ CFU) via i.p. injection alongside a control group of sham-immunised (with PBS) mice. At 72 h post-infection, bacterial burden was assessed in the peritoneal cavity, kidneys and spleen. Results expressed as log₁₀ CFU/ml with means indicated by bars. n = 5–10 per group. **p<0.005, ***p<0.001.</p