ОСОБЕННОСТИ ХАРАКТЕРИСТИКИ ТРИАЛКИЛТИОФОСФАТОВ ИНДЕКСАМИ УДЕРЖИВАНИЯ В ОБРАЩЕННО-ФАЗОВОЙ ВЫСОКОЭФФЕКТИВНОЙ ЖИДКОСТНОЙ ХРОМАТОГРАФИИ В СОЧЕТАНИИ С МАСС-СПЕКТРОМЕТРИЕЙ

HPLC-MS characterization of 12 homologues of trialkyl thiophosphate series was conducted including the determination of their retention indices (RI) and the registration of the mass spectra with the electro­spray ionization in the positive mode. The correlation of RI(HPLC) and RI(GC) values for trialkyl phos­phates was confirmed. It was revealed that the dependence of RI(HPLC) vs. molecular masses of ho­mo­logues with the high precision could be approximated by the linear regression RI = aM + b. The ano­malies of this dependence were caused by the features of two analytical methods: the branches of the carbon skeleton of analytes’ molecules strongly influence the GC retention parameters, while in HPLC such influence was much less. The possibilities of the application of so-called homologous increments of retention indi­ces, iRI = RI - xDRI(CH2), where  х = int(M/14),  “int” is the integer part of the quotient from the division of the molecular mass number by 14, that is equivalent to M = 14x + y,  уМ – the number of homologous group of analyte, yМ º M(mod14), DRI(CH2) – the retention index increment of homologous difference СН2 (in GC it is equal to 100) were considered. It was demonstra­ted that in HPLC this increment may not be equal to 100; for instance, for trialkyl thiophosphates the more informative value was DRI(CH2) = 74. The application of the iRI concept seems to be most useful for revealing the compounds which mass spectra are like those of the target analytes. In the case of trialkyl thiophosphates these are the products of their partial hydrolysis – dialkyl thiophosphates (RO)2PS-OH. These acidic esters could not be analyzed using the GC techniques due to the presence of active hydrogen atoms in their molecules.Keywords: Trialkyl thiophosphates, high performance liquid chromatography, mass spect­ro­metry, electrospray ionization, retention indices, homologous increments of retention indices, revealing dialkyl thiophosphates in reaction mixtures.DOI: http://dx.doi.org/10.15826/analitika.2019.23.3.012(Russian)1Igor G. Zenkevich, 1Tatiana I. Pushkareva, 2Georgy V. Karakashev1St. Petersburg State University, Universitetskii prosp., 26, St. Petersburg, 198504, Russian Federation2Research Institute of hygiene, occupational pathology, and human ecology,                 Federal Medico-Biological Agency,  p/o Kuzmolovsky, Vsevolozhsky District, Leningrad reg., 18866, Russian FederationХроматомасс-спектрометрическая характеристика 12 гомологов ряда триалкилтио­фос­фатов в режиме ВЭЖХ-МС включала определение их индексов удерживания (RI) и регистрацию масс-спектров с ионизацией электрораспылением при детектировании по­ло­жительно заряженных ионов. Подтверждена  корреляция RI(ВЭЖХ) триалкилтио­фос­фатов и RI(ГЖХ) их структурных аналогов – триалкилфосфатов. Установлено, что зависимость RI(ВЭЖХ) от молекулярных масс гомологов с высокой точностью может быть аппроксимирована уравнением линейной регрессии, RI = aM + b. Аномалии этой зависимости обусловлены тем, что в ГЖХ разветвления углеродного скелета молекул гомологов существенно влияют на характеристики удерживания, а в ВЭЖХ проявляют­ся в незна­чи­тельной степени. Впервые рассмотрены возможности использования гомологических инкрементов ин­­дексов удерживания, iRI = RI - xDRI(CH2), где  х = int(M/14),  int – функция, обозна­ча­ющая целую часть частного от деления моле­ку­лярного массового числа на 14, эквива­лен­тная за­пи­си M = 14x + y,  уМ – но­мер гомоло­гической группы соединения, yМ º M(mod14), DRI(CH2) – инкремент индекса удерживания для гомоло­гической раз­ности СН2 (в ГЖХ равен 100). Показано, что в ВЭЖХ этот инкремент может принимать другие значения; например в ряду триалкилтиофосфатов более информативна величина DRI(CH2) = 74. Применение концепции iRI наиболее эффективно для выявления соедине­ний, масс-спе­кт­ры которых незначительно отличаются от масс-спектров целевых анали­тов. В случае триалкилтиофосфатов это продукты частичного гидролиза таких эфиров – диалкилтио­фос­фаты (RO)2P(S)-OH, которые не могут быть проанализированы методом ГЖХ из-за наличия активного атома водорода в молекулах.Ключевые слова: Триалкилтиофосфаты, высокоэффективная жидкостная хроматогра­фия, масс-спектрометрия с ионизацией электрораспылением, индексы удерживания, го­мо­логические инкременты индексов удерживания, обнаружение диалкилтиофосфатов в реакционных смесяхDOI: http://dx.doi.org/10.15826/analitika.2019.23.3.01

Investigation of interaction femtosecond laser pulses with skin and eyes mathematical model

We present a mathematical model of linear and nonlinear processes that takes place under the action of femtosecond laser radiation on the cutaneous covering. The study is carried out and the analytical solution of the set of equations describing the dynamics of the electron and atomic subsystems and investigated the processes of linear and nonlinear interaction of femtosecond laser pulses in the vitreous of the human eye, revealed the dependence of the pulse duration on the retina of the duration of the input pulse and found the value of the radiation power density, in which there is a self-focusing is obtained. The results of the work can be used to determine the maximum acceptable energy, generated by femtosecond laser systems, and to develop Russian laser safety standards for femtosecond laser systems

HPLC-MS separation and detection of dialkyl phosphonates and trialkyl phosphites in reaction mixtures of 1-alkanols with phosphorous trichloride

To evaluate the rationality and separation conditions of alkyl esters of phosphorous P(III) and P(V) acids using reversed phase HPLC with mass spectrometric detection, the analyses of reaction mixtures of two 1-alkanols (1-butanol and 1-heptanol) with PCl3 in the presence of N,N-dimethyl aniline (for pH correction) have been carried out. In accordance with the previous results, these mixtures preferably contain trialkyl phosphites (RO)3P and dialkyl phosphonates (RO)2PH=O. However, the results of HPLC-MS analyses indicate the prevalence of oxidation products P(III) ® P(V) in the composition of these mixtures, namely trialkyl phosphates (RO)3OP. In accordance with this scheme, the appearance of diheptyl phosphate (C7H15O)2P(=O)-OH is caused by the oxidation of diheptyl phosphonate. Possible reasons of such discrepancies in the composition of reaction mixtures are discussed. One of them may be oxidation of P(III) derivatives by air oxygen during storage, or, tentatively, due to electrochemical reactions during electrospray ionization. The reaction mixture of 1-heptanol with PCl3 contains two components with the same molecular weights ( M = 294) and identical mass spectra, but strongly different retention parameters ( t R 5.4 and 16.0 min). The second of them is diheptyl phosphonate. To explain the appearance the first of them, existence of more hydrophilic prototropic tautomer (C7H15O)P-OH (contains hydroxyl group in the molecule) was proposed. Comparing the analytical results obtained in positive and negative modes of detection indicates that the first of them seems to be more effective for detection of alkyl esters of P(III) and P(V) phosphorous acids.Для оценки целесообразности и характеристики особенностей разделения алкиловых эфиров фосфорных кислот P(III) и P(V) с использованием обращенно-фазовой высокоэффективной жидкостной хроматографии (ОФ ВЭЖХ) и их масс-спектрометрического детектирования проведен анализ реакционных смесей двух 1-алканолов (ROH) (1-бутанола и 1-гептанола) с трихлоридом фосфора (PCl3) в присутствии N,N-диметиланилина для регулирования рН. В соответствии с предварительными данными, такие смеси содержат трилкилфосфиты (RO)3P и диалкилфосфонаты (RO)2PH=O. Однако по данным ВЭЖХ-МС-МС анализа в их составе преобладают продукты окисления производных Р(III) до производных P(V), а именно соответствующие триалкилфосфаты (RO)3P=O. В реакционной смеси 1-гептанола с PCl3 обнаружен дигептилфосфат (C7H15O)2P(O)-OH, вероятнее всего образующийся при окислении дигептилфосфоната. Обсуждаются возможные причины выявленных несоответствий в результатах определения состава реакционных смесей разными методами, в том числе окисление производных P(III) кислородом воздуха при их хранении или, предположительно, в результате электрохимических трансформаций аналитов в процессе электрораспылительной ионизации. В реакционной смеси 1-гептанола с PCl3 обнаружены два компонента с одинаковыми молекулярными массами ( М = 294) и идентичными масс-спектрами, но значительно отличающимися по параметрам удерживания ( t R = 5.4 и 16.0 мин). Второй из них однозначно соответствует дигептилфосфонату (C7H15O)2PH=O. Высказано предположение, что первый пик может принадлежать прототропному таутомеру (C7H15O)P-OH, более гидрофильному за счет наличия гидроксильной группы в молекуле. Показано, что детектирование положительно заряженных ионов в условиях ВЭЖХ-МС значительно более эффективно при определении алкиловых эфиров кислот P(III) и P(V), чем отрицательных.Работа выполнена в соответствии с темой и при финансовой поддержке РФФИ (грант № 18-03-00151а). Авторы выражают благодарность руководству ФГУП “НИИ ГПЭЧ” ФМБА (Санкт-Петербург, Россия) за предоставленную возможность использования аналитического оборудования.This work is fulfilled in accordance with the frame and under financial support of RFBR grant № 18-03-00151a. The authors are grateful to the authorities of Research Institute of Hygiene, Occupational Pathology, and Human Ecology (St. Petersburg, Russia) for permission to use the analytical equipment

Тромботическая окклюзия у пациентов с острым ишемическим инсультом

Currently, reperfusion therapy is the main method of treating patients with ischemic stroke (IS). The safety and efficacy of systemic thrombolytic therapy with a recombinant tissue plasminogen activator in patients with IS within 3 hours, and then 4.5 hours after the onset of symptoms of the disease was demonstrated in the NINDS (1995) and ECASS III (2008) studies. In 2018, based on the results of five studies, clear indications were formulated for performing thrombectomy (TE) in patients with IS, which involve the detection of thrombosis of a large stroke-associated artery. Given the continuous growth in the number of the adult population, which constitutes the bulk of patients with IS, information on the prevalence of patients with thrombotic occlusion of cerebral arteries, who are potential candidates for TE, may be important for regional vascular centers.Aim of study. To describe IS patients admitted within the 6-hour “therapeutic window”.Materials and methods. The study included 145 patients with cerebral IS who were admitted within the first 6 hours after the onset of symptoms of the disease. All patients underwent computed tomographic (CT) angiography in order to verify the occlusion of the cerebral artery.Results. In our study, a correlation was established between the NIHSS severity of IS and the likelihood of verification of stroke-related artery thrombosis by CT angiography, but in 32.6% of patients with severe stroke (NIHSS at least score 14), no thrombotic occlusion was detected, and in 13% of patients with a clinic of mild acute cerebrovascular accident (NIHSS no more than 6), on the contrary, thrombotic occlusion was detected. Mortality in patients with verified thrombotic occlusion of the cerebral artery was higher than in patients without it (38% versus 10.5%, p<0.001). Such a significant difference in the mortality rate was due to the initially more severe stroke (NIHSS at admission 17 [10; 23] versus 5 [2; 10], p><0.001) in patients with thrombotic occlusion of a stroke-related artery, as well as a higher incidence of severe swallowing disorders (30% versus 9.5%, p ><0.002), which are a risk factor for pneumonia, as well as a higher frequency of such a comorbid background as chronic kidney disease and atrial fibrillation (30% versus 13.7%, p=0.018% and 58% versus 29.5%, p=0.001, respectively). CONCLUSION 1. Thrombosis of the cerebral stroke-associated artery was detected in 34.5% of patients with ischemic stroke who were admitted within the first 6 hours from the onset of the disease. 2. The main reason for the failure to perform thrombectomy in patients with ischemic stroke admitted within the 6-hour therapeutic window is the lack of verification of stroke-related artery thrombosis using computed tomographic angiography. Due to thrombosis at a different location (other than thrombosis of the internal carotid artery and / or M1 segment of the middle cerebral artery), 10% of patients with verified thrombosis did not meet the currently existing selection criteria for thrombectomy. Keywords: ischemic stroke, reperfusion therapy, cerebral artery thrombosis, cryptogenic stroke>˂0.001). Such a significant difference in the mortality rate was due to the initially more severe stroke (NIHSS at admission 17 [10; 23] versus 5 [2; 10], p˂0.001) in patients with thrombotic occlusion of a stroke-related artery, as well as a higher incidence of severe swallowing disorders (30% versus 9.5%, p˂0.002), which are a risk factor for pneumonia, as well as a higher frequency of such a comorbid background as chronic kidney disease and atrial fibrillation (30% versus 13.7%, p=0.018% and 58% versus 29.5%, p=0.001, respectively).Conclusion. 1. Thrombosis of the cerebral stroke-associated artery was detected in 34.5% of patients with ischemic stroke who were admitted within the first 6 hours from the onset of the disease. 2. The main reason for the failure to perform thrombectomy in patients with ischemic stroke admitted within the 6-hour therapeutic window is the lack of verification of stroke-related artery thrombosis using computed tomographic angiography. Due to thrombosis at a different location (other than thrombosis of the internal carotid artery and / or M1 segment of the middle cerebral artery), 10% of patients with verified thrombosis did not meet the currently existing selection criteria for thrombectomy. В настоящее время реперфузионная терапия является основным методом лечения пациентов с ишемическим инсультом (ИИ). Безопасность и эффективность системной тромболитической терапии при помощи рекомбинантного тканевого активатора плазминогена у пациентов с ИИ в пределах 3 часов, а в последующем 4,5 часа от начала симптомов заболевания была продемонстрирована в исследованиях NINDS (1995) и ECASS III (2008). В 2018 году, основываясь на результатах пяти исследований, были сформулированы четкие показания для выполнения тромбэктомии (ТЭ) у пациентов с ИИ, которые подразумевают выявление тромбоза крупной инсульт-связанной артерии. В условиях непрерывного роста числа взрослого населения, составляющего основную массу пациентов с ИИ, информация о распространенности больных с тромботической окклюзией церебральных артерий, являющихся потенциальными претендентами для выполнения ТЭ, может быть важной для региональных сосудистых центров.Цель исследования. Охарактеризовать пациентов с ИИ, поступающих в 6-часовом «терапевтическом окне».Материал и методы. В исследование включены 145 пациентов с церебральным ИИ, поступивших в первые 6 часов от начала развития симптомов заболевания. Всем пациентам с целью верификации окклюзии церебральной артерии выполняли компьютерную томографическую (КТ) ангиографию.Результаты. В нашем исследовании была установлена корреляция между тяжестью ИИ по шкале NIHSS и вероятностью верификации при помощи КТ-ангиографии тромбоза инсульт-связанной артерии, но у 32,6% пациентов с клиникой тяжелого инсульта (NIHSS не менее 14 баллов) не было выявлено тромботической окклюзии, а у 13% пациентов с клиникой легко протекающего острого нарушения мозгового кровообращения (NIHSS не более 6 баллов), напротив, тромботическая окклюзия была выявлена. Летальность у пациентов с верифицированной тромботической окклюзией церебральной артерии была статистически значимо выше, чем у пациентов без таковой (38% против 10,5%, р<0,001). Столь значительная разница между показателями летальности была обусловлена исходно более тяжелым инсультом (оценка по NIHSS при поступлении 17 [10; 23] против 5 [2; 10], p><0,001, статистически значимо) у больных с тромботической окклюзией инсульт-связанной артерии, а также большей частотой статистически значимых грубых расстройств глотания (30% против 9,5%, p><0,002, статистически значимо), являющихся фактором риска развития пневмонии и такого коморбидного фона, как хроническая болезнь почек и фибрилляция предсердий (30% против 13,7%, р=0,018 и 58% против 29,5%, р=0,001 соответственно). Выводы 1. Тромбоз церебральной инсульт-связанной артерии выявлен у 34,5% пациентов с ишемическим инсультом, поступающих в первые 6 часов от начала заболевания. 2. Основной причиной невыполнения тромбэктомии у пациентов с ишемическим инсультом, поступивших в 6-часовом «терапевтическом окне», является отсутствие верификации тромбоза инсульт-связанной артерии при помощи компьютерной томографической ангиографии. По причине тромбоза другой локализации (отличной от тромбоза внутренней сонной артерии и/или М1 сегмента средней мозговой артерии) 10% пациентов с верифицированным тромбозом не соответствовали существующим в настоящее время критериям отбора для выполнения тромбэктомии. Ключевые слова: ишемический инсульт, реперфузионная терапия, тромбоз мозговой артерии, криптогенный инсульт>˂ 0,001). Столь значительная разница между показателями летальности была обусловлена исходно более тяжелым инсультом (оценка по NIHSS при поступлении 17 [10; 23] против 5 [2; 10], p˂ 0,001, статистически значимо) у больных с тромботической окклюзией инсульт-связанной артерии, а также большей частотой статистически значимых грубых расстройств глотания (30% против 9,5%, p˂ 0,002, статистически значимо), являющихся фактором риска развития пневмонии и такого коморбидного фона, как хроническая болезнь почек и фибрилляция предсердий (30% против 13,7%, р=0,018 и 58% против 29,5%, р=0,001 соответственно).Выводы. 1. Тромбоз церебральной инсульт-связанной артерии выявлен у 34,5% пациентов с ишемическим инсультом, поступающих в первые 6 часов от начала заболевания. 2. Основной причиной невыполнения тромбэктомии у пациентов с ишемическим инсультом, поступивших в 6-часовом «терапевтическом окне», является отсутствие верификации тромбоза инсульт-связанной артерии при помощи компьютерной томографической ангиографии. По причине тромбоза другой локализации (отличной от тромбоза внутренней сонной артерии и/или М1 сегмента средней мозговой артерии) 10% пациентов с верифицированным тромбозом не соответствовали существующим в настоящее время критериям отбора для выполнения тромбэктомии.

Высокая суммарная доза облучения улучшает выживаемость больных локализованной формой мелкоклеточного рака легкого: результаты одноцентрового ретроспективного анализа

The overall survival of patients with locally advanced small cell lung cancer who received at least 2 courses of chemotherapy and external beam radiation therapy at a total dose >50 Gy delivered to the primary tumor was retrospectively studied. Patients were dividedinto 2 groups. Patients in the standard treatment group (n=71) were treated to 50–58 Gy total dose. The dose escalation group (n=69) was treated to 60–74 Gy. Accelerated fractionation regimen in radiotherapy was more frequently given in dose escalation treatment group. The 1-, 3- and 5-year survival rates in the dose escalated and standard dose groups were respectively 54 % (95 % CI 42–65 %) and 32 % (95 % CI 23–44 %), р=0,11; 25 % (95 % CI 16–36 %) and 1 % (95% CI 0–8 %), р=0,0003; 17 % (95 % CI 10–28 %) and 0 % (95 % CI 0–5 %) (р=0.0007). The median survival was 14 months (95 % CI 10–17 months) in the dose escalated treatment group and 9 months (95 % CI 8–11months) in patients of the standard treatment group (χ2=16,8, р<0,0001). Multifactorial analysis showed that a total dose of ≥60 Gy resulted in reduction in risk of death (RR 0,57 (CI 0,37–0,88), р=0,012). Radiation dose escalation can result in improvement of local control for patients with locally advanced small cell lung cancer. Prospective randomized studies are required to finally confirm this hypothesis. Проведено ретроспективное изучение общей выживаемости больных Л-МРЛ, получавших не менее 2 курсов химиотерапии и дистанционную ЛТ в СОД не менее 50 Гр на первичный очаг. Больные группы СОДст (n=71) получили облучение грудной клетки в стандартно рекомендованной дозе, в группе СОДэск (n=69) суммарная доза составляла 60–74 Гр по биологическому эквиваленту. Лучевую терапию в режиме ускоренного фракционирования с эскалацией дозы (УГФЭД) чаще применяли в группе СОДэск. Более 1, 3 и 5 лет жили пациенты из группы СОДэск и СОДст соответственно в 54 % (95 % ДИ 42–65 %) и 32 % (95 % ДИ 23–44 %), р=0,11; в 25 % (95 % ДИ 16–36 %) и 1 % (95% ДИ 0–8 %), р=0,0003; в 17 % (95 % ДИ 10–28 %) и 0 % (95 % ДИ 0–5 %) случаях (р=0,0007). Медиана выживаемости в группах составила 14 (95 % ДИ 10–17 мес) и 9 (95 % ДИ 8–11 мес) мес, χ2=16,8, р<0,0001 соответственно. При многофакторном анализе только СОД 60 Гр и выше независимо снижала риск смерти (ОР 0,57 (ДИ 0,37–0,88), р=0,012). Увеличение СОД выше стандартно рекомендуемых 50–58 Гр может привести к улучшению выживаемости больных Л-МРЛ. Окончательное подтверждение этой гипотезы возможно только в рамках проспективного рандомизированного исследования

Five decades of terrestrial and freshwater research at Ny-Ålesund, Svalbard

For more than five decades, research has been conducted at Ny-Alesund, in Svalbard, Norway, to understand the structure and functioning of High Arctic ecosystems and the profound impacts on them of environmental change. Terrestrial, freshwater, glacial and marine ecosystems are accessible year-round from Ny-Alesund, providing unique opportunities for interdisciplinary observational and experimental studies along physical, chemical, hydrological and climatic gradients. Here, we synthesize terrestrial and freshwater research at Ny-Alesund and review current knowledge of biodiversity patterns, species population dynamics and interactions, ecosystem processes, biogeochemical cycles and anthropogenic impacts. There is now strong evidence of past and ongoing biotic changes caused by climate change, including negative effects on populations of many taxa and impacts of rain-on-snow events across multiple trophic levels. While species-level characteristics and responses are well understood for macro-organisms, major knowledge gaps exist for microbes, invertebrates and ecosystem-level processes. In order to fill current knowledge gaps, we recommend (1) maintaining monitoring efforts, while establishing a longterm ecosystem-based monitoring programme; (2) gaining a mechanistic understanding of environmental change impacts on processes and linkages in food webs; (3) identifying trophic interactions and cascades across ecosystems; and (4) integrating long-term data on microbial, invertebrate and freshwater communities, along with measurements of carbon and nutrient fluxes among soils, atmosphere, freshwaters and the marine environment. The synthesis here shows that the Ny-Alesund study system has the characteristics needed to fill these gaps in knowledge, thereby enhancing our understanding of High-Arctic ecosystems and their responses to environmental variability and change

Five decades of terrestrial and freshwater research at Ny-Ålesund, Svalbard

For more than five decades, research has been conducted at Ny-Ålesund, in Svalbard, Norway, to understand the structure and functioning of High-Arctic ecosystems and the profound impacts on them of environmental change. Terrestrial, freshwater, glacial and marine ecosystems are accessible year-round from Ny-Ålesund, providing unique opportunities for interdisciplinary observational and experimental studies along physical, chemical, hydrological and climatic gradients. Here, we synthesize terrestrial and freshwater research at Ny-Ålesund and review current knowledge of biodiversity patterns, species population dynamics and interactions, ecosystem processes, biogeochemical cycles and anthropogenic impacts. There is now strong evidence of past and ongoing biotic changes caused by climate change, including negative effects on populations of many taxa and impacts of rain-on-snow events across multiple trophic levels. While species-level characteristics and responses are well understood for macro-organisms, major knowledge gaps exist for microbes, invertebrates and ecosystem-level processes. In order to fill current knowledge gaps, we recommend (1) maintaining monitoring efforts, while establishing a long-term ecosystem-based monitoring programme; (2) gaining a mechanistic understanding of environmental change impacts on processes and linkages in food webs; (3) identifying trophic interactions and cascades across ecosystems; and (4) integrating long-term data on microbial, invertebrate and freshwater communities, along with measurements of carbon and nutrient fluxes among soils, atmosphere, freshwaters and the marine environment. The synthesis here shows that the Ny-Ålesund study system has the characteristics needed to fill these gaps in knowledge, thereby enhancing our understanding of High-Arctic ecosystems and their responses to environmental variability and change

Athlome Project Consortium: a concerted effort to discover genomic and other "omic" markers of athletic performance.

Despite numerous attempts to discover genetic variants associated with elite athletic performance, injury predisposition, and elite/world-class athletic status, there has been limited progress to date. Past reliance on candidate gene studies predominantly focusing on genotyping a limited number of single nucleotide polymorphisms or the insertion/deletion variants in small, often heterogeneous cohorts (i.e., made up of athletes of quite different sport specialties) have not generated the kind of results that could offer solid opportunities to bridge the gap between basic research in exercise sciences and deliverables in biomedicine. A retrospective view of genetic association studies with complex disease traits indicates that transition to hypothesis-free genome-wide approaches will be more fruitful. In studies of complex disease, it is well recognized that the magnitude of genetic association is often smaller than initially anticipated, and, as such, large sample sizes are required to identify the gene effects robustly. A symposium was held in Athens and on the Greek island of Santorini from 14-17 May 2015 to review the main findings in exercise genetics and genomics and to explore promising trends and possibilities. The symposium also offered a forum for the development of a position stand (the Santorini Declaration). Among the participants, many were involved in ongoing collaborative studies (e.g., ELITE, GAMES, Gene SMART, GENESIS, and POWERGENE). A consensus emerged among participants that it would be advantageous to bring together all current studies and those recently launched into one new large collaborative initiative, which was subsequently named the Athlome Project Consortium

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study

Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75–1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58–1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91–1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70–1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11–0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50–0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38–0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45–0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study

Background Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75–1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58–1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91–1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70–1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11–0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50–0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38–0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45–0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health