Tackling social disconnection: an umbrella review of RCT-based interventions targeting social isolation and loneliness.

BACKGROUND: Social isolation and loneliness are urgent public health concerns associated with negative physical and mental health outcomes. Understanding effective remedies is crucial in addressing these problems. This umbrella review aimed to synthesize and critically appraise scientific evidence on the effectiveness of social isolation and loneliness interventions overall and across subgroups. We focused on systematic reviews (SRs) of randomized controlled trials (RCTs). METHODS: We searched seven databases (June 2022 and updated June 2023) and supplemented the search with grey literature and reference screening to identify SRs published since 2017. Screening, data extraction, and quality assessment using the AMSTAR2 tool were conducted independently by author pairs, with disagreements resolved through discussion. RESULTS: We included 29 SRs, 16 with meta-analysis and 13 with narrative synthesis. All SRs focused on loneliness, with 12 additionally examining social isolation. Four SRs focused on young people, 11 on all ages, and 14 on older adults. The most frequently examined intervention types were social (social contact, social support), psychological (therapy, psychoeducation, social skills training), and digital (e.g., computer use and online support). Meta-analyses indicated small-to-moderate beneficial effects, while narrative synthesis demonstrated mixed or no effect. Social interventions for social isolation and psychological interventions for loneliness were the most promising. However, caution is warranted due to the effects' small magnitude, significant heterogeneity, and the variable quality of SRs. Digital and other interventions showed mixed or no effect; however, caution is advised in interpreting these results due to the highly diverse nature of the interventions studied. CONCLUSIONS: This overview of SRs shows small to moderate effectiveness of social interventions in reducing social isolation and psychological ones in tackling loneliness. Further rigorously conducted RCTs and SRs are needed to guide policy decisions regarding the implementation of efficacious and scalable interventions. Evaluation should focus on both preventive structural interventions and tailored mitigating strategies that address specific types and causes of loneliness.

General practitioner consultations for mental health reasons prior to and following bereavement by suicide.

PURPOSE: Prior research has shown that the majority of those bereaved by suicide express a need for mental health care services. However, there is a lack of knowledge about these individuals' use of primary health care. The objective of our study was to estimate the association between suicide bereavement and general practitioner (GP) consultations for mental health reasons. METHODS: A population-wide, register-based cohort study identifying 25,580 individuals bereaved by suicide. Estimations of increases in consultation rate were modeled through individual fixed-effects linear analyses adjusted for age and time-period. RESULTS: Overall, 35% of those bereaved by suicide had a GP consultation for mental health reasons during the first 1-2 months, and 53% after two years. In the month immediately after bereavement by suicide, there was a large increase in the consultation rate with a GP for mental health reasons. In the months that followed, the consultation rate gradually decreased. One year after bereavement, the consultation rate stabilized at a somewhat higher level than before the death. The increase in consultation rate was evident across all kinship groups, and the increase was greatest for partners and smallest for siblings. Women had more contact with the GP before the suicide and a greater increase in contact than men. CONCLUSION: Our findings suggest that many of those bereaved by suicide seek assistance from primary health care, and that some are in need of prolonged follow-up from the GP. Health governments should be aware of this and seek to strengthen the GPs knowledge of the needs and challenges associated with this patient group. Measures should also be taken to remove barriers to contact the health care system, especially for men and bereaved siblings.

Variations in healthcare utilization for mental health problems prior to suicide by socioeconomic status: a Norwegian register-based population study.

BACKGROUND: Suicide poses a major public health challenge, claiming around 650 lives annually in Norway. There is limited understanding of mental healthcare utilization patterns preceding suicide, particularly relating to socioeconomic status (SES). This study analyzes mental health service use among Norwegian citizens aged 20-64 from 2009 to 2021, emphasizing disparities related to SES. METHODS: This is a population-wide registry-based study. We include mental health consultations with both primary and specialist healthcare services, and investigate patterns of service use regarding educational attainment, employment status and income and compare this to the population in general. All suicides in the period (N = 4731) are included in the study. The aim is to investigate potential discrepancies in service use the year and month preceding suicide, seeking to enhance targeted preventive interventions. RESULTS: Our results show significant variations in healthcare use for mental health problems the last year preceding suicide, according to the components of SES, for both men and women. Those with higher education utilize the mental healthcare services prior to suicide to a higher degree than men and women with high school education or less, whereas employed men and men with high income level have significantly lower mental healthcare usage prior to suicide both the last year and month compared to the non-employed men and men with low-income level. Employed women also had a lower mental healthcare usage, whereas the results regarding income are not significant for women. CONCLUSION: Mental healthcare use prior to suicide varies across the SES components. Notably, the SES groups exhibit heterogeneity, with gendered patterns. Targeted interventions for low consultation rates among employed men, and men with high income and lower education are needed, while women, and men in at-risk groups, such as the non-employed and those with low income, demonstrate higher mental healthcare utilization, warranting comprehensive suicide prevention measures.

Widening the knowledge of non-employment as a risk factor for suicide: a Norwegian register-based population study.

BACKGROUND: There is a known association between employment status and suicide risk. However, both reason for non-employment and the duration affects the relationship. These factors are investigated to a lesser extent. About one third of the Norwegian working age population are not currently employed. Due to the share size of this population even a small increase in suicide risk is of importance, and hence increased knowledge about this group is needed. METHODS: We used discrete time event history analysis to examine the relationship between suicide risk and non-employment due to either unemployment or health-problems, and the duration of these non-employment periods. We analyze data from the Norwegian population registry from 2004 to 2014, which includes all Norwegian residents in the ages 19-58 born between 1952 and 1989. In total the data consists of 1 063 052 men and 1 024 238 women, and 2 039 suicides. RESULTS: The suicide risk among the non-employed men and women is significantly higher than that of the employed. For the unemployed men, the suicide risk is significantly higher than the employed within the first 18 months. For the unemployed women we only find a significant association with suicide risk among those unemployed for six to twelve months. The suicide risk is especially increased among those with temporary health-related benefits. In the second year of health-related non-employment men have eightfold and women over twelvefold the OR for suicide, compared to the employed. CONCLUSION: There is an association between non-employment and suicide risk. Compared to the employed both unemployed men and men and women with health-related non-employment have elevated suicide risk, and the duration of non-employment may be the driving force. Considering the large share of the working age population that are not employed, non-employment status should be considered in suicide risk assessment by health care professionals and welfare providers.

Allocating operating room capacity to non-elective neurosurgical patients improves access and safety for elective patients at Aarhus University Hospital.

INTRODUCTION: This study addresses surgical scheduling within the Department of Neurosurgery at Aarhus University Hospital (AUH). The department provides neurosurgical care to a population of 1.3 million in central Denmark, and has treatment obligations for specific neurosurgical diseases for the entire country, which has a population of 5.8 million. Efficient utilisation of the department's four operating suites is crucial to ensure that patients have timely access to both non-elective and elective neurosurgical procedures. Historically, the elective operating room (OR) schedule was made without consideration of the possible arrival of non-elective patients; consequently, elective surgeries were often cancelled to accommodate those with more urgent indications. The challenge was thus to introduce a structured way of planning for these non-elective surgical procedures that would minimise the need for cancelling elective surgeries without decreasing overall productivity. METHODS: Using a mathematical model developed in a previous study at Leiden University Medical Center, the effect of allocating OR time during regular working hours for non-elective neurosurgical procedures at AUH was analysed, so that a weighted trade-off could be made between cancellations of elective patients due to an overflow of non-elective patients and unused OR time due to excessive reservation of time for non-elective patients. This allocation was tested in a six-week pilot study during weeks 24 & 25 and weeks 34-37 of 2020 before being implemented in 2021. RESULTS: In the 35 weeks following the implementation, the new allocation strategy resulted in a significant 77% decrease in the cancellation of elective neurosurgical procedures when compared with the same time period in 2019, with a significant 16% increase in surgical productivity. CONCLUSIONS: This study shows that with mathematical modelling complex problems in the distribution of neurosurgical OR capacity can be solved, improving both patient safety and the working environment of neurosurgeons and OR staff.

Amphiphilic Cyclodextrin Nanoparticles as Delivery System for Idebenone: A Preformulation Study.

Idebenone (IDE), a synthetic short-chain analogue of coenzyme Q10, is a potent antioxidant able to prevent lipid peroxidation and stimulate nerve growth factor. Due to these properties, IDE could potentially be active towards cerebral disorders, but its poor water solubility limits its clinical application. Octanoyl-ß-cyclodextrin is an amphiphilic cyclodextrin (ACyD8) bearing, on average, ten octanoyl substituents able to self-assemble in aqueous solutions, forming various typologies of supramolecular nanoassemblies. Here, we developed nanoparticles based on ACyD8 (ACyD8-NPs) for the potential intranasal administration of IDE to treat neurological disorders, such as Alzheimer's Disease. Nanoparticles were prepared using the nanoprecipitation method and were characterized for their size, zeta potential and morphology. STEM images showed spherical particles, with smooth surfaces and sizes of about 100 nm, suitable for the proposed therapeutical aim. The ACyD8-NPs effectively loaded IDE, showing a high encapsulation efficiency and drug loading percentage. To evaluate the host/guest interaction, UV-vis titration, mono- and two-dimensional NMR analyses, and molecular modeling studies were performed. IDE showed a high affinity for the ACyD8 cavity, forming a 1:1 inclusion complex with a high association constant. A biphasic and sustained release of IDE was observed from the ACyD8-NPs, and, after a burst effect of about 40%, the release was prolonged over 10 days. In vitro studies confirmed the lack of toxicity of the IDE/ACyD8-NPs on neuronal SH-SY5Y cells, and they demonstrated their antioxidant effect upon H2O2 exposure, as a general source of ROS.

Met and unmet need for mental health care before and during the COVID-19 pandemic.

There is a concern that the coronavirus disease 2019 (COVID-19) pandemic will generate large unmet needs for mental health care. Using data from an epidemiological psychiatric diagnostic interview survey (n = 2159) conducted on a probability sample from the general population, the proportions of met and unmet need for mental health care among individuals with and without mental disorders were compared before and during the COVID-19 pandemic. The results showed no statistical difference in met and unmet need for mental health care, but point estimates were suggestive of a higher unmet need for care among those with a current mental disorder after the lock-down period.

Prognostic and discriminative accuracy of the quick Sepsis-related Organ Failure Assessment compared with an early warning score: a Danish cohort study.

BACKGROUND: The clinical benefit of implementing the quick Sepsis-related Organ Failure Assessment (qSOFA) instead of early warning scores (EWS) to screen all hospitalised patients for critical illness has yet to be investigated in a large, multicentre study. METHODS: We conducted a cohort study including all hospitalised patients ≥18 years with EWS recorded at hospitals in the Central Denmark Region during the year 2016. The primary outcome was intensive care unit (ICU) admission and/or death within 2 days following an initial EWS. Prognostic accuracy was examined using sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV). Discriminative accuracy was examined by the area under the receiver operating characteristic curve (AUROC). RESULTS: Among 97 332 evaluated patients, 1714 (1.8%) experienced the primary outcome. The qSOFA ≥2 was less sensitive (11.7% (95% CI: 10.2% to 13.3%) vs 25.1% (95% CI: 23.1% to 27.3%)) and more specific (99.3% (95% CI: 99.2% to 99.3%) vs 97.5% (95% CI: 97.4% to 97.6%)) than EWS ≥5. The NPV was similar for the two scores (EWS ≥5, 98.6% (95% CI: 98.6% to 98.7%) and qSOFA ≥2, 98.4% (95% CI: 98.3% to 98.5%)), while the PPV was 15.1% (95% CI: 13.8% to 16.5%) for EWS ≥5 and 22.4% (95% CI: 19.7% to 25.3%) for qSOFA ≥2. The AUROC was 0.72 (95% CI: 0.70 to 0.73) for EWS and 0.66 (95% CI: 0.65 to 0.67) for qSOFA. CONCLUSION: The qSOFA was less sensitive (qSOFA ≥2 vs EWS ≥5) and discriminatively accurate than the EWS for predicting ICU admission and/or death within 2 days after an initial EWS. This study did not support replacing EWS with qSOFA in all hospitalised patients.

Fibrin Network Formation and Lysis in Septic Shock Patients.

BACKGROUND: Septic shock patients are prone to altered fibrinolysis, which contributes to microthrombus formation, organ failure and mortality. However, characterisation of the individual patient's fibrinolytic capacity remains a challenge due to a lack of global fibrinolysis biomarkers. We aimed to assess fibrinolysis in septic shock patients using a plasma-based fibrin clot formation and lysis (clot-lysis) assay and investigate the association between clot-lysis parameters and other haemostatic markers, organ dysfunction and mortality. METHODS: This was a prospective cohort study including adult septic shock patients (n = 34). Clot-lysis was assessed using our plasma-based in-house assay. Platelet count, activated partial thromboplastin time (aPTT), international normalised ratio (INR), fibrinogen, fibrin D-dimer, antithrombin, thrombin generation, circulating fibrinolysis markers and organ dysfunction markers were analysed. Disseminated intravascular coagulation score, Sequential Organ Failure Assessment (SOFA) score and 30-day mortality were registered. RESULTS: Three distinct clot-lysis profiles emerged in the patients: (1) severely decreased fibrin formation (flat clot-lysis curve), (2) normal fibrin formation and lysis and (3) pronounced lysis resistance. Patients with abnormal curves had lower platelet counts (p = 0.05), more prolonged aPTT (p = 0.04), higher lactate (p < 0.01) and a tendency towards higher SOFA scores (p = 0.09) than patients with normal clot-lysis curves. Fibrinogen and fibrin D-dimer were not associated with clot-lysis profile (p ≥ 0.37). CONCLUSION: Septic shock patients showed distinct and abnormal clot-lysis profiles that were associated with markers of coagulation and organ dysfunction. Our results provide important new insights into sepsis-related fibrinolysis disturbances and support the importance of assessing fibrinolytic capacity in septic shock.

The Effect of α-, ß- and γ-Cyclodextrin on Wheat Dough and Bread Properties.

Cyclodextrins (CDs) are cyclic oligosaccharides that have found widespread application in numerous fields. CDs have revealed a number of various health benefits, making them potentially useful food supplements and nutraceuticals. In this study, the impact of α-, ß-, and γ-CD at different concentrations (up to 8% of the flour weight) on the wheat dough and bread properties were investigated. The impact on dough properties was assessed by alveograph analysis, and it was found that especially ß-CD affected the viscoelastic properties. This behavior correlates well with a direct interaction of the CDs with the proteins of the gluten network. The impact on bread volume and bread staling was also assessed. The bread volume was in general not significantly affected by the addition of up to 4% CD, except for 4% α-CD, which slightly increased the bread volume. Larger concentrations of CDs lead to decreasing bread volumes. Bread staling was investigated by texture analysis and low field nuclear magnetic resonance spectroscopy (LF-NMR) measurements, and no effect of the addition of CDs on the staling was observed. Up to 4% CD can, therefore, be added to wheat bread with only minor effects on the dough and bread properties.

Parental mortality following the loss of a child to a drug-related death.

BACKGROUND: The drug-related death of a child has been linked to higher prevalence of complicated grief and mental health problems than bereavement by other causes of death. Whether this leads to an increased risk of mortality following the loss has not yet been examined. METHODS: Employing register data covering the years 1986-2015 and encompassing the entire Norwegian population, parents with at least one child aged 15 or older were analyzed using Cox regression. Drug-death bereaved parents were compared with both non-bereaved parents and parents bereaved by other causes of death. RESULTS: Parents bereaved by a drug-related death generally had a higher natural cause mortality throughout the follow-up. Drug-death bereaved parents had a particularly high external cause mortality in the first 2 years subsequent to bereavement when compared with non-bereaved parents (mothers: hazard ratio 4.82, 95% CI = 3.11-7.47; fathers: hazard ratio 2.50, 95% CI = 1.57-3.97). There was also an elevated, but significantly lower mortality risk from external causes 2 to 10 years subsequent to bereavement. This indicates that the associations observed are not solely due to selection. CONCLUSIONS: Parents bereaved by the drug-related death of a child had a higher mortality than both non-bereaved parents and parents bereaved by other causes of death. Drug-death bereaved parents had particularly high external cause mortality. Our results indicate that losing a child to a drug-related death is associated with adverse health outcomes and that these might be more severe than bereavement due to other causes of death.

Quantum dots-ßcyclodextrin-histidine labeled human adipose stem cells-laden chitosan hydrogel for bone tissue engineering.

Mesenchymal stem cells with differentiation ability to diverse cells play a crucial role in tissue engineering. Tracking the fate of these cells during the regeneration of tissue helps to obtain more information about their function. In this study, histidine conjugated ß-cyclodextrin as a cell-penetrating carrier with drug loading ability was attached to QDs nanoparticle (QD-ßCD-His) for stem cell labeling. Traceability of QD-ßCD-His labeled human adipose stem cells (hASCs) was monitored in 2D cell culture and 3D temperature-sensitive chitosan hydrogel scaffold. Dexamethasone (Dex) as an osteoinductive drug was loaded into QD-ßCD-His nano-carrier (QD-ßCD-His@Dex) to induce bone differentiation of labeled cells. Overall results indicated that QD-ßCD-His@Dex is a promising dual-purpose nano-carrier for stem cell labeling with osteoinductive potential in cell therapy as well as tissue engineering scaffolds.

Contact with primary and mental health care prior to suicide: A systematic review of the literature from 2000 to 2017.

AIM: To examine rates of contact with primary and mental health care prior to suicide in men and women and across a range of age categories. METHOD: The authors performed a systematic review of 44 studies from 2000 to 2017 of which 36 reported rates on contact with primary health care and 14 reported on contact with mental health care prior to suicide. RESULTS: Contact with primary health care was highest in the year prior to suicide with an average contact rate of 80%. At one month, the average rate was 44%. The lifetime contact rate for mental health care was 57%, and 31% in the final 12 months. In general, women and those over 50 years of age had the highest rates of contact with health care prior to suicide. CONCLUSIONS: Contact with primary health care prior to suicide is common even in the final month before death. The findings presented in this study highlight the importance of placing suicide prevention strategies and interventions within the primary health care setting.

Use of primary health care services prior to suicide in the Norwegian population 2006-2015.

BACKGROUND: Studies report high rates of contact with general practitioners (GPs) in primary care in the time leading up to suicide, particularly among individuals with a history of mental health contact. However, the near lack of studies including population representative controls have prevented investigations into how the contact patterns of suicide victims compares to those of the general population. METHODS: By linking data from two national registries, this study investigated primary health care use in suicide victims aged 15 years and older during the period from 2007 to 2015 (n = 4926). Their rates of contact one year and one month prior to suicide were compared to the average rates in the general Norwegian population during the period by estimating relative risks across sex and age. Contact patterns one month prior to suicide were also investigated according to prior mental health consultations in primary care. RESULTS: The findings revealed a stable trend in contact with GPs in primary care during the observation period, with 79.6% of male and 89.0% of female suicide victims having consulted their GP within a year of the suicide. Corresponding rates one month prior to the suicide were 34.8 and 46.4%, respectively. At both points in time and across all age groups, suicide victims were considerably more likely to consult their GP than were the general population. Suicide victims without prior mental health contact were only modestly more likely to consult their GP within a month of the suicide as compared to the general population, while both the general population and suicide victims with prior mental health consultations had rates of contact well above those without, evident for both sexes. CONCLUSIONS: Contact with GPs in primary care prior to suicide is common in both sexes and across most age groups, in particular for victims with prior mental health consultations. Younger males show the overall lowest rates of contact, and increased alternative efforts to reach this group, in addition to larger population strategies, may pose the most prominent preventive measures.

Site-specific photocoupling of pBpa mutated scFv antibodies for use in affinity proteomics.

Recombinant antibody libraries can provide a source of renewable and high-performing binders tailored for use in affinity proteomics. In this context, the process of generating site-specific 1:1 tagging/functionalization and/or orientated surface immobilization of antibodies has, however, proved to be challenging. Hence, novel ways of generating such engineered antibodies for use in affinity proteomics could have a major impact on array performance. In this study, we have further tailored the design of human recombinant scFv antibodies for site-specific photocoupling through the use of an unnatural amino acid (UAA) and the Dock'n'Flash technology. In more detail, we have generated the 2nd generation of scFvs carrying the photoreactive UAA p-benzoyl-l-phenylalanine (pBpa). Based on key properties, such as expression levels, activity, and affinity, a preferred choice of site for pBpa, located in the beginning of the C-terminal affinity-tag, was for the first time pin-pointed. Further, the results showed that pBpa mutated antibody could be site-specifically photocoupled to free and surface immobilized ß-cyclodextrin (an affinity ligand to pBpa). This paves the way for use of scFv antibodies, engineered for site-specific photochemical-based tagging, functionalization, and orientated surface immobilization, in affinity proteomics.

Emotional and behavioral problems in late preterm and early term births: outcomes at child age 36 months.

BACKGROUND: Recent findings has shown that late preterm births (gestational weeks 34-36) and early term births (gestational weeks 37-38) is associated with an increased risk of several psychological and developmental morbidities. In this article we investigate whether late preterm and early term births is associated with an increased risk of emotional and behavioral problems at 36 months of age and whether there are gender differences in risk of these outcomes. METHODS: Forty-three thousand, two hundred ninety-seven children and their mothers participating in the Norwegian Mother and Child Cohort Study (MoBa). One thousand, eight hundred fifty-three (4.3%) of the children in the sample were born late preterm and 7,835 (18.1%) were born early term. Information on gestational age and on prenatal and postnatal risk factors was retrieved from the Medical Birth Registry of Norway. Information on emotional and behavioral problems was assessed by standardized questionnaires (CBCL/ITSEA) filled out by the mothers. Gender-stratified logistic regression analyses were used to explore the association between late preterm / early term and emotional and behavioral problems at 36 months of age. RESULTS: We found a gender-specific increased risk of emotional problems in girls born late preterm (OR 1.47 95%CI 1.11-1.95) and in girls born early term (OR 1.21 95%CI 1.04-1.42). We did not find an increased risk of emotional problems in boys born late preterm (OR 1.09 95%CI 0.82-1.45) or early term (OR 0.93 95%CI 0.79-1.10). Behavioral problems were not increased in children born late preterm or early term. CONCLUSION: Girls born late preterm and early term show an increased risk of emotional problems at 36 months of age. This finding suggests that gender should be taken into account when evaluating children born at these gestational ages.

Molecular design of recombinant scFv antibodies for site-specific photocoupling to ß-cyclodextrin in solution and onto solid support.

The ability to design and tailor-make antibodies to meet the biophysical demands required by the vast range of current and future antibody-based applications within biotechnology and biomedicine will be essential. In this proof-of-concept study, we have for the first time tailored human recombinant scFv antibodies for site-specific photocoupling through the use of an unnatural amino acid (UAA) and the dock'n'flash technology. In more detail, we have successfully explored the possibility to expand the genetic code of E. coli and introduced the photoreactive UAA p-benzoyl-L-phenylalanine (pBpa), and showed that the mutated scFv antibody could be expressed in E. coli with retained structural and functional properties, as well as binding affinity. The pBpa group was then used for affinity capture of the mutated antibody by ß-cyclodextrin (ß-CD), which provided the hydrogen atoms to be abstracted in the subsequent photocoupling process upon irradiation at 365nm. The results showed that the pBpa mutated antibody could be site-specifically photocoupled to free and surface (array) immobilized ß-CD. Taken together, this paves the way for novel means of tailoring recombinant scFv antibodies for site-specific photochemical-based tagging, functionalization and immobilization in numerous applications.

Invasive Candida infections and the harm from antibacterial drugs in critically ill patients: data from a randomized, controlled trial to determine the role of ciprofloxacin, piperacillin-tazobactam, meropenem, and cefuroxime.

OBJECTIVE: Use of antibiotics in critically ill patients may increase the risk of invasive Candida infection. The objective of this study was to determine whether increased exposure to antibiotics is associated with increased prevalence of invasive Candida infection. DESIGN: Substudy using data from a randomized controlled trial, the Procalcitonin And Survival Study 2006-2010. SETTING: Nine multidisciplinary ICUs across Denmark. PATIENTS: A total of 1,200 critically ill patients. INTERVENTION: Patients were randomly allocated to either a "high exposure" antibiotic therapy (intervention arm, n = 604) or a "standard exposure" guided by current guidelines (n = 596). MEASUREMENTS AND MAIN RESULTS: Seventy-four patients met the endpoint, "invasive Candida infection," 40 in the high exposure arm and 34 in standard exposure arm (relative risk = 1.2; 95% CI, 0.7-1.8; p = 0.52). Among medical patients in the high exposure arm, the use of ciprofloxacin and piperacillin/tazobactam was 51% and 75% higher than in the standard exposure arm; no difference in antibiotic exposure was observed between the randomized arms in surgical patients. Among medical intensive care patients, invasive Candida infection was more frequent in the high exposure arm (6.2%; 27/437) than in standard exposure arm (3.3%; 14/424) (hazard ratio = 1.9; 95% CI, 1.0-3.6; p = 0.05). Ciprofloxacin used at study entry independently predicted invasive Candida infection (adjusted hazard ratio = 2.1 [1.1-4.1]); the risk gradually increased with duration of ciprofloxacin therapy: six of 384 in patients not exposed (1.6%), eight of 212 (3.8%) when used for 1-2 days (hazard ratio = 2.5; 95% CI, 0.9-7.3), and 31 of 493 (6.3%) when used for 3 days (hazard ratio = 3.8; 95% CI, 1.6-9.3; p = 0.002). Patients with any ciprofloxacin-containing antibiotic regimen the first 3 days in the trial had a higher risk of invasive Candida infection than did patients on any antibiotic regimen not containing ciprofloxacin (unadjusted hazard ratio = 3.7; 95% CI, 1.6-8.7; p = 0.003; adjusted hazard ratio, 3.4; 95% CI, 1.4-8.0; p = 0.006). CONCLUSIONS: High exposure to antibiotics is associated to increased risk of invasive Candida infection in medical intensive care patients. Patients with ciprofloxacin-containing regimens had higher risk of invasive Candida infection. Other antibiotics, such as meropenem, piperacillin/tazobactam, and cefuroxime, were not associated with such a risk.