Acute Aseptic Meningitis Temporally Associated with Intravenous Polyclonal Immunoglobulin Therapy: A Systematic Review.

An acute aseptic meningitis has been occasionally observed on intravenous polyclonal human immunoglobulin therapy. Since case reports cannot be employed to draw inferences about the relationships between immunoglobulin therapy and meningitis, we conducted a systematic review and meta-analysis of the literature. Eligible were cases, case series, and pharmacovigilance studies. We found 71 individually documented cases (36 individuals ≤ 18 years of age) of meningitis. Ninety percent of cases presented ≤ 3 days after initiating immunoglobulin therapy and recovered within ≤ 7 days (with a shorter disease duration in children: ≤ 3 days in 29 (94%) cases). In 22 (31%) instances, the authors noted a link between the onset of meningitis and a rapid intravenous infusion of immunoglobulins. Cerebrospinal fluid analysis revealed a predominantly neutrophilic (N = 46, 66%) pleocytosis. Recurrences after re-exposure were observed in eight (N = 11%) patients. Eight case series addressed the prevalence of meningitis in 4089 patients treated with immunoglobulins. A pooled prevalence of 0.6% was noted. Finally, pharmacovigilance data revealed that meningitis temporally associated with intravenous immunoglobulin therapy occurred with at least five different products. In conclusion, intravenous immunoglobulin may cause an acute aseptic meningitis. The clinical features remit rapidly after discontinuing the medication.

Valproic Acid-Associated Acute Pancreatitis: Systematic Literature Review.

Long-term medication with valproic acid has been associated with acute pancreatitis. The purpose of this report is to gain insight into the features of this pancreatitis. A preregistered literature search (CRD42023438294) was performed on the National Library of Medicine, Excerpta Medica, Web of Science, and Google Scholar. Patients with alcohol abuse disorder, gallstone disease, hypertriglyceridemia or hypercalcemia, patients with acute valproic acid intoxication, and patients with a pre-existing pancreatitis were excluded. For the final analysis, we retained 73 reports published between 1979 and 2023, which described 125 subjects (83 children and 42 adults predominantly affected by an epilepsy) with an acute pancreatitis related to valproic acid. The diagnosis was made 11 (3.0-24) months (median and interquartile range) after starting valproic acid. One hundred and five cases (84%) recovered and twenty (16%) died. Sex, age, dosage or circulating level of valproic acid, latency time, prevalence of intellectual disability, and antiepileptic co-medication were similar in cases with and without a lethal outcome. Nineteen subjects were rechallenged with valproic acid after recovery: sixteen (84%) cases developed a further episode of pancreatitis. In conclusion, pancreatitis associated with valproic acid presents at any time during treatment and has a high fatality rate.

Propofol-Associated Urine Discoloration: Systematic Literature Review.

INTRODUCTION: Propofol occasionally induces a green or pink-cloudy urine discoloration. A lesser-known effect is green discoloration of hair, milk, liver, or stool. We aimed to gain insight into the features of these disturbances. METHODS: The terms ("propofol" OR "fospropofol") AND ("green" OR "pink" OR "cloudy" OR "pink-cloudy") were searched in Excerpta Medica, MEDLINE/PubMed®, and Web of Sciences databases, with no language limit, from inception up to February 2023 (CRD4202236804). Articles reporting individually documented cases were retained, and data were extracted using a checklist. RESULTS: Seventy-seven original reports documented 95 cases (including 13 subjects ≤18 years of age). Completeness of reporting was satisfactory in 33, good in 35, and excellent in 27 cases. Propofol-associated green urine discoloration was observed in 54 patients. In most instances (n = 21, 39%), propofol was given for ≥24 h. Sometimes, however, the urine discoloration developed after propofol for ≤3 h (n = 12, 22%). Propofol-associated urine discoloration was usually observed during the administration of this agent, but it was at times (n = 11) first recognized ≥3 h after propofol discontinuation. The duration of green urine discoloration was usually ≤24 h after stopping propofol. Propofol-associated green urine discoloration was never associated with worsening kidney function. A pink-cloudy urine discoloration was observed in 32 subjects with an acidic urine pH and increased uric acid excretion given propofol for ≤24 h. A stage I acute kidney injury was observed in 2 cases (6.3%) of propofol-associated pink-cloudy urine discoloration. Nine cases of non-urinary green discoloration were observed: hair (n = 4), breast milk (n = 1), liver (n = 1), stool (n = 1). CONCLUSION: Propofol is sometimes associated with a green (benign) or pink-cloudy (occasionally associated with mild acute kidney injury) urine discoloration. Rarely, non-urinary green discoloration has been reported.

Splenic rupture or infarction associated with Epstein-Barr virus infectious mononucleosis: a systematic literature review.

BACKGROUND: Epstein-Barr virus (EBV), also known as human herpesvirus 4, is one of the most common pathogenic viruses in humans. EBV mononucleosis always involves the spleen and as such it predisposes to splenic rupture, often without a trauma, and splenic infarction. Nowadays the goal of management is to preserve the spleen, thereby eliminating the risk of post-splenectomy infections. METHODS: To characterise these complications and their management, we performed a systematic review (PROSPERO CRD42022370268) following PRISMA guidelines in three databases: Excerpta Medica, the United States National Library of Medicine, and Web of Science. Articles listed in Google Scholar were also considered. Eligible articles were those describing splenic rupture or infarction in subjects with Epstein-Barr virus mononucleosis. RESULTS: In the literature, we found 171 articles published since 1970, documenting 186 cases with splenic rupture and 29 with infarction. Both conditions predominantly occurred in males, 60% and 70% respectively. Splenic rupture was preceded by a trauma in 17 (9.1%) cases. Approximately 80% (n = 139) of cases occurred within three weeks of the onset of mononucleosis symptoms. A correlation was found between the World Society of Emergency Surgery splenic rupture score, which was retrospectively calculated, and surgical management: splenectomy in 84% (n = 44) of cases with a severe score and in 58% (n = 70) of cases with a moderate or minor score (p = 0.001). The mortality rate of splenic rupture was 4.8% (n = 9). In splenic infarction, an underlying haematological condition was observed in 21% (n = 6) of cases. The treatment of splenic infarction was always conservative without any fatal outcomes. CONCLUSIONS: Similarly to traumatic splenic rupture, splenic preservation is increasingly common in the management of mononucleosis-associated cases as well. This complication is still occasionally fatal. Splenic infarction often occurs in subjects with a pre-existing haematological condition.

Atypical primary varicella rash: Systematic literature review.

AIM: In previously healthy subjects, primary varicella presents with a distinctive vesicular rash that is more intense on the trunk and head than on the extremities. However, an atypical presentation may occasionally develop. We aimed at systematically assessing the characteristics of cases affected by atypical primary varicella rash. METHODS: The United States National Library of Medicine, Excerpta Medica and Web of Science databases were reviewed, without date or language restrictions. Articles were eligible if reporting previously healthy and immunocompetent subjects with a primary varicella rash (i.e., a photo-localised primary varicella or skin inflammation-associated primary varicella). RESULTS: Thirty-eight reports providing information on 59 cases of atypical primary varicella were identified. Twenty-four cases (median 8.5 years of age, 19 females) were photo-localised and 35 (median 4.8 years of age, 15 females) were associated with pre-existing skin inflammation (including cast occlusion, diaper irritation, operative sites, burns, insect bites, vaccinations or pre-existing skin disease). The skin rash was monomorphic and without a "starry sky" appearance. CONCLUSION: Primary varicella may have a modified presentation in areas of irritation such as sun exposure or pre-existing inflammation. There is a need for a wider awareness of these modulators of varicella rash.

An Adolescent With Intermittent Claudication.

ABSTRACT: Intermittent claudication is very uncommon in children and adolescents. We describe the case of a 14-year-old adolescent girl experiencing left calf pain for a year that occurs during running and becomes unbearable after around 2 km. She was ultimately diagnosed with extrinsic compression of the popliteal artery caused by an osteocartilaginous exostosis (osteochondroma) originating from the fibula.

Magnesium Metabolism in Chronic Alcohol-Use Disorder: Meta-Analysis and Systematic Review.

Chronic alcohol-use disorder has been imputed as a possible cause of dietary magnesium depletion. The purpose of this study was to assess the prevalence of hypomagnesemia in chronic alcohol-use disorder, and to provide information on intracellular magnesium and on its renal handling. We carried out a structured literature search up to November 2020, which returned 2719 potentially relevant records. After excluding non-significant records, 25 were retained for the final analysis. The meta-analysis disclosed that both total and ionized circulating magnesium are markedly reduced in chronic alcohol-use disorder. The funnel plot and the Egger's test did not disclose significant publication bias. The I2-test demonstrated significant statistical heterogeneity between studies. We also found that the skeletal muscle magnesium content is reduced and the kidney's normal response to hypomagnesemia is blunted. In conclusion, magnesium depletion is common in chronic alcohol-use disorder. Furthermore, the kidney plays a crucial role in the development of magnesium depletion.

Which laboratory technique is used for the blood sodium analysis in clinical research? A systematic review.

BACKGROUND: Circulating sodium is analyzed by flame spectrometry and indirect or direct potentiometry. The differences between estimates returned by the three techniques are often relevant. It is unknown whether peer-reviewed international publications focusing on this parameter provide information about the technique. Objectives of the study were to ascertain if information about the employed technique is provided. CONTENT: A search in the National Library of Medicine for articles whose title contains "hyponatr[a]emia" was performed. We restricted the search to clinical reports including 10 or more humans published in the 2013-2015 and 2017-2019 periods. Authors of papers not reporting the technique were contacted to obtain this information. The study design and journal quartile ranking of each article were also evaluated. SUMMARY: For the final analysis, we included 361 articles (2013-2015, n=169; 2017-2019, n=192). Information about the laboratory technique was given in 61(17%) articles. Thanks to our inquiry, we collected this information for 116(32%) further reports. Indirect potentiometry was the most frequently used technique, followed by direct potentiometry. Spectrometry was used in a small minority of studies. Study design, journal ranking and study period did not modulate the mentioned frequency. OUTLOOK: Most articles focusing on hyponatremia do not provide information on the laboratory technique. This parameter is nowadays analyzed by indirect or, less frequently, direct potentiometry. The figures are similar for high and low impact factor journals and for the 2013-2015 and the 2017-2019 periods. Many authors, reviewers and editors likely assume that the results of this parameter are not influenced by the technique.

Atypical Bacterial Pathogens and Small-Vessel Leukocytoclastic Vasculitis of the Skin in Children: Systematic Literature Review.

Leukocytoclastic small-vessel vasculitis of the skin (with or without systemic involvement) is often preceded by infections such as common cold, tonsillopharyngitis, or otitis media. Our purpose was to document pediatric (≤18 years) cases preceded by a symptomatic disease caused by an atypical bacterial pathogen. We performed a literature search following the Preferred Reporting of Systematic Reviews and Meta-Analyses guidelines. We retained 19 reports including 22 cases (13 females and 9 males, 1.0 to 17, median 6.3 years of age) associated with a Mycoplasma pneumoniae infection. We did not find any case linked to Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Francisella tularensis, or Legionella pneumophila. Patients with a systemic vasculitis (N = 14) and with a skin-limited (N = 8) vasculitis did not significantly differ with respect to gender and age. The time to recovery was ≤12 weeks in all patients with this information. In conclusion, a cutaneous small-vessel vasculitis with or without systemic involvement may occur in childhood after an infection caused by the atypical bacterial pathogen Mycoplasma pneumoniae. The clinical picture and the course of cases preceded by recognized triggers and by this atypical pathogen are indistinguishable.

Trimethoprim-associated electrolyte and acid-base abnormalities.

INTRODUCTION: The antimicrobial trimethoprim is structurally related to potassium-sparing diuretics and may consequently lead to derangements in electrolyte and acid-base balance. Since no report so far analyzed the literature documenting individual cases with electrolyte and acid-base derangements induced by trimethoprim, a systematic review was carried out. EVIDENCE ACQUISITION: We retained 53 reports documenting 68 cases (42 males and 26 females 23 to 96 years of age) of electrolyte or acid-base derangements occurring on trimethoprim for about 5 days. EVIDENCE SYNTHESIS: One hundred five electrolyte imbalances were detected in the 68 patients: hyperkalemia (>5.0 mmol/L) in 62 (91%), hyponatremia (<135 mmol/L) in 29 (43%) and metabolic acidosis (pH<7.38 and bicarbonate <19 mmol/L) in 14 (21%) cases. Following possible predisposing factors for electrolyte and acid-base abnormalities were found in 54 (79%) patients: high-dose trimethoprim, comedication with drugs that have been associated with electrolyte and acid-base derangements, preexisting kidney disease, age ≥80 years and diabetes mellitus. CONCLUSIONS: High-dose trimethoprim, comedicated with drugs that have been associated with electrolyte and acid-base derangements, poor kidney function, age ≥80 years and diabetes mellitus predispose to trimethoprim-associated electrolyte and acid-base abnormalities. Clinicians must recognize patients at risk, possibly avoid drug combinations that may worsen the problem and monitor the laboratory values.

Myositis and acute kidney injury in bacterial atypical pneumonia: Systematic literature review.

BACKGROUND: Bacterial community-acquired atypical pneumonia is sometimes complicated by a myositis or by a renal parenchymal disease. Available reviews do not mention the concurrent occurrence of both myositis and acute kidney injury. METHODS: In order to characterize the link between bacterial community-acquired atypical pneumonia and both myositis and a renal parenchymal disease, we reviewed the literature (United States National Library of Medicine and Excerpta Medica databases). RESULTS: We identified 42 previously healthy subjects (35 males and 7 females aged from 2 to 76, median 42 years) with a bacterial atypical pneumonia associated both with myositis (muscle pain and creatine kinase ≥5 times the upper limit of normal) and acute kidney injury (increase in creatinine to ≥1.5 times baseline or increase by ≥27 µmol/L above the upper limit of normal). Thirty-six cases were caused by Legionella species (N = 27) and by Mycoplasma pneumoniae (N = 9). Further germs accounted for the remaining 6 cases. The vast majority of cases (N = 36) presented a diffuse myalgia. Only a minority of cases (N = 3) were affected by a calf myositis. The diagnosis of rhabdomyolysis-associated kidney injury was retained in 37 and that of acute interstitial nephritis in the remaining 5 cases. CONCLUSION: Bacterial atypical pneumonia may occasionally induce myositis and secondary kidney damage.

Breastfeeding-Associated Hypernatremia: A Systematic Review of the Literature.

There are increasing reports on hypernatremia, a potentially devastating condition, in exclusively breastfed newborn infants. Our purposes were to describe the clinical features of the condition and identify the risk factors for it. We performed a review of the existing literature in the National Library of Medicine database and in the search engine Google Scholar. A total of 115 reports were included in the final analysis. Breastfeeding-associated neonatal hypernatremia was recognized in infants who were ≤ 21 days of age and had ≥ 10% weight loss of birth weight. Cesarean delivery, primiparity, breast anomalies or breastfeeding problems, excessive prepregnancy maternal weight, delayed first breastfeeding, lack of previous breastfeeding experience, and low maternal education level were significantly associated with breastfeeding-associated hypernatremia. In addition to excessive weight loss (≥ 10%), the following clinical findings were observed: poor feeding, poor hydration state, jaundice, excessive body temperature, irritability or lethargy, decreased urine output, and epileptic seizures. In conclusion, the present survey of the literature identifies the following risk factors for breastfeeding-associated neonatal hypernatremia: cesarean delivery, primiparity, breastfeeding problems, excessive maternal body weight, delayed breastfeeding, lack of previous breastfeeding experience, and low maternal education level.

Acute hemorrhagic edema of young children: a prospective case series.

UNLABELLED: Acute hemorrhagic edema of young children is a rare leukocytoclastic vasculitis that has been reported exclusively in small retrospective cases series, case reports, or quizzes. Considering that retrospective experience deserves confirmation in at least one observational prospective study, we present our experience with 16 children (12 boys and 4 girls, 5-28 months of age) affected by acute hemorrhagic edema. The patients were in good general conditions and with a low-grade or even absent fever. They presented with non-itching red to purpuric targetoid lesions not changing location within hours, with non-pitting and sometimes tender indurative swelling, and without mucous membrane involvement or scratch marks. Signs for articular, abdominal, or kidney involvement were absent. Antinuclear or antineutrophil cytoplasmic autoantibodies were never detected. The cases were managed symptomatically as outpatients and fully resolved within 4 weeks or less. No recurrence or familiarity was noted. CONCLUSION: This is the first prospective evaluation of hemorrhagic edema. Our findings emphasize its distinctive tetrad: a well-appearing child; targetoid lesions that do not change location within hours; non-pitting, sometimes tender edema; complete resolution without recurrence. What is known • Acute hemorrhagic edema of young children is considered a benign vasculitis. • There have been ≈100 cases reported in small retrospective case series. What is new • The first prospective evaluation of this condition emphasizes its features: febrile prodrome; well-appearing child; targetoid lesions not changing location within hours; non-pitting, sometimes tender indurative edema; absent extracutaneous involvement; resolution within 3 weeks. • Antineutrophil cytoplasmic autoantibodies do not play a pathogenic role.

Gallbladder and Pancreas in Henoch-Schönlein Purpura: Review of the Literature.

OBJECTIVE: Involvement of the pancreato-biliary system has been occasionally noted in Henoch-Schönlein purpura. Furthermore, cases of this vasculitis syndrome sometimes develop in the context of a viral hepatitis or after hepatitis vaccination. METHODS: We completed a review of the literature. RESULTS: Fifty reports published between 1977 and 2015 were retained for the analysis. A pancreato-biliary involvement was recognized in 34 individually well-described patients (♂:♀ = 19:15) with severe abdominal pain: pancreatitis (N = 20), acalculous cholecystitis (N = 11), both pancreatitis and cholecystitis (N = 3). In all of the pancreatitis patients, full recovery occurred (within ≤3 weeks in three-fourths of the patients). Cholecystectomy was performed in 8 cholecystitis patients. Seventeen Henoch-Schönlein patients (♂:♀ = 9:8) were associated with a viral liver disease and 4 (♂:♀ = 1:3) with a hepatitis vaccination. The vasculitis syndrome rapidly remitted in the 7 patients accompanying hepatitis A or E, in 2 patients of hepatitis B, and in the 4 patients preceded by a vaccination. Henoch-Schönlein purpura seemed to be serious in 5 patients with chronic hepatitis B and in 3 with chronic hepatitis C. CONCLUSIONS: This analysis indicates that pancreato-biliary involvement is unusual in Henoch-Schönlein purpura. This complication deserves consideration in patients with especially severe abdominal pain. Finally, viral hepatitides and hepatitis vaccinations seem to be rare triggers of Henoch-Schönlein purpura.

Micro- and macroscopic hematuria caused by renal vein entrapment: systematic review of the literature.

BACKGROUND: Hematuria secondary to renal vein entrapment is mentioned only passing in textbooks and reviews. METHODS: We performed a search of the National Library of Medicine database for peer-reviewed publications using the terms "renal vein" or "nutcracker" and "hematuria". RESULTS: We identified 187 published reports/studies that covered 736 patients, of whom 288 had microscopic hematuria and 448 had macroscopic hematuria. The patient cohort comprised 159 patients aged ≤17 years. Abdominal pain was absent in approximately 65% of all patients, and a clinically relevant left-sided varicocele was observed in 29% of the male patients. A normal pre-aortic left renal vein and an anomalous anatomy were noted in 680 and 56 patients, respectively. The body mass index (BMI) was lower in patients with renal vein entrapment than in the controls, with a regression of hematuria correlating with an increase in BMI. A surgical procedure was attempted in 34% of the patients, of which the most common were endovascular stenting and transposition of the renal vein distally into the vena cava. CONCLUSIONS: In cases of unexplained hematuria with or without abdominal pain, clinicians should consider the diagnosis of renal vein congestion, especially in males with varicocele. Ultrasonic Doppler flow scanning is the recommended initial diagnostic modality in these patients. Expectation management is advised in the great majority of cases.

Italo-Swiss "Chalk and blackboard interactive 2-day workshop"-participants feedback.

Ten "chalk and blackboard interactive workshops" have taken place between 2011 and 2015 in Southern Switzerland or Italy. Students, residents and expert pediatricians meet during 2 days and discuss 10-15 cases. Pediatricians promote reasoning, provide supporting information and correct statements. Emphasis is placed on history taking and examination, and on all participants being involved in a stimulating atmosphere. Thirty-seven participants were asked, ≥3 months after workshop-completion, to evaluate the workshop and a recent teaching session. Thirty answered and scored the workshop as excellent (N = 24) or above average (N = 6). The scores assigned to the workshop were higher (P < 0.001) than those assigned to the lecture-based teaching.

Hypomagnesemia Induced by Long-Term Treatment with Proton-Pump Inhibitors.

In 2006, hypomagnesemia was first described as a complication of proton-pump inhibitors. To address this issue, we systematically reviewed the literature. Hypomagnesemia, mostly associated with hypocalcemic hypoparathyroidism and hypokalemia, was reported in 64 individuals on long-term proton-pump inhibitors. Hypomagnesemia recurred following replacement of one proton-pump inhibitor with another but not with a histamine type-2 receptor antagonist. The association between proton-pump inhibitors and magnesium metabolism was addressed in 14 case-control, cross-sectional studies. An association was found in 11 of them: 6 reports found that the use of proton-pump inhibitors is associated per se with a tendency towards hypomagnesemia, 2 found that this tendency is more pronounced in patients concurrently treated with diuretics, carboplatin, or cisplatin, and 2 found a relevant tendency to hypomagnesemia in patients with poor renal function. Finally, findings likely reflecting decreased intestinal magnesium uptake were observed on treatment with proton-pump inhibitors. Three studies did not disclose any relationship between magnesium metabolism and treatment with histamine type-2 receptor antagonists. In conclusion, proton-pump inhibitors may cause hypomagnesemia. In these cases, switching to a histamine type-2 receptor antagonist is advised.

Unusual Eruptions Associated with Mycoplasma pneumoniae Respiratory Infections: Review of the Literature.

BACKGROUND: Maculopapular or urticarial eruptions and erythema multiforme sometimes occur in patients affected with Mycoplasma pneumoniae respiratory infections. Further eruptions have also been reported. OBJECTIVE: To review the literature addressing M. pneumoniae respiratory infection and rather unusual eruptions. METHODS: Computer-based search in the U.S. National Library of Medicine database as well as in the search engine Google. RESULTS: We found a possible relationship between M. pneumoniae infection and Fuchs' syndrome (n = 37), varicella-like eruptions (n = 8), Henoch-Schönlein syndrome and further leukocytoclastic vasculitides (n = 21) and erythema nodosum (n = 11). A temporal relationship was also observed with 2 cases of Gianotti-Crosti syndrome. Finally, there exists reasonable evidence that pityriasis rosea Gibert and pityriasis lichenoides et varioliformis acuta Mucha-Habermann are not associated with Mycoplasma infections. CONCLUSION: This review implies that M. pneumoniae may cause, in addition to erythematous maculopapular (or urticarial) eruptions and erythema multiforme, Fuchs' syndrome and varicella-like eruptions. Furthermore, there is an intriguing link with leukocytoclastic vasculitides or erythema nodosum that deserves further investigation.

The great fluid debate: saline or so-called "balanced" salt solutions?

BACKGROUND: Intravenous fluids are commonly prescribed in childhood. 0.9 % saline is the most-used fluid in pediatrics as resuscitation or maintenance solution. Experimental studies and observations in adults suggest that 0.9 % saline is a poor candidate for fluid resuscitation. Although anesthesiologists, intensive care specialists, perioperative physicians and nephrologists have been the most active in this debate, this issue deserves some physiopathological considerations also among pediatricians. RESULTS: As compared with so-called "balanced" salt crystalloids such as lactated Ringer, administration of large volumes of 0.9 % saline has been associated with following deleterious effects: tendency to hyperchloremic metabolic acidosis (called dilution acidosis); acute kidney injury with reduced urine output and salt retention; damaged vascular permeability and stiffness, increase in proinflammatory mediators; detrimental effect on coagulation with tendency to blood loss; detrimental gastrointestinal perfusion and function; possible uneasiness at the bedside resulting in unnecessary administration of more fluids. Nevertheless, there is no firm evidence that these adverse effects are clinically relevant. CONCLUSIONS: Intravenous fluid therapy is a medicine like insulin, chemotherapy or antibiotics. Prescribing fluids should fit the child's history and condition, consider the right dose at the right rate as well as the electrolyte levels and other laboratory variables. It is unlikely that a single type of fluid will be suitable for all pediatric patients. "Balanced" salt crystalloids, although more expensive, should be preferred for volume resuscitation, maintenance and perioperatively. Lactated Ringer appears unsuitable for patients at risk for brain edema and for those with overt or latent chloride-deficiency. Finally, in pediatrics there is a need for new fluids to be developed on the basis of a better understanding of the physiology and to be tested in well-designed trials.