Search

Background: Chronic infectious diseases are increasingly being considered as potential contributors to dementia risk. Among those infections, Helicobacter pylori, the main cause of chronic gastritis worldwide, has been suggested. As the prevalence of H. pylori infection has decreased, the main objective of this work was to reconsider the association between H. pylori infection and the risk of incident dementia, including Alzheimer's disease. Methods: Prospective cohort of 689 older (≥65 years) agricultural workers from Southwest France. Descriptive and comparative analyses were performed according to H. pylori status determined by serology at baseline. The risk of incident dementia according to H. pylori status over a 7‐year follow‐up was explored by survival analyses: Kaplan–Meier curve and Cox proportional hazards models. Results: Two‐hundred (29.0%) participants were H. pylori‐positive at baseline. Compared to H. pylori‐negative participants, they showed worse cognitive performances at baseline. Eighty‐five incident dementia cases were diagnosed during the follow‐up period. After adjustment for age, sex, education, apolipoprotein ε4, and several cardiovascular risk factors, H. pylori remained associated with an increased risk of dementia (HR 1.70, 95% CI, 1.05–2.74). The risk was stronger for Alzheimer's disease (HR 2.85, 95% CI, 1.58–5.12). Conclusions: Despite an observed decrease in H. pylori infection prevalence, this study provides evidence for the association between H. pylori infection and dementia. These results should encourage further research on the mechanisms underlying the contribution of infectious diseases to pathological brain aging, especially the influence of gut inflammation on the brain. [ABSTRACT FROM AUTHOR]

Background: In geriatrics, explicit criteria for potentially inappropriate prescriptions (PIPs) are useful for optimizing drug use. Objective: To produce an expert consensus on explicit definitions of antibiotic-PIPs for hospitalized older patients. Methods: We conducted a Delphi survey involving French experts on antibiotic stewardship in hospital settings. During the survey's rounds, the experts gave their opinion on each explicit definition, and could suggest new definitions. Definitions with a 1-to-9 Likert score of between 7 and 9 from at least 75% of the participants were adopted. The results were discussed during consensus meetings after each round. Results: Of the 155 invited experts, 128 (82.6%) participated in the whole survey: 59 (46%) infectious diseases specialists, 45 (35%) geriatricians, and 24 (19%) other specialists. In Round 1, 65 explicit definitions were adopted and 21 new definitions were suggested. In Round 2, 35 other explicit definitions were adopted. The results were validated during consensus meetings (with 44 participants after Round 1, and 54 after Round 2). Conclusions: The present study is the first to have provided a list of explicit definitions of potentially inappropriate antibiotic prescriptions for hospitalized older patients. It might help to disseminate key messages to prescribers and reduce inappropriate prescriptions of antibiotics. [ABSTRACT FROM AUTHOR]

Background Infective endocarditis (IE) is increasingly affecting older patients. However, data on their management are sparse, and the benefits of surgery in this population are unclear. Methods We included patients with left-sided IE (LSIE) aged ≥ 80 years enrolled in a prospective endocarditis cohort managed in Acquitaine, France, from 2013 to 2020. Geriatric data were collected retrospectively to identify factors associated with the 1-year risk of death using Cox regression. Results We included 163 patients with LSIE (median age, 84 years; men, 59%; rate of prosthetic LSIE, 45%). Of the 105 (64%) patients with potential surgical indications, 38 (36%) underwent valve surgery: they were younger, more likely to be men with aortic involvement, and had a lower Charlson comorbidity index. Moreover, they had better functional status at admission (ie, the ability to walk unassisted and a higher median activities of daily living [ADL] score; n = 5/6 vs 3/6, P =.01). The 1-year mortality rate in LSIE patients without surgical indications was 28%; it was lower in those who were operated on compared with those who were not despite a surgical indication (16% vs 66%, P <.001). Impaired functional status at admission was strongly associated with mortality regardless of surgical status. In patients unable to walk unassisted or with an ADL score <4, there was no significant surgical benefit for 1-year mortality. Conclusions Surgery improves the prognosis of older patients with LSIE and good functional status. Surgical futility should be discussed in patients with altered autonomy. The endocarditis team should include a geriatric specialist. [ABSTRACT FROM AUTHOR]

In June 2021, a cluster of seven cases of Campylobacter fetus infections occurred in a rehabilitation center and caused significant morbidity in elderly patients including five with bacteremia and two with osteoarticularmedical device infections. The genetic identity identified by whole genome sequencing of the different Campylobacter fetus strains confirms a common source. This foodborne illness outbreak may have resulted from the consumption of unpasteurized dairy products, such as a cow's raw milk cheese resulting from a farm-to-fork strategy. [ABSTRACT FROM AUTHOR]

Objectives: Age-related physiological changes, particularly immune system decline, may contribute to greater vulnerability to infectious diseases in older individuals. A growing body of evidence shows that both, acute, and chronic infections may be accompanied by cognitive disturbances as part of their manifestations. Given the importance of cognition in aging trajectories, the objective of this article was to review current knowledge on cognitive outcomes of infectious diseases in older adults, and to emphasize the importance of considering cognition as a domain of interest in its own rights in these diseases. Methods: A MEDLINE/PubMed database search was conducted to identify articles reporting cognitive impairment associated with various severe acute infections and specific chronic infectious conditions such as human immune deficiency virus, the herpes virus family, hepatitis C virus, Lyme borreliosis, Helicobacter pylori, periodontitis, and emerging pathogens like SARS-CoV-2, as well as potentially preventive strategies like vaccination. Results/ Conclusions: Taken together, the studies examined in the present review emphasize that numerous acute and chronic infectious diseases share mechanisms that, when added to specific risk factors frequently found in older persons, contribute to considerably increase the risk of cognitive outcomes such as cognitive decline and dementia. This review may help to appreciate the role that infectious diseases play in cognitive trajectories and thus promote further investigation on the topic. [ABSTRACT FROM AUTHOR]

Background: Vitamin D supplementation has been proposed as a treatment for Coronavirus Disease 2019 (COVID-19) based on experimental data and data from small and uncontrolled observational studies. The COvid19 and VITamin d TRIAL (COVIT-TRIAL) study was conducted to test whether a single oral high dose of cholecalciferol (vitamin D3) administered within 72 hours after the diagnosis of COVID-19 improves, compared to standard-dose cholecalciferol, the 14-day overall survival among at-risk older adults infected with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Methods and findings: This multicenter, randomized, controlled, open-label, superiority trial involved collaboration of 9 medical centers in France. Patients admitted to the hospital units or living in nursing homes adjacent to the investigator centers were eligible if they were ≥65 years, had SARS-CoV-2 infection of less than 3 days, and at least 1 COVID-19 worsening risk factor (among age ≥75 years, SpO2 ≤94%, or PaO2/FiO2 ≤300 mm Hg). Main noninclusion criteria were organ failure requiring ICU, SpO2 ≤92% despite 5 L/min oxygen, life expectancy <3 months, vitamin D supplementation >800 IU/day during the preceding month, and contraindications to vitamin D supplements. Eligible and consenting patients were randomly allocated to either a single oral high-dose (400,000 IU) or standard-dose (50,000 IU) cholecalciferol administered under medical supervision within 72 hours after the diagnosis of COVID-19. Participants and local study staff were not masked to the allocated treatment, but the Steering Committee and the Data and Safety Monitoring Board were masked to the randomization group and outcome data during the trial. The primary outcome was 14-day overall mortality. Between April 15 and December 17, 2020, of 1,207 patients who were assessed for eligibility in the COVIT-TRIAL study, 254 met eligibility criteria and formed the intention-to-treat population. The median age was 88 (IQR, 82 to 92) years, and 148 patients (58%) were women. Overall, 8 (6%) of 127 patients allocated to high-dose cholecalciferol, and 14 (11%) of 127 patients allocated to standard-dose cholecalciferol died within 14 days (adjusted hazard ratio = 0.39 [95% confidence interval [CI], 0.16 to 0.99], P = 0.049, after controlling for randomization strata [i.e., age, oxygen requirement, hospitalization, use of antibiotics, anti-infective drugs, and/or corticosteroids] and baseline imbalances in important prognostic factors [i.e., sex, ongoing cancers, profuse diarrhea, and delirium at baseline]). The number needed to treat for one person to benefit (NNTB) was 21 [NNTB 9 to ∞ to number needed to treat for one person to harm (NNTH) 46]. Apparent benefits were also found on 14-day mortality due to COVID-19 (7 (6%) deaths in high-dose group and 14 (11%) deaths in standard-dose group; adjusted hazard ratio = 0.33 [95% CI, 0.12 to 0.86], P = 0.02). The protective effect of the single oral high-dose administration was not sustained at 28 days (19 (15%) deaths in high-dose group and 21 (17%) deaths in standard-dose group; adjusted hazard ratio = 0.70 [95% CI, 0.36 to 1.36], P = 0.29). High-dose cholecalciferol did not result in more frequent adverse effects compared to the standard dose. The open-label design and limited study power are the main limitations of the study. Conclusions: In this randomized controlled trial (RCT), we observed that the early administration of high-dose versus standard-dose vitamin D3 to at-risk older patients with COVID-19 improved overall mortality at day 14. The effect was no longer observed after 28 days. Trial registration: ClinicalTrials.gov NCT04344041. In a randomized trial, Cedric Annweiler and colleagues evaluate whether a single high dose of vitamin D3 improves survival among older adults in France with SARS-CoV-2 infection. Author summary: Why was this study done?: Preclinical data suggest that vitamin D may attenuate the effects of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by exerting anti-inflammatory effects and by regulating the renin–angiotensin system, thus potentially preventing the cytokine storm and its lethal consequences. Observational studies have reported that, while accounting for confounders, participants with lower 25-hydroxyvitamin D (25(OH)D) concentrations were more likely to progress to severe forms of Coronavirus Disease 2019 (COVID-19) and to die from COVID-19. Observational studies have also found that vitamin D3 supplementation prior to or during COVID-19 was associated with improved survival in older adults with COVID-19. Clinical trials to evaluate the impact on survival of high-dose vitamin D supplementation in COVID-19 patients have yet not been performed. What did the researchers do and find?: In this multicenter, open-label, randomized controlled trial (RCT), we randomly assigned 254 at-risk older adults with COVID-19 to a single oral high-dose (400,000 IU) or standard-dose (50,000 IU) vitamin D3 administered within 72 hours after the diagnosis of COVID-19, with 14-day survival as the primary outcome. We found that the early administration of 400,000 IU versus 50,000 IU vitamin D3 to at-risk older patients with COVID-19 was associated with reduced overall mortality at day 14. The protective effect was not sustained at 28 days. High-dose cholecalciferol did not result in more frequent adverse effects compared to the standard dose. What do these findings mean?: In the absence of toxicity and given the benefits of high-dose vitamin D found on 14-day mortality, a combination therapy with both standard treatments for COVID-19 and high doses of vitamin D3 may be proposed to at-risk older patients with COVID-19 within the first hours of the infection. The lack of protection after 28 days should encourage examination of the possible benefit of a continuous daily (or weekly) vitamin D supplementation following the initial loading dose. Our study was not designed to determine whether vitamin D supplementation helps with prevention of SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Background: Post-stroke comorbid cognitive impairment and depression (PSCCID) is a severe neuropsychiatric complication after acute stroke. Gut microbiota dysbiosis is associated with many psychiatric disorders. Alterations in the composition of gut microbiota may serve as a critical role in patients with PSCCID.Objective: We aimed to characterize the microbial profiles of patients with PSCCID.Method: A total of 175 stroke patients were recruited in the study. The composition of gut bacterial communities of patients was determined by 16S ribosomal RNA Miseq sequencing, and Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was used to demonstrate the functional alterations of gut microbiota. We further identified the characteristic gut microbiota of PSCCID using linear discriminant analysis effect size.Results: Patients with PSCCID exhibited an increased abundance of Proteobacteria, including Gammaproteobacteria, Enterobacteriales, and Enterobacteriaceae, and a decreased abundance of several short-chain fatty acids-producing bacteria compared with non-PSCCID patients. The abundance of Gammaproteobacteria and Enterobacteriaceae showed negative correlations with the MoCA score. Moreover, the Kyoto Encyclopedia of Genes and Genomes results demonstrated the enriched orthologs of glycan biosynthesis and metabolism and decreased orthologs of amino acid metabolism in PSCCID patients. Importantly, the characteristic gut microbiota was identified and achieved an area under the curve of 0.847 between the two groups.Conclusion: In this study, we characterized the gut microbiota of PSCCID patients, and revealed the correlations of the altered gut microbiota with clinical parameters, which took a further step towards non-invasive diagnostic biomarkers for PSCCID from fecal samples. [ABSTRACT FROM AUTHOR]

Despite extensive research, the origin of Alzheimer's disease (AD) remains unknown. The role of infectious pathogens has recently emerged. Epidemiological studies have shown that Helicobacter pylori infection increases the risk of developing AD. We hypothesized that H. pylori-induced gastritis may be associated with a systemic inflammation and finally neuroinflammation. C57BL/6 mice were infected with H. pylori (n = 15) or Helicobacter felis (n = 13) or left uninfected (n = 9) during 18 months. Gastritis, amyloid deposition, astroglial and microglial cell area, and systemic and brain cytokines were assessed. The infection (H. felis> H. pylori) induced a severe gastritis and an increased neuroinflammation but without brain amyloid deposition or systemic inflammation. [ABSTRACT FROM AUTHOR]

Background: Antibiotic administration by subcutaneous (SC) injection is common practice in French geriatric wards as an alternative to the intravenous (IV) route, but few pharmacokinetic/pharmacodynamic data are available. Ertapenem is useful for the treatment of infections with ESBL-producing enterobacteria.Objectives: To report and compare ertapenem pharmacokinetic data between IV and SC routes in older persons.Methods: Patients >65 years of age receiving ertapenem (1 g once daily) for at least 48 h (IV or SC, steady-state) were prospectively enrolled. Total ertapenem concentrations [residual (C0), IV peak (C0.5) and SC peak (C2.5)] were determined by UV HPLC. Individual-predicted AUC0-24 values were calculated and population pharmacokinetic analyses were performed. Using the final model, a Monte Carlo simulation involving 10 000 patients evaluated the influence of SC or IV administration on the PTA. Tolerance to ertapenem and recovery were also monitored. ClinicalTrials.gov identifier: NCT02505386.Results: Ten (mean ± SD age=87±7 years) and 16 (age=88±5 years) patients were included in the IV and SC groups, respectively. The mean C0 and C2.5 values were not significantly different between the IV and SC groups (C0=12±5.9 versus 12±7.4 mg/L, P=0.97; C2.5=97±42 versus 67±41 mg/L, P=0.99). The mean C0.5 was higher in the IV group compared with the SC group (C0.5=184±90 versus 51±66 mg/L, P=0.001). The mean individual AUCs (1126.92±334.99 mg·h/L for IV versus 1005.3±266.0 mg·h/L for SC, P=0.38) and PTAs were not significantly different between groups. No severe antibiotic-related adverse effects were noted.Conclusions: SC administration of ertapenem is an alternative to IV administration in older patients. [ABSTRACT FROM AUTHOR]

Background: In older patients, the agreement is low between creatinine clearance estimated with the Cockcroft-Gault equation (eCrCl) and glomerular filtration rate estimated with the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI). The implications of these discrepancies for drug prescription have so far been assessed only for a few selected molecules.Objective: The aim of this study was to investigate the proportion of geriatric patients receiving drugs with a different recommended dose or indication (i.e. an adjustment discrepancy) depending on eCrCl versus eGFRCKD-EPI estimates of kidney function.Methods: Patients admitted to acute geriatric care units in our university hospital were eligible for inclusion. All drug classes were studied. We retrospectively determined recommended prescriptions according to eCrCl and eGFRCKD-EPI.Results: Sixty percent of patients received at least one drug requiring dose adjustment and/or received a drug with a relative contraindication based on their estimated kidney function. Thirty-one percent of patients received at least one drug with an adjustment discrepancy: 20% received at least one drug for which the recommended dose differed depending on eCrCl versus eGFRCKD-EPI estimates of kidney function, 4% received a drug with a relative contraindication according to eCrCl but not eGFRCKD-EPI, and 7% received both. Factors independently associated with an adjustment discrepancy were older age and lower weight. Main drug classes involved were benzodiazepines, anticoagulants, and anti-microbial drugs.Conclusion: In acute geriatric care units, recommended drug dose adjustments are frequently discordant according to the equations used to estimate kidney function, notably for benzodiazepines, anticoagulants, and anti-microbial drugs. The consequences for treatment efficacy and safety should be investigated. [ABSTRACT FROM AUTHOR]

The incidence of infective endocarditis (IE) rises in industrialized countries. Older people are more affected by this severe disease, notably because of the increasing number of invasive procedures and intracardiac devices implanted in these patients. Peculiar clinical and echocardiographic features, microorganisms involved, and prognosis of IE in elderly have been underlined in several studies. Additionally, elderly population appears quite heterogeneous, from healthy people without past medical history to patients with multiple diseases or who are even bedridden. However, the management of IE in this population has been poorly explored, and international guidelines do not recommend adapting the therapeutic strategy to the patient's functional status and comorbidities. Yet, if IE should be treated according to current recommendations in the healthiest patients, concerns may rise for older patients who suffer from several chronic diseases, especially renal failure, and are on polypharmacy. Treating frailest patients with high-dose intravenous antibiotics during a prolonged hospital stay as recommended for younger patients could also expose them to functional decline and toxic effect. Likewise, the place of surgery according to the aging characteristics of each patient is unclear. The aim of this article is to review the recent data on epidemiology of IE and its peculiarities in the elderly. Then, its management and various therapeutic approaches that can be considered according to and beyond guidelines depending on patient comorbidities and frailty are discussed. [ABSTRACT FROM AUTHOR]

In the last year, several diseases from outside of the gastrointestinal tract have been associated with Helicobacter pylori infection. Indeed, this bacterium produces a low-grade inflammatory state, induces molecular mimicry mechanisms, and interferes with the absorbance of nutrients and drugs possibly influencing the occurrence or the evolution of many diseases. In addition to its role in some hematologic conditions, such as immune thrombocytopenic purpura, idiopathic sideropenic anemia, and vitamin B12 deficiency, which were included in the current guidelines, several other conditions such as cardiovascular diseases, diabetes mellitus, hepatobiliary diseases, and neurologic disorders have also shown promising results. [ABSTRACT FROM AUTHOR]

Objectives To determine whether Helicobacter pylori infection was associated with dementia and risk of developing dementia in a longitudinal population-based cohort of elderly adults living in the community. Design Prospective community-based cohort study. Setting The population-based Personnes Agées QUID ( PAQUID) Study. Participants Six hundred three noninstitutionalized individuals aged 65 and older living in the southwest of France followed from 1989 to 2008. Measurements A descriptive and comparative analysis including dementia prevalence, according to H. pylori status (serology), was made at baseline. Cox proportional hazard models were used to study the risk of developing dementia according to H. pylori status assessed on sera samples from elderly adults initially free of dementia and followed for 20 years. A neurologist diagnosed dementia according to Diagnostic and Statistical Manual of Mental Disorders Third Edition criteria. Results At baseline, 391 (64.8%) subjects (348 women, mean age 73.9 ± 6.5) were seropositive for H. pylori. Dementia prevalence was higher in the infected group (5.4% vs 1.4%, P = .02). After 20 years of follow-up, 148 incident cases of dementia were diagnosed. After controlling for age, sex, educational level, apolipoprotein E4 status, cardiovascular risk factors, and Mini- Mental State Examination score, H. pylori infection was determined to be a risk factor for developing dementia (hazard ratio = 1.46, P = .04). Conclusion This longitudinal population-based study provides additional epidemiological support to the hypothesis of an association between dementia and H. pylori infection, which may enhance neurodegeneration. [ABSTRACT FROM AUTHOR]

Depression symptoms and lower health-related quality of life (HRQoL) are associated with inflammation. This multicenter dietary intervention was shown to reduce inflammation in older people. This was the main outcome. Here, we describe the effects on HRQoL, anxiety, and depressive symptoms according to inflammation status. Overall, 125 healthy older subjects (65–80 year) were recruited (Italy, France, and Germany) and randomized into four arms (A, Healthy diet (HD); B, HD plus De Simone Formulation probiotic blend; C, HD plus AISA d-Limonene; D, HD plus Argan oil). The HD was weight maintaining, rich in antioxidant vitamins, polyphenols, polyunsaturated fatty acids (n6: n3 ratio = 3:1), and fiber. Data on inflammatory parameters, mental (MCS) and physical (PCS) component summaries of HRQoL (SF−36), anxiety symptoms (STAI state), and depressive symptoms (CES-D) were collected before and after 56 days of intervention. Body fat mass proportion (BFM) was considered a co-variable. A decrease of CES-D score was seen in the four arms (A: −40.0%, p = 0.001; B: −32.5%, p = 0.023; C: −42.8%, p = 0.004; and D: −33.3%, p = 0.21). Within the subgroups of subjects with medium/high inflammation a similar decrease in CES-D score occurred in all groups (A: −44.8%, p = 0.021; B, −46.7%, p = 0.024; C, −52.2%, p = 0.039; D, −43.8%, p = 0.037). The effect of interventions on CES-D was not related to baseline inflammation. MCS-HRQoL improved in A and C. There was no change in anxiety or PCS-HRQoL. In this trial with no control group, a decrease in depressive symptoms in healthy older volunteers was observed after a 2-month healthy diet intervention, independently of inflammation but with possible limitations due to participation. [ABSTRACT FROM AUTHOR]

In the last year, many studies have demonstrated a potential role of Helicobacter pylori in the pathogenic mechanisms of different extragastric diseases. While the role of H pylori in idiopathic thrombocytopenic purpura, idiopathic iron deficiency anemia, and vitamin B12 deficiency has already been demonstrated, there is growing evidence of other related conditions, especially cardiovascular, metabolic, and neurologic disorders, including neurodegenerative diseases. A summary of the results of the most relevant studies published over the last year on this attractive topic is presented in this review. [ABSTRACT FROM AUTHOR]

Abstract: Method: We reviewed retrospectively the demographic, clinical, biological characteristics and outcomes of 11 patients with HSV meningitis. Results: Among the 11 patients, six were infected with HIV, four had a documented history of genital herpes, and one recurrent meningitis. In all cases, the onset of symptoms was abrupt, with severe headache and fever. On admission, 9/11 patients had severe meningismus; two patients had HSV anogenital ulcerations. CSF analysis showed in every case a significant increased of leukocytes with a lymphocytic pleocytosis, a mild elevated protein level and a normal glucose level. HSV was detected in the CSF in every case by PCR: the typing performed on six patients was positive in every case for HSV-2. Intravenous acyclovir (IV ACV) was started in 10/11 cases (range: 3–10 days), switched to valaciclovir (VACV) (range: 5–7 days); one patient was treated with ACV per os for 10 days. The total resolution of symptoms occurred within 48hours in every case. Two patients presented with recurrent HSV-2 meningitis in the next two months, with favorable outcome under IV ACV: a switch to long term VACV 500mg/day was prescribed without any recurrence. No patient presented with recurrence after a median follow-up of 30 months. Conclusion: Early recognition and treatment might improve the outcome of such infections. Adjunctive oral VACV after IV ACV treatment seems to be associated with a good clinical response in patients presenting with HSV meningitis. The duration of such treatments, including prophylactic treatments to prevent recurrent episodes must be better documented. [Copyright &y& Elsevier]

To describe the rationale for subcutaneous (SC) administration of antibiotics from available published data and to make propositions to help clinicians in daily practice. Narrative review. Hospitalized patients, persons in long-term care facilities and ambulatory care. We searched the MEDLINE/PubMed electronic database for evidence supporting SC administration of antibiotics up to September 2019; the results of this primary search were supplemented by searching the references of the identified articles, as well as by searching in Google Scholar. Regarding tolerability, efficacy, and pharmacokinetic/pharmacodynamic profiles, most studies suggest that the SC route could be an alternative to the intravenous route, particularly for time-dependent antibiotics and among certain patient populations, such as patients with poor venous access, swallowing disorders, or behavioral disturbance. However, clinical evidence of the benefits and risks of SC antibiotic administration is still scarce and of low level. SC administration of antibiotics may be useful in various settings such as in hospitalized patients and among those in long-term care facilities or being cared for at home. However, further clinical studies are needed to assess the pharmacokinetic/pharmacodynamic properties, as well as the risks and benefits of SC administration of antibiotics. In this review, we highlight the potential benefits of SC administration of antibiotics and address practical recommendations for its use. This information will enable improvement of treatment strategies and present the SC route as a potential option in specific situations. [ABSTRACT FROM AUTHOR]