OBJECTIVES: To provide a new value-based immunization approach collating the available scientific evidence on the topic. METHODS: Four value pillars (personal, allocative, technical, and societal) applied to vaccination field were investigated. A systematic literature review was performed querying three database from December 24th, 2010 to May 27th, 2020. It included studies on vaccine-preventable diseases (VPDs) that mentioned the term value in any part and which were conducted in advanced economies. An in-depth analysis was performed on studies addressing value as key element. RESULTS: Overall, 107 studies were considered. Approximately half of the studies addressed value as a key element but in most of cases (83.3%) only a single pillar was assessed. Furthermore, the majority of papers addressed the technical value by looking only at classical methods for economic assessment of vaccinations whereas very few dealt with societal and allocative pillars. CONCLUSIONS: Estimating the vaccinations value is very complex, even though their usefulness is certain. The assessment of the whole value of vaccines and vaccinations is still limited to some domains and should encompass the wider impact on economic growth and societies.

High nitrogen (N) fertilizer inputs accelerate soil acidification and degradation in tea plantations, thus posing a threat to soil microbial diversity, species composition, and ecosystem service functions. The effects of organic fertilizer and biochar applications on improving soil fertility have been extensively studied on cropland;however, little is known about their effectiveness in promoting soil multifunctionality on rapidly expanding acidic soils in tea plantations. In this study, we conducted a two\year field experiment in a subtropical tea plantation to investigate the effects of organic fertilizer substitution and biochar amendment on soil microbial communities and multifunctionality. The results showed that soil multifunctionality was enhanced in plots amended with organic fertilizer and biochar. Soil multifunctionality was significantly and positively correlated with alpha\diversity of bacteria but not fungi. We also found that organic fertilizer substitution and biochar amendment improved soil multifunctionality by altering the abundance of keystone species. The abundance of keystone species classified as module hubs in the bacterial co\occurrence network contributed significantly and positively to soil multifunctionality. In contrast, the keystone species categorized as module hubs in the fungal co\occurrence network negatively affected soil multifunctionality. Soil pH was a key driver of soil microbial community composition, indicating that the increase in soil pH under organic fertilizer and biochar amendment had a crucial role in biological processes. These results suggest that organic substitution and biochar amendment are beneficial in preventing soil degradation and maintaining soil multifunctionality in subtropical tea plantations.

Protecting Health Care Workers (HCWs) during routine care of suspected or confirmed COVID-19 patients is of paramount importance to halt the SARS-CoV-2 (Severe Acute Respiratory Syndrome-Coronavirus-2) pandemic. The WHO, ECDC and CDC have issued conflicting guidelines on the use of respiratory filters (N95) by HCWs. We searched PubMed, Embase and The Cochrane Library from the inception to March 21, 2020 to identify randomized controlled trials (RCTs) comparing N95 respirators versus surgical masks for prevention of COVID-19 or any other respiratory infection among HCWs. The grading of recommendations, assessment, development, and evaluation (GRADE) was used to evaluate the quality of evidence. Four RCTs involving 8736 HCWs were included. We did not find any trial specifically on prevention of COVID-19. However, wearing N95 respirators can prevent 73 more (95% CI 46-91) clinical respiratory infections per 1000 HCWs compared to surgical masks (2 RCTs; 2594 patients; low quality of evidence). A protective effect of N95 respirators in laboratory-confirmed bacterial colonization (RR = 0.41; 95%CI 0.28-0.61) was also found. A trend in favour of N95 respirators was observed in preventing laboratory-confirmed respiratory viral infections, laboratory-confirmed respiratory infection, and influenza like illness. We found no direct high quality evidence on whether N95 respirators are better than surgical masks for HCWs protection from SARS-CoV-2. However, low quality evidence suggests that N95 respirators protect HCWs from clinical respiratory infections. This finding should be contemplated to decide the best strategy to support the resilience of healthcare systems facing the potentially catastrophic SARS-CoV-2 pandemic.

INTRODUCTION Chronic postherniorrhaphy pain is the foremost setback of today's inguinal hernia repair. Finding predictors for it affects implants, operative techniques and allows for preventive measures. METHODS Prospectively collected data from 932 outpatient open inguinal hernia operations between 2003 and 2010 were subjected to regression analysis. Visual analogue scale score (VAS) at least a year after operation and a measurement of chronic pain at one year were the target variables. RESULTS Chronic pain was present in 99 (11.5%) patients one year after operation. Independent predictors for the occurrence of chronic pain were positively recurrence (Odds ratio, OR 6.77 vs. no recurrence, P = 0.005), complication (OR 5.16 vs. no complication, P = 0.002), mid-density mesh (OR 2.28 vs. lightweight mesh, P = 0.012), higher preoperative VAS score (OR 1.15, P = 0.006) and negatively higher age (OR 0.98, P = 0.027). Predictors for a higher postoperative VAS score were recurrence (regression coefficient, RC, 1.49 vs. no recurrence, P = 0.001), complication (RC 0.76 vs. no complication, P = 0.016), heavyweight mesh (RC 0.50 vs. lightweight mesh, P = 0.046) and higher preoperative VAS level (RC 0.10, P < 0.001). CONCLUSIONS Recurrence, complication, mesh weight, preoperative VAS score and age are predictors for the occurrence chronic pain after open mesh based inguinal hernia repair. Recurrence, complication, mesh weight and preoperative VAS score are predictors of postherniorrhaphy VAS level.

(1) Background: Evidence shows that facilitated advance decisions can increase the number of meaningful and valid Advance Care Directives (ACDs) and improve the quality of care when End-Of-Life (EOL) is near. Little is known about the awareness and attitudes of Portuguese adults towards ACDs. The present study aims to assess the knowledge, attitudes, and preferences of a sample of Portuguese adults regarding EOL care decisions and ACDs. (2) Methods: A total of 1024 adults were assessed with an online cross-sectional survey collecting information on sociodemographic factors, knowledge, attitudes and preferences regarding advance decisions and EOL care. (3) Results: Participants had a mean age of 40.28 11.41 years. Most were female and had a professional background related to healthcare. While 76.37% of participants had heard of ACDs, only a small percentage (2.34%) had actually ever made an ACD. Knowledge levels were weakly correlated with attitudes regarding ACDs (r = ?0.344; p < 0.01). (4) Conclusions: Participants lacked a comprehensive understanding about ACDs, but revealed positive attitudes towards their use and usefulness. Further research can inform efforts to improve ACD engagement in this population. The discussion about ACDs should be part of health promotion education with a focus on planning for a comfortable and peaceful death.

Brazil and many countries are now experiencing a second wave of the COVID-19 outbreak. The objective of this study is to compare results with statistical samples involving millions of people in the two largest neighboring states in Brazil, Amazonas and Par, which in the first wave were similar but now show significant different results in combating COVID-19. During the first wave, in May 2020, the maximums of the 7-day average daily deaths per population of Amazonas and Par were similar: 15.7 and 17.1 deaths per day per million people, respectively, which means a ratio 15.7/17.1 = 0.92 &#8776; 1. Now, in the second wave of COVID-19 outbreak, Amazonas has entered a serious situation; meanwhile, Par has presented a much smaller growth in the mortality. The accumulated mortality per population from 11 November 2020 to 15 March 2021 of Amazonas and Par are 1645 and 296 deaths per million people, respectively. As 1645/296 = 5.55, Amazonas is presenting an accumulated mortality per population more than five times that of Par. Future in-depth research can provide a grounded answer to explain this significant difference, nonetheless the explicit support of the Par state government, after 21 May 2020, to early ambulatory treatment may have played some role on this result.

We developed a novel approach to induce antigen-specific CD8+ T cytotoxic lymphocyte (CTL) immunity based on in vivo engineering of extracellular vesicles (EVs). This is an innovative vaccination approach employing a DNA vector expressing a mutated HIV-1 Nef protein (Nefmut) that has lost the anti-cellular effects typical of the wild-type isoform, meanwhile showing an unusual efficiency of incorporation into EVs. This function persists even when foreign antigens are fused to its C-terminus. In this way, Nefmut traffics large amounts of antigens fused to it into EVs spontaneously released by cells expressing the Nefmut_based DNA vector. We previously provided evidence that the inoculation in mice of a DNA vector expressing the Nefmut/HPV16-E7 fusion protein induced an E7-specific CTL immune response as detected 2 weeks after the second immunization. In an effort to optimize the anti-HPV16 CD8+ T cell immune response, we found that the co-injection of DNA vectors expressing Nefmut fused with E6 and E7 generated a stronger anti-HPV16 immune response compared to that we observed in mice injected with the single vectors. When TC-1 cells, i.e., a tumor cell line co-expressing E6 and E7, were implanted before immunization, all mice survived until day 44, whereas no mice injected with either void or Nefmut_expressing vectors survived until day 32 after tumor implantation. A substantial part of mice (7 out of 12) cleared the tumor. When cured mice were re-challenged with a second sub cute implantation of TC-1 cells, and followed for additional 135 days, whereas none of them developed tumors. Both E6- and E7-specific CD8+ T immunity was still detectable at the end of the observation time. Hence, the immunity elicited by engineered EVs, besides curing already developed tumors, is strong enough to guarantee the resistance to additional tumor attack. This results is of relevance for therapy against both metastatic and relapsing tumors.

Singapore implements a school closure policy for institutional hand, foot, and mouth disease (HFMD) outbreaks, but there is a lack of empirical evidence on the effect of closure on HFMD transmission. We conducted a retrospective analysis of 197,207 cases of HFMD over the period 2003C2012 at the national level and of 57,502 cases in 10,080 institutional outbreaks over the period 2011C2016 in Singapore. The effects of school closure due to 1) institutional outbreaks, 2) public holidays, and 3) school vacations were assessed using a Bayesian time series modeling approach. School closure was associated with a reduction in HFMD transmission rate. During public holidays, average numbers of secondary cases having onset the week after dropped by 53% (95% credible interval 44C62%), and during school vacations, the number of secondary cases dropped by 7% (95% credible interval 3C10%). Schools being temporarily closed in response to an institutional outbreak reduced the average number of new cases by 1,204 (95% credible interval 1,140C1,297). Despite the positive effect in reducing transmission, the effect of school closure is relatively small and may not justify the routine use of this measure.

Ebola virus (EBOV) infection is a widespread infection that has created a bad memory in Africa. In the 2014 and 2015 outbreak, more than 28,000 infections were reported by the World Health Organization, with about 11,300 deaths in Guinea, Liberia, and Sierra Leone. Heat shock protein A5 (HSPA5), termed also GRP78, is a host cell chaperone protein responsible for the unfolded protein response in the endoplasmic reticulum. Under stress, HSPA5 is upregulated and becomes cell-surface exposed. Recent studies report the association of cell-surface HSPA5 with EBOV glycoproteins GP1 and GP2. In this study, structural and sequence analysis and molecular docking are used to predict the possible binding site between the cell-surface HSPA5 and EBOV GP1. The results show a promising binding site that supports the hypothesis of HSPA5 selectivity for binding to a specific peptide sequence (pep42). This study paves the way to suggest possible inhibitors to stop viral association with cell-surface receptors and subsequently reduce viral infection. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12192-020-01106-z) contains supplementary material, which is available to authorized users.

Shortly after the COVID-19 pandemic reached Aotearoa New Zealand, a stringent lockdown lasting seven weeks was introduced to manage community spread of the virus. This paper reports the findings of a qualitative study examining how lockdown policies impacted upon the lives of those caring for community-based patients. The study involved nationwide surveys and ethnographic interviews with 15 registered nurses (RN) employed in community settings, two community midwives, and five personal care assistants (PCAs). During the strict lockdown levels 4 and 3, RNs and PCAs in the community showed considerable courage in answering their 'call to duty' by taking on heightened care responsibilities and going 'the extra mile' to help others. They faced significant risks to personal and professional relationships when they were required to take on additional and complex responsibilities for community-based patients. Despite, and sometimes due to the hypervigilant monitoring of their personal protective equipment (PPE), the need to safeguard family and community members generated considerable stress and anxiety. Many also faced personal isolation and loneliness as a result of lockdown restrictions. Although 'care' and 'kindness' became social expectations throughout Aotearoa New Zealand during the lockdown, RNs and PCAs who were already doing care work in patient homes had to do more. This article makes five core service delivery and policy recommendations for supporting community-based nurses and PCAs in respiratory disease pandemics: acknowledging the crucial role played by community-based carers and the associated stress and anxiety endured, through championing respect and compassion; demystifying the 'heroism' or 'self-sacrifice' projected onto care workers to facilitate boundary setting; the timely provision of adequate protective equipment; improving remuneration with adequate provision for time off; and regular counselling, peer support groups, and education on work-life balance delivered by support workers in recognition of stressors arising from these complex and isolated working conditions.

Surgery in patients with hemophilia is a serious challenge. It requires a comprehensive approach, as well as careful postoperative monitoring. We present here the first case of a transperitoneal laparoscopic radical nephrectomy (TLRN) for renal cell carcinoma, of the clear-cell type, performed in a hemophilia B patient. The level of factor IX clotting activity before surgery and on postoperative days 1-6 was maintained at 65-130% and at 30-40% on subsequent days until healing of the post-operative wound was achieved. The intraoperative and postoperative courses were uneventful. TLRN can therefore be considered safe and effective for renal cell carcinoma. In hemophilia patients, the TLRN procedure requires proper preparation, as well as adequate substitution therapy for the deficient coagulation factor provided by a multidisciplinary team in a comprehensive center.

Here, drug repurposing and molecular docking were employed to screen approved MPP inhibitors and their derivatives to suggest a specific therapeutic agent for the treatment of COVID-19. The approved MPP inhibitors against HIV and HCV were prioritized, while RNA dependent RNA Polymerase (RdRp) inhibitor remdesivir including Favipiravir, alpha-ketoamide were studied as control groups. The target drug surface hotspot was also investigated through the molecular docking technique. Molecular dynamics was performed to determine the binding stability of docked complexes. Absorption, distribution, metabolism, and excretion analysis was conducted to understand the pharmacokinetics and drug-likeness of the screened MPP inhibitors. The results of the study revealed that Paritaprevir (-10.9 kcal/mol) and its analog (CID 131982844) (-16.3 kcal/mol) showed better binding affinity than the approved MPP inhibitors compared in this study, including remdesivir, Favipiravir, and alpha-ketoamide. A comparative study among the screened putative MPP inhibitors revealed that the amino acids T25, T26, H41, M49, L141, N142, G143, C145, H164, M165, E166, D187, R188, and Q189 are at potentially critical positions for being surface hotspots in the MPP of SARS-CoV-2. The top 5 predicted drugs (Paritaprevir, Glecaprevir, Nelfinavir, and Lopinavir) and the topmost analog showed conformational stability in the active site of the SARS-CoV-2 MP protein. The study also suggested that Paritaprevir and its analog (CID 131982844) might be effective against SARS-CoV-2. The current findings are limited to in silico analysis and lack in vivo efficacy testing; thus, we strongly recommend a quick assessment of Paritaprevir and its analog (CID 131982844) in a clinical trial.

This paper compares todays corporate management in developing markets (BRICS countries) vs developed markets (the OECD countries) The influence of determining a new social corporate management season considering social distancing amid the COVID-19 pandemic on emerging markets' economic growth is ascertained and set apart from corporate management in developing markets This paper helps clarifying and better understanding the role of corporate social responsibility in the conditions of an economic crisis against the background of the COVID-19 pandemic This work provides scientific arguments that allow solving critical discussions regarding the advantages (growth of quality of life, an increase of business's competitiveness) and costs (limitation of economic growth, non-commercial use of profit, and increased price for goods and services) of domestic production and consumption In the long-term, responsible financial practices return all investments and allow countries to better cope with a crisis The research supplies a new view of corporate social responsibility as a measure of crisis management It reflects its advantages at a time of social distancing in the conditions of the COVID-19 pandemic The institutionalization of corporate social responsibility in emerging countries is not predetermined by internal factors (approach to doing business or organizational culture), if not by external factors (market status, state regulation, and consumer awareness) These circumstances prove the high complexity of strengthening corporate social responsibility in developing countries In the conditions of social distancing C due to the COVID-19 pandemic C corporate social responsibility goes to a new level In both developing and developed countries, one of the most widespread manifestations of corporate social responsibility is the entrepreneurship's transition to the remote form of activities This envisages the provision of remote employment for workers and the online purchase of goods and services for consumers

Background : The limited knowledge on the diagnosis of Coronavirus disease 2019 (COVID-19) at the early stage of the pandemic may lead to misdiagnoses, especially when the nucleic acid inspection cannot meet the mass requirement This condition is even actual for people who are living with HIV/AIDS (PLWHA), for the latter is vulnerable to variable infections Case Presentation : In this short communication, we introduced two HIV infected individuals who had PCP but was misdiagnosed as COVID-19 initially, and finally infected with SARS-CoV-2 in hospital in Wuhan, China Eventually, both patients improved soon after they were switched to the treatment of SMZ/TMP Conclusions : We suggested that the hospitalized COVID-19 cases should be screened with HIV and other pathogens, to prevent that PLWHA who have PCP from being misdiagnosed as COVID-19

The WHO declared the global outbreak of SARS-CoV-2 a pandemic on March 11, 2020, and "call(ed) on all countries to exchange country experiences and practices in a transparent and timely way" (http://www.euro.who.int/en/health-topics/health-emergencies/pages/news/news/2020/03/who-announces-covid-19-outbreak-a-pandemic). To date, many medical societies have announced their intention to collect and analyze data from COVID-19 patients and some large-scale prospective data collections are already running, such as the LEOSS registry (Lean European Open Survey on SARS-CoV-2 Infected Patients) or the CAPACITYCOVID registry (registry of patients with COVID-19 including cardiovascular risk and complications). The necessity to mobilize and harmonize basic and applied research worldwide is of utmost importance (Sansonetti, 2020).

Our review aims to highlight the neurological complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the available treatments according to the existing literature, discussing the underlying mechanisms. Since the end of 2019, SARS-CoV-2 has induced a worldwide pandemic that has threatened numerous lives. Fever, dry cough, and respiratory symptoms are typical manifestations of COVID-19. Recently, several neurological complications of the central and peripheral nervous systems following SARS-CoV-2 infection have gained clinicians' attention. Encephalopathy, stroke, encephalitis/meningitis, GuillainCBarr syndrome, and multiple sclerosis are considered probable neurological signs of COVID-19. The virus may invade the nervous system directly or induce a massive immune inflammatory response via a cytokine storm. Specific antiviral drugs are still under study. To date, immunomodulatory therapies and supportive treatment are the predominant strategies. In order to improve the management of COVID-19 patients, it is crucial to monitor the onset of new neurological complications and to explore drugs/vaccines targeted against SARS-CoV-2 infection.

Background Intimate partner violence (IPV) is a global social and public health problem but published literature regarding the exacerbation of physical IPV during the COVID-19 pandemic is lacking. Purpose To assess the incidence, patterns, and severity of injuries in victims of intimate partner violence (IPV) during the COVID-19 pandemic in 2020, compared with the prior three years. Materials and Methods The demographics, clinical presentation, injuries, and radiological findings of patients reporting physical abuse arising from IPV during the statewide COVID-19 pandemic between March 11th and May 3rd, 2020 were compared with the same period over the past three years. Pearson's chi-squared and Fischer's exact have been used for analysis. Results 26 physical IPV victims from 2020 (37+/-13 years, 25 women) were evaluated and compared with 42 physical IPV victims (41+/-15 years, 40 women) from 2017-2019. While the overall number of patients reporting IPV decreased during the pandemic, the incidence of physical IPV was 1.8 times greater (95% confidence interval [CI] 1.1 to 3.0, p = 0.01). The total number of deep injuries was 28 during 2020 versus 16 from 2017-2019; the number of deep injuries per victim was 1.1 during 2020 compared with 0.4 from 2017-2019 (p<0.001). The incidence of high-risk abuse defined by mechanism was greater by 2 times (95% CI 1.2 to 4.7, p = 0.01). Patients with IPV in during the COVID-19 pandemic were more likely to be ethnically white, 17 (65%) victims in 2020 were ethnically white compared to 11 (26%) in the prior years (p=0.007). Conclusion There was a higher incidence and severity of physical intimate partner violence (IPV) during the COVID 19 pandemic compared with the prior three years. These results suggest that IPV victims delayed reaching out to health care services until the late stages of the abuse cycle during the COVID-19 pandemic.

BACKGROUND: Attempts to manage the COVID-19 pandemic have led to radical reorganisations of health care systems worldwide. General practitioners (GPs) provide the vast majority of patient care, and knowledge of their experiences with providing care for regular health issues during a pandemic is scarce. Hence, in a Danish context we explored how GPs experienced reorganising their work in an attempt to uphold sufficient patient care while contributing to minimizing the spread of COVID-19. Further, in relation to this, we examined what guided GPs choices between telephone, video and face-to-face consultations. METHODS: This study consisted of qualitative interviews with 13 GPs. They were interviewed twice, approximately three months apart in the initial phase of the pandemic, and they took daily notes for 20 days. All interviews were audio recorded, transcribed, and inductively analysed. RESULTS: The GPs re-organised their clinical work profoundly. Most consultations were converted to video or telephone, postponed or cancelled. The use of video first rose, but soon declined, once again replaced by an increased use of face-to-face consultations. When choosing between consultation forms, the GPs took into account the need to minimise the risk of COVID-19, the central guidelines, and their own preference for face-to-face consultations. There were variations over time and between the GPs regarding which health issues were dealt with by using video and/or the telephone. For some health issues, the GPs generally deemed it acceptable to use video or telephone, postpone or cancel appointments for a short term, and in a crisis situation. They experienced relational and technical limitations with video consultation, while diagnostic uncertainty was not regarded as a prominent issue CONCLUSION: This study demonstrates how the GPs experienced telephone and video consultations as being useful in a pandemic situation when face-to-face consultations had to be severely restricted. The GPs did, however, identify several limitations similar to those known in non-pandemic times. The weighing of pros and cons and their willingness to use these alternatives shifted and generally diminished when face-to-face consultations were once again deemed viable. In case of future pandemics, such alternatives seem valuable, at least for a short term.

Purpose: The purpose of this study is to develop a Pandemic Risk Exposure Measurement (PREM) model to determine the factors that affect a countrys prospective vulnerability to a pandemic risk exposure also considering the current COVID-19 pandemic Methods: To develop the model, drew up an inventory of possible factor variables that might expose a countrys vulnerability to a pandemic such as COVID-19 This model was based on the analysis of existing literature and consultations with some experts and associa-tions To support the inventory of selected possible factor variables, we have conducted a survey with participants sampled from people working in a risk management environment carrying out a risk management function The data were subjected to statistical analysis, specifically exploratory factor analysis and Cronbach Alpha to determine and group these factor variables and determine their reliability, respectively This enabled the development of the PREM model To eliminate possible bias, hierarchical regression analysis was carried out to examine the effect of the Level of Experienced Hazard of the Participant (LEH) considering also the Level of Expertise and Knowledge about Risk and Risk Management (LEK) Results: Exploratory factor analysis loaded best on four factors from 19 variables: Demographic Features, Countrys Activity Features, Economic Exposure and Societal Vulnerability (i e the PREM Model) This model explains 65 5% of the variance in the level of experienced hazard (LEH) Additionally, we determined that LEK explains only about 2% of the variance in LEH Conclusion: The developed PREM model shows that monitoring of Demographic Features, Countrys Activity Features, Economic Exposure and Societal Vulnerability can help a country to identify the possible impact of pandemic risk exposure and develop policies, strategies, regulations, etc , to help a country strengthen its capacity to meet the economic, social and in turn healthcare demands due to pandemic hazards such as COVID-19

Immunosuppressive and immunomodulatory treatments are critical for the management of inflammatory and autoimmune conditions such as psoriasis or psoriatic arthritis. Similar to those illnesses, the lung injury and acute respiratory distress shown in coronavirus disease 2019 (COVID-19) patients are the result of a disruption in the balance of pro- and anti-inflammatory cytokines. This hyperinflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), associated with the severity of the coronavirus disease, is called the cytokine storm. There is a growing concern regarding how patients on immunosuppressant biologic therapies might be at higher risk of being infected and whether they need to discontinue their treatment preemptively. Clinical data on COVID-19-infected patients with psoriasis or psoriatic arthritis are still scarce. Here, we presented seven cases of these type of patients. The patient infected with COVID-19 on apremilast and the one on apremilast with infected spouse showed the best safety profile and mildest symptoms. One of the secukinumab patients also presented a relatively good outcome. Infliximab patients and the one with serious comorbidities showed the worst outcome. Even though more clinical data are yet needed to draw strong conclusions, apremilast could be a safer alternative for dermatology and rheumatology patients in case of clinically important active infection.