The intensive care medicine clinical research agenda in paediatrics

BACKGROUND: Intensive Care Medicine set us the task of outlining a global clinical research agenda for paediatric intensive care (PIC). In line with the clinical focus of this journal, we have limited this to research that may directly influence patient care. METHODS: Clinician researchers from PIC research networks of varying degrees of formality from around the world were invited to answer two main questions: (1) What have been the major recent advances in paediatric critical care research? (2) What are the top 10 studies for the next 10 years? RESULTS: (1) Inclusive databases are well established in many countries. These registries allow detailed observational studies and feasibility testing of clinical trial protocols. Recent trials are larger and more valuable, and (2) most common interventions in PIC are not evidenced-based. Clinical studies for the next 10 years should address this deficit, including: ventilation techniques and interfaces; fluid, transfusion and feeding strategies; optimal targets for vital signs; multiple organ failure definitions, mechanisms and treatments; trauma, prevention and treatment; improving safety; comfort of the patient and their family; appropriate care in the face of medical complexity; defining post-PICU outcomes; and improving knowledge generation and adoption, with novel trial design and implementation strategies. The group specifically highlighted the need for research in resource-limited environments wherein mortality remains often tenfold higher than in well-resourced settings. CONCLUSIONS: Paediatric intensive care research has never been healthier, but many gaps in knowledge remain. We need to close these urgently. The impact of new knowledge will be greatest in resource-limited environments

Catalyst-free Hydrophosphinylation of Isocyanates and Isothiocyanates under Low-Added-Solvent Conditions

A catalyst-free, low-solvent method for the hydrophosphinylation of isocyanates and isothiocyanates is reported. A range of phosphorus nucleophiles including secondary phosphine oxides HP(O)R2 (R = Ph, i Pr), phosphites HP(O)(OR)2 (R = Me, Et), and methyl phenylphosphinate are tested. The procedure tolerates isocyanates and isothiocyanates featuring a wide range of substituents and, by using four equivalents of 2-methyltetrahydrofuran (2-MeTHF), solid substrates can be utilized. Twenty-five compounds are prepared, with improved functional group tolerance compared to previous methods and allowing access to new compounds (16 are novel). Facile scale up and simple reaction conditions make this a straightforward and practical methodology for obtaining phosphorus analogues of ureas and thioureas, which are challenging to synthesize by other methods

Catalyst-free hydrophosphinylation of isocyanates and isothiocyanates under low-added-solvent conditions

A catalyst-free, low-solvent method for the hydrophosphinylation of isocyanates and isothiocyanates is reported. A range of phosphorus nucleophiles including secondary phosphine oxides HP(O)R2 (R = Ph, iPr), phosphites HP(O)(OR)2 (R = Me, Et), and methyl phenylphosphinate were tested. The procedure tolerated isocyanates and isothiocyanates featuring a wide range of substituents and, with use of 4 equiv of 2-methyltetrahydrofuran (2-MeTHF), solid substrates can be utilized. Twenty-five compounds were prepared with improved functional group tolerance compared to previous methods allowing access to new compounds (16 are novel). Facile scale up and simple reaction conditions make this a straightforward and practical methodology for obtaining phosphorus analogues of ureas and thioureas, which are challenging to synthesize by other methods

Photophysics of cage/guest assemblies : photoinduced electron transfer between a coordination cage containing osmium(II) luminophores, and electron-deficient bound guests in the central cavity

An octanuclear cubic Os4Zn4 coordination cage, containing Os(II) tris-diimine units at four of the eight vertices which are good photoelectron donors from their 3MLCT excited state, performs photoinduced electron transfer to electron-accepting organic guests which bind in the central cavity in water via the hydrophobic effect: the resulting charge-separated states have lifetimes of ca. 200 ps and have been characterized by transient absorption spectroscopy

Epidemiology and aetiology of community-acquired pneumonia in children: South African Thoracic Society guidelines (part 1)

Background. Pneumonia remains a major cause of morbidity and mortality among South African (SA) children. Improved immunisation regimens, strengthening of HIV programmes, better socioeconomic conditions and new preventive strategies have influenced the epidemiology of pneumonia. Furthermore, sensitive diagnostic tests and better sampling methods in young children improve aetiological diagnosis.Objectives. To summarise current information on childhood community-acquired pneumonia (CAP) epidemiology and aetiology in children as part of the revised South African Thoracic Society guidelines.Methods. The Paediatric Assembly of the South African Thoracic Society and the National Institute for Communicable Diseases expert subgroup on epidemiology and aetiology revised the existing SA guidelines.The subgroup reviewed the published evidence in their area; in the absence of evidence, expert opinion was accepted. Evidence was graded using the British Thoracic Society (BTS) grading system, and the relevant section underwent peer review.Results. Respiratory viruses, particularly respiratory syncytial virus, are the key pathogens associated with hospitalisation for radiologically confirmed pneumonia in HIV-uninfected children. Opportunistic organisms, including Pneumocystis jirovecii, are important pathogens in HIV-infected infants, while non-typable Haemophilus influenzae and Staphylococcus aureus are important in older HIV-infected children. Co-infections with bacteria or other respiratory viruses are common in hospitalised children. Mycobacterium tuberculosis is common in children hospitalised with CAP in SA.Conclusions. Numerous public health measures, including changes in immunisation schedules and expansion of HIV prevention and treatment programmes, have influenced the epidemiology and aetiology of CAP in SA children. These changes have necessitated a revision of the South African Paediatric CAP guidelines, further sections of which will be published as part of a CME series in SAMJ

Diagnosis of community-acquired pneumonia in children: South African Thoracic Society guidelines (part 2)

Background. Accurate diagnosis and attribution of the aetiology of pneumonia are important for measuring the burden of disease, implementing appropriate treatment strategies and developing more effective interventions.Objectives. To produce revised guidelines for the diagnosis of pneumonia in South African (SA) children, encompassing clinical, radiological and aetiological methods.Methods. An expert group was established to review diagnostic evidence and make recommendations for a revised SA guideline. Published evidence was reviewed and graded using the British Thoracic Society grading system.Results. Diagnosis of pneumonia should be considered in a child with acute cough, fast breathing or difficulty breathing. Revised World Health Organization guidelines classify such children into: (i) severe pneumonia; (ii) pneumonia (tachypoea or lower chest indrawing); or (iii) no pneumonia. Malnourished or immunocompromised children with lower chest indrawing should be managed as cases of severe pneumonia. Pulse oximetry should be done, with hospital referral for oxygen saturation <92%. A chest X-ray is indicated in severe pneumonia or when tuberculosis (TB) is suspected. Microbiological investigations are recommended in hospitalised patients or in outbreak settings. Improved aetiological methods show the importance of co-infections. Blood cultures have a low sensitivity (<5%), for diagnosing bacterial pneumonia. Highly sensitive, multiplex tests on upper respiratory samples or sputum detect multiple potential pathogens in most children. However, even in symptomatic children, it may be impossible to distinguish colonising from causative organisms, unless identification of the organism is strongly associated with attribution to causality, e.g. respiratory syncytial virus, Mycobacterium tuberculosis, Bordetella pertussis, influenza, para-influenza or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Investigations for TB should be considered in children with severe pneumonia who have been hospitalised, in a case of a known TB contact, if the tuberculin skin test is positive, if a child is malnourished or has lost weight, and in children living with HIV. Induced sputum may provide a higher yield than upper respiratory sampling for B. pertussis, M. tuberculosis and Pneumocystis jirovecii. Conclusions. Advances in clinical, radiological and aetiological methods have improved the diagnosis of childhood pneumonia

Prevention of community-acquired pneumonia in children: South African Thoracic Society guidelines (part 4)

Background. More comprehensive immunisation regimens, strengthening of HIV prevention and management programmes and improved socioeconomic conditions have impacted on the epidemiology of paediatric community-acquired pneumonia (CAP) in South Africa (SA).Objectives. To summarise effective preventive strategies to reduce the burden of childhood CAP.Methods. An expert subgroup reviewed existing SA guidelines and new publications focusing on prevention. Published evidence on pneumonia prevention informed the revisions; in the absence of evidence, expert opinion was used. Evidence was graded using the British Thoracic Society (BTS) grading system.Recommendations. General measures for prevention include minimising exposure to tobacco smoke or air pollution, breastfeeding, optimising nutrition, optimising maternal health from pregnancy onwards, adequate antenatal care and improvement in socioeconomic and living conditions. Prevention of viral transmission, including SARS-CoV-2, can be achieved by hand hygiene, environmental decontamination, use of masks and isolation of infected people. Specific preventive measures include vaccines as contained in the Expanded Programme on Immunisation schedule, isoniazid prophylaxis for tuberculosis, co-trimoxazole prophylaxis for HIV-infected infants and children who are immunosuppressed, and timely diagnosis of HIV, as well as antiretroviral therapy (ART) initiation. HIV-infected children treated with ART from early infancy, and HIV-exposed children, have similar immunogenicity and immune responses to most childhood vaccines as HIV-unexposed infants.Validation. These recommendations are based on available published evidence supplemented by the consensus opinion of SA paediatric experts, and are consistent with those in published international guidelines

One guest or two? A crystallographic and solution study of guest binding in a cubic coordination cage

A crystallographic investigation of a series of host/guest complexes in which small‐molecule organic guests occupy the central cavity of an approximately cubic M 8 L 12 coordination cage has revealed some unexpected behaviour. Whilst some guests form 1:1 H•G complexes as we have seen before, an extensive family of bicyclic guests – including some substituted coumarins and various saturated analogues – form 1:2 H•G 2 complexes in the solid state, despite the fact that solution titrations are consistent with 1:1 complex formation, and the combined volume of the pair of guests significantly exceeds the Rebek 55±9% packing for optimal guest binding, with packing coefficients of up to 87%. Re‐examination of solution titration data for guest binding in two cases showed that, although conventional fluorescence titrations are consistent with 1:1 binding model, alternative forms of analysis – Job plot and an NMR titration – at higher concentrations do provide evidence for 1:2 H•G 2 complex formation. The observation of guests binding in pairs in some cases opens up new possibilities for altered reactivity of bound guests, and also highlights the recently‐articulated difficulties associated with determining stoichiometry of supramolecular complexes in solution

Highly electron deficient diketopyrrolopyrroles

The synthesis, spectroelectrochemical and structural characteristics of highly electron-accepting diketopyrrrolopyrrole (DPP) molecules with adjoining pyridinium rings is reported, along with an assessment of their toxicity, which is apparently low. The compounds show reversible electrochemistry and in one subfamily a massive increase in molar extinction coefficient upon electrochemical reduction