Glucocorticoid withdrawal and glucocorticoid-induced adrenal insufficiency: Study protocol of the randomized controlled «TOASST" (Taper Or Abrupt Steroid STop) multicenter trial.

BACKGROUND: Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects. METHODS: We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis. CONCLUSION: This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1.

Admission kidney function is a strong predictor for the response to nutritional support in patients at nutritional risk.

BACKGROUND: Patients with chronic kidney disease (CKD) are at substantial risk of malnutrition, which negatively affects clinical outcomes. We investigated the association of kidney function assessed at hospital admission and effectiveness of nutritional support in hospitalized medical patients at risk of malnutrition. METHODS: This is a secondary analysis of an investigator-initiated, randomized-controlled, Swiss multicenter trial (EFFORT) that compared individualised nutritional support with usual hospital food on clinical outcomes. We compared effects of nutritional support on mortality in subgroups of patients stratified according to kidney function at the time of hospital admission (estimated glomerular filtration rates [eGFR] <15, 15-29, 30-59, 60-89 and ≥ 90 ml/min/1.73 m2). RESULTS: We included 1943 of 2028 patients (96%) from the original trial with known admission creatinine levels. Admission eGFR was a strong predictor for the beneficial effects of nutritional support in regard to lowering of 30-day mortality. Patients with an eGFR <15, 15-29 and 30-59 had the strongest mortality benefit (odds ratios [95%CI] of 0.24 [0.05 to 1.25], 0.37 [0.14 to 0.95] and 0.39 [0.21 to 0.75], respectively), while patients with less severe impairment in kidney function had a less pronounced mortality benefits (p for interaction 0.001). A similar stepwise association of kidney function and response to nutritional support was found also for other secondary outcomes. CONCLUSION: In medical inpatients at nutritional risk, admission kidney function was a strong predictor for the response to nutritional therapy. Initial kidney function may help to individualize nutritional support in the future by identification of patients with most clinical benefit. CLINICAL TRIAL REGISTRATION: Registered under ClinicalTrials.gov Identifier no. NCT02517476.

Nutritional risk screening (NRS 2002) is a strong and modifiable predictor risk score for short-term and long-term clinical outcomes: secondary analysis of a prospective randomised trial.

INTRODUCTION: The Nutritional Risk Screening 2002 (NRS 2002) identifies patients at risk of malnutrition. We studied the prognostic implications of this score with regard to short-term and long-term clinical outcomes in a well-characterised cohort of medical inpatients from a previous trial. METHODS: This is a secondary analysis of an investigator-initiated, prospective randomised controlled multicenter trial in Switzerland (EFFORT) that compared the effects of an individualised nutritional support intervention with standard of care. We investigated associations between admission NRS and several short-term and long-term outcomes using multivariable regression analyses. RESULTS: Of the 2028 patients, 31% had an NRS of 3, 38% of 4 and 31% of ≥5 points, and 477 (24%) died during the 180 days of follow-up. For each point increase in NRS, we found a stepwise increase in risk of 30-day mortality (adjusted Hazard Ratio (HR) 1.22 (95% CI 1.00 to 1.48), p = 0.048) and 180-day mortality (adjusted HR 1.37 (95% CI 1.22 to 1.55), p < 0.001). NRS was associated with length of hospital stay (adjusted difference of 0.60 days per NRS point increase, 95%CI 0.23 to 0.97, p = 0.002) and functional outcomes at 180 days (adjusted decrease in Barthel index of -4.49 points per NRS point increase, 95%CI -6.54 to -2.45, p < 0.001). In a subgroup analysis, associations of NRS and short-term adverse outcomes were less pronounced in patients receiving nutritional support (intervention group) compared to control group patients (adjusted HR for 30-day mortality 1.12 [95%CI 0.83 to 1.52, p = 0.454] vs. 1.33 [95%CI 1.02 to 1.72, p = 0.032]). CONCLUSION: The NRS is a strong and independent risk score for malnutrition-associated mortality and adverse outcomes over 180 days. Our data provide strong evidence that the nutritional risk, however, is modifiable and can be reduced by the provision of adequate nutritional support.

Psoas Abscess Due to Mycobacterium avium in A Patient with Chronic Lymphocytic Leukemia－Case Report and Review.

Infections may constitute a serious complication in patients with chronic lymphocytic leukemia (CLL). New treatment agents including obinutuzumab and ibrutinib have improved the progression-free survival in CLL, and data suggest a similar overall infection risk and a limited risk of opportunistic infections when compared to standard chemo-immunotherapy. Nevertheless, cases of opportunistic infections including non-tuberculous mycobacterial (NTM) in CLL patients have recently been published. We present a case of a 74-year old man with extensive prior CLL treatment history, including most recently obinutuzumab. He developed an abscess of the psoas muscle and inguinal lymphadenopathy. An inguinal node biopsy specimen showed infection with Mycobacterium avium, confirmed by broad-spectrum mycobacterial PCR, M. avium-specific PCR, and mycobacterial culture. This case and our literature review suggest that physicians should be aware of opportunistic infections in patients with CLL. Diagnostic differentiation from CLL disease progression, Richter's transformation to aggressive lymphoma, and secondary malignancy relies on histological and appropriate microbiological studies from biopsy material of affected organs. Infection prophylaxis in CLL should be considered, including vaccinations and intravenous immune globulin replacement.

ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis.

Peptide hormones are crucial regulators of many aspects of human physiology. Mutations that alter these signaling peptides are associated with physiological imbalances that underlie diseases. However, the conformational maturation of peptide hormone precursors (prohormones) in the ER remains largely unexplored. Here, we report that conformational maturation of proAVP, the precursor for the antidiuretic hormone arginine-vasopressin, within the ER requires the ER-associated degradation (ERAD) activity of the Sel1L-Hrd1 protein complex. Serum hyperosmolality induces expression of both ERAD components and proAVP in AVP-producing neurons. Mice with global or AVP neuron-specific ablation of Se1L-Hrd1 ERAD progressively developed polyuria and polydipsia, characteristics of diabetes insipidus. Mechanistically, we found that ERAD deficiency causes marked ER retention and aggregation of a large proportion of all proAVP protein. Further, we show that proAVP is an endogenous substrate of Sel1L-Hrd1 ERAD. The inability to clear misfolded proAVP with highly reactive cysteine thiols in the absence of Sel1L-Hrd1 ERAD causes proAVP to accumulate and participate in inappropriate intermolecular disulfide-bonded aggregates, promoted by the enzymatic activity of protein disulfide isomerase (PDI). This study highlights a pathway linking ERAD to prohormone conformational maturation in neuroendocrine cells, expanding the role of ERAD in providing a conducive ER environment for nascent proteins to reach proper conformation.

Predictors of re-exacerbation after an index exacerbation of chronic obstructive pulmonary disease in the REDUCE randomised clinical trial.

BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) compromise physical activity and quality of life and contribute significantly to health care costs. Systemic glucocorticoids benefit clinical outcome in AECOPD, and the REDUCE trial demonstrated noninferiority of a 5-day treatment course with prednisone compared with 14 days therapy regarding clinical outcome over 6 months of follow-up. Unexpectedly, we found an inverse correlation between circulating cortisol levels and exacerbation risk during a 6-month follow-up period. OBJECTIVE: To evaluate whether additional predictors of COPD re-exacerbation can be identified after the index exacerbation in the REDUCE cohort. METHODS: Of 314 patients with AECOPD randomised to 5 or 14 days of prednisone treatment, 311 were included in the analysis. Parameters tested as predictors of re-exacerbation were sex, age, smoking status, forced expiratory volume in one second (FEV1), dyspnoea as assessed with the Medical Research Council (MRC) dyspnoea scale, home oxygen therapy, pretreatment with systemic glucocorticoids, pretreatment with antibiotics, duration of hospitalisation, blood pressure, oxygen saturation, admission to the Intensive Care Unit (ICU) and relevant infections in follow-up. The risks for re-exacerbation were estimated by means of logistic regression and Cox proportional hazard models and expressed as odds ratios and hazard ratios, respectively. RESULTS: After multivariate adjustment, significant predictors at hospital discharge for COPD re-exacerbation during follow-up were: duration of hospital stay >8 days (hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.03-2.28); FEV1 <30% predicted (HR 1.76, 95% CI 1.06-2.91); hypertension (HR 2.39, 95% CI 1.04-5.48) and MRC dyspnoea scale (HR 1.61, 95% CI 1.30-2.01, per unit increment). Present cigarette smoking (HR 0.60, 95% CI 0.38-0.92) was negatively associated with re-exacerbation. CONCLUSION: In addition to biochemical suppression of the adrenal glands, other standard clinical parameters predict re-exacerbation in patients admitted to the emergency department with AECOPD. (REDUCE trial registration: ISRCTN29646069).

Amyloid-like aggregation of provasopressin in diabetes insipidus and secretory granule sorting.

BACKGROUND: Aggregation of peptide hormone precursors in the trans-Golgi network is an essential process in the biogenesis of secretory granules in endocrine cells. It has recently been proposed that this aggregation corresponds to the formation of functional amyloids. Our previous finding that dominant mutations in provasopressin, which cause cell degeneration and diabetes insipidus, prevent native folding and produce fibrillar aggregates in the endoplasmic reticulum (ER) might thus reflect mislocalized amyloid formation by sequences that evolved to mediate granule sorting. RESULTS: Here we identified two sequences responsible for fibrillar aggregation of mutant precursors in the ER: the N-terminal vasopressin nonapeptide and the C-terminal glycopeptide. To test their role in granule sorting, the glycopeptide was deleted and/or vasopressin mutated to inactivate ER aggregation while still permitting precursor folding and ER exit. These mutations strongly reduced sorting into granules and regulated secretion in endocrine AtT20 cells. CONCLUSION: The same sequences - vasopressin and the glycopeptide - mediate physiological aggregation of the wild-type hormone precursor into secretory granules and the pathological fibrillar aggregation of disease mutants in the ER. These findings support the amyloid hypothesis for secretory granule biogenesis.

Medical care of type 2 diabetes mellitus in light of international and national recommendations: a retrospective analysis.

QUESTION UNDER STUDY: Type 2 diabetes mellitus (T2Dm) is a chronic disease with great economic impact. In 2009, the Swiss Society for Endocrinology and Diabetes (SSED) published recommendations for treatment of T2Dm. In Switzerland, few data are currently available on metabolic control and physician compliance with treatment guidelines. We aimed to investigate clinical care in T2Dm in the year after the publication of SSED recommendations. METHODS: We retrospectively studied the charts of all patients with T2Dm admitted to our general internal medicine clinic during 2009. Metabolic control was judged from glycated haemoglobin A1c (HbA1c) levels. Antidiabetic therapy was analysed, and frequencies of screening for end-organ damage were investigated. A group with newly diagnosed T2Dm was analysed separately from patients with known T2Dm upon admission. RESULTS: In patients with known T2Dm, the mean (± standard deviation) HbA1c level was 7.66% ± 1.73%. Only 44% of patients showed HbA1c levels at the target of ≤7%. Prior to admission and at discharge, 56% and 55% of patients, respectively, were treated with metformin. Among patients with HbA1c >8.5%, the proportion of those treated with insulin increased from 49% upon admission to 76% at discharge. Only half the patients received a lifestyle intervention in the year prior to admission or during hospital stay. Screening for diabetic retinopathy and nephropathy was performed in approximately one-third and two-thirds of patients, respectively. CONCLUSIONS: In the majority of unselected T2Dm patients admitted to our hospital, metabolic control was suboptimal. Implementation of treatment recommendations by both general practitioners and hospitals should be improved.

Statins in clinical medicine.

Statins inhibit cholesterol biosynthesis. Their main effect is a decrease in circulating levels of LDL cholesterol, which translates into a ~ 20% relative reduction of major vascular events and coronary mortality per mmol/L LDL reduction achieved. Statins are efficient in preventing first cardiovascular events, but the cost-efficiency of primary prevention remains controversial. In primary prevention particularly, the pros and cons of statin therapy should be weighted by considering patient-specific life circumstances and assessing the individual cardiovascular risk, as provided by risk calculators. Since diabetes mellitus poses a high risk even in the absence of known coronary artery disease, statin treatment is generally indicated in these patients. There is no lower LDL threshold defining the limit of treatment benefit; rather, LDL target levels should be sought according to individual cardiovascular risk. If the necessary precautions are taken, e.g., by considering age, co-morbidities and co-medication when choosing the dose, statins are well tolerated and safe, as evidenced by many randomised controlled trials and meta-analyses. If a patient will not tolerate a statin dose necessary to achieve his or her LDL target level, ezetimibe may be added. There is no indication that statins alter cancer risk. Despite recent evidence that statin treatment is associated with a small risk of incident diabetes mellitus, this disadvantage is outweighed by the vascular benefits. Statins have pleiotropic effects, such as anti-inflammatory properties. It is still debated to what extent these effects translate into cardiovascular risk reduction beyond that conferred by LDL reduction.

Dominant pro-vasopressin mutants that cause diabetes insipidus form disulfide-linked fibrillar aggregates in the endoplasmic reticulum.

Autosomal dominant neurohypophyseal diabetes insipidus results from mutations in the precursor protein of the antidiuretic hormone arginine vasopressin. Mutant prohormone is retained in the endoplasmic reticulum of vasopressinergic neurons and causes their progressive degeneration by an unknown mechanism. Here, we show that several dominant pro-vasopressin mutants form disulfide-linked homo-oligomers and develop large aggregations visible by immunofluorescence and immunogold electron microscopy, both in a fibroblast and a neuronal cell line. Double-labeling showed the pro-vasopressin aggregates to colocalize with the chaperone calreticulin, indicating that they originated from the endoplasmic reticulum. The aggregates revealed a remarkable fibrillar substructure. Bacterially expressed and purified mutant pro-vasopressin spontaneously formed fibrils under oxidizing conditions. Mutagenesis experiments showed that the presence of cysteines, but no specific single cysteine, is essential for disulfide oligomerization and aggregation in vivo. Our findings assign autosomal dominant diabetes insipidus to the group of neurodegenerative diseases associated with the formation of fibrillar protein aggregates.

Anterior and posterior pituitary function testing with simultaneous insulin tolerance test and a novel copeptin assay.

CONTEXT: Posterior pituitary function in patients with suspected diabetes insipidus is usually assessed by a water deprivation test. Alternatively, a nonosmotic stimulus such as hypoglycemia may be used to stimulate vasopressin [arginine vasopressin (AVP)] secretion. Plasma AVP measurement may aid in the diagnosis and, especially, differential diagnosis of diabetes insipidus and polydipsia. However, AVP measurement is cumbersome. Copeptin, the stable C-terminal glycopeptide of the AVP prohormone, is stoichiometrically secreted from the posterior pituitary. OBJECTIVE: The aim was to study the value of copeptin levels in the diagnosis of diabetes insipidus during insulin-induced hypoglycemia. PATIENTS AND METHODS: A total of 38 patients were studied during insulin-induced hypoglycemia as part of a combined pituitary function test for possible anterior pituitary disease. There were 29 patients who had normal posterior pituitary function, and nine had central diabetes insipidus. Blood sampling was done before and 30, 45, and 90 min after iv insulin injection. Copeptin was measured with a new sandwich immunoassay. RESULTS: Patients with intact posterior pituitary function had basal copeptin levels of 3.7 +/- 1.5 pm, with a maximal increase to 11.1 +/- 4.6 pm 45 min after insulin injection. Copeptin levels in patients with diabetes insipidus were 2.4 +/- 0.5 pm before insulin injection, with a maximum increase to 3.7 +/- 0.7 pm. Both basal and stimulated copeptin levels were lower in patients with diabetes insipidus as compared with patients with intact posterior pituitary function. A stimulated copeptin level 45 min after insulin injection of less than 4.75 pm had an optimal diagnostic accuracy to detect diabetes insipidus. CONCLUSION: Copeptin measurement may be used to assess posterior together with anterior pituitary function during insulin-induced hypoglycemia.

The role of statins in clinical medicine--LDL--cholesterol lowering and beyond.

In the past years, statins have emerged as the most important class of lipid lowering agents. Through inhibition of HMG-CoA reductase, they restrict the rate-limiting step of cholesterol synthesis, which leads to upregulation of LDL receptors on the cell membrane and thus reduction of atherogenic LDLs. This effect translates into clinical benefit by reducing cardiovascular events both in primary and secondary prevention settings. As an approximate rule, statin therapy leads to a relative risk reduction of 25-30% in most of the large randomised controlled trials. Stroke risk is reduced to a similar degree. Despite initial concerns, the currently available statins have a favourable safety profile; however, potential interactions with other drugs must be considered. Recently, characteristics unrelated to LDL lowering have been intensively studied. These pleiotropic statin effects result from decreased levels of isoprenoid intermediates of cholesterol synthesis. They include--among others--anti-inflammatory, anti-proliferative, and immunomodulatory actions. Pleiotropic effects favourably influence pathomechanisms of plaque formation. Furthermore, they may prove beneficial in the prevention or treatment of diseases unrelated to atherosclerosis, eg rheumatoid arthritis, multiple sclerosis, or cancer.

Degradation of wild-type vasopressin precursor and pathogenic mutants by the proteasome.

Mutations in the gene encoding the antidiuretic hormone arginine vasopressin cause autosomal dominant neurogenic diabetes insipidus. Autoptic data in affected individuals suggest that the neurons expressing mutant vasopressin undergo selective degeneration. Expression studies have shown that the mutants are retained in the endoplasmic reticulum, but how this trafficking defect is linked to neurotoxicity is unknown. One possibility is that unsecreted mutant precursors, or degradation products thereof, are cytotoxic. We therefore investigated the fate of endoplasmic reticulum-retained pathogenic mutants. Our data show that the mutants are retrotranslocated to the cytosol and degraded by the proteasome. In the presence of proteasomal inhibitors, three distinct un- or deglycosylated cytosolic species of vasopressin precursors were stabilized: pre-pro-vasopressin, pro-vasopressin, and an N-terminally truncated form. In addition to the retrotranslocated forms, a fraction of the newly synthesized precursor was not translocated, but was synthesized into the cytosol due to inefficient function of the vasopressin signal peptide. As a result, cytosolic pre-pro-vasopressin and its degradation product were also recovered when wild-type vasopressin was expressed. Cytosolic forms of vasopressin might trigger cytotoxicity in vivo, as has been proposed in the case of prion protein, which also contains an inefficient N-terminal signal peptide.

Functional characterization of pendrin in a polarized cell system. Evidence for pendrin-mediated apical iodide efflux.

Pendred's syndrome is an autosomal recessive disorder characterized by sensorineural deafness, goiter, and impaired iodide organification. It is caused by mutations in the PDS/SLC26A4 gene that encodes pendrin. Functionally, pendrin is a transporter of chloride and iodide in Xenopus oocytes and heterologous mammalian cells and a chloride/base exchanger in beta-intercalated cells of the renal cortical collecting duct. The partially impaired thyroidal iodide organification in Pendred's syndrome suggests a possible role of pendrin in iodide transport at the apical membrane of thyroid follicular cells, but experimental evidence for this concept is lacking. The iodide transport properties of pendrin were determined in polarized Madin-Darby canine kidney cells expressing the sodium iodide symporter (NIS), pendrin, or NIS and pendrin using a bicameral system-permitting measurement of iodide content in the basal, intracellular, and apical compartments. Moreover, we determined the functional consequences of two naturally occurring mutations (L676Q and FS306>309X). In polarized Madin-Darby canine kidney cells, NIS mediates uptake at the basolateral membrane. Only minimal amounts of iodide reach the apical compartment in the absence of pendrin. In cells expressing NIS and pendrin, pendrin mediates transport of iodide into the apical chamber. Wild type pendrin also mediates iodide efflux in transiently transfected cells. In contrast, both pendrin mutants lose the ability to promote iodide efflux. These results provide evidence that pendrin mediates apical iodide efflux from polarized mammalian cells loaded with iodide. Consistent with the partial organification defect observed in patients with Pendred's syndrome, naturally occurring mutations of pendrin lead to impaired transport of iodide.

Endoplasmic reticulum storage diseases.

The endoplasmic reticulum represents the cell's quality control site for accurate folding of secretory and membrane proteins. Quality control is achieved through the association of ER chaperones with unfolded or misfolded polypeptide chains. In the ER stress response, upregulation of chaperones occurs as a consequence of misfolded proteins accumulating in the ER lumen; if these proteins fail to assume their native structure, they are retained in the ER and targeted for degradation by the proteasome. ER storage diseases (ERSDs) are a group of genetically based disorders in which mutant proteins fail to pass the ER quality control. Because all eukaryotic cells contain the ER, the clinical phenotype of ERSDs is very heterogeneous. Disease may result from the mere lack of the mutant protein in question and/or may be caused indirectly by toxic effects of the misfolded protein or aggregates thereof on the cell. Additionally, the cell's reaction to the ER stress may include signaling pathways which are ultimately detrimental. Experimentally, ERSDs serve as models to study the cellular reactions to a variety of perturbations. In particular, understanding the links between ER stress and cell degeneration may give valuable insights into the pathogenesis of other diseases where the accumulation of indigestible toxic material leads to cell injury.

Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene.

OBJECTIVE: To test further the hypothesis that autosomal dominant neurohypophyseal diabetes insipidus (adFNDI) is caused by heterozygous mutations in the vasopressin-neurophysin II (AVP-NPII) gene that exert a dominant negative effect by producing a precursor that misfolds, accumulates and eventually destroys the neurosecretory neurons. METHODS: Antidiuretic function, magnetic resonance imaging (MRI) of the posterior pituitary and AVP-NPII gene analysis were performed in 10 affected members of three unreported families with adFNDI. RESULTS: As in previously studied patients, adFNDI apparently manifested after birth, was due to a partial or severe deficiency of AVP, and was associated with absence or diminution of the hyperintense MRI signal normally emitted by the posterior pituitary, and with a heterozygous mutation in the AVP-NPII gene. In family A, a transition 275G-->A, which predicts replacement of cysteine 92 by tyrosine (C92Y), was found in the index patient, but not in either parent, indicating that it arose de novo. The six affected members of family B had a transversion 160G-->C, which predicts replacement of glycine 54 by arginine (G54R). It appeared de novo in the oldest affected member, and was transmitted in a dominant manner. In family C, six of 15 living affected members were tested and all had a novel transition, 313T-->C, which predicts replacement of cysteine 105 by arginine (C105R). It, too, was transmitted in a dominant manner. As in other patients with adFNDI, the amino acids replaced by the mutations in these three families are known to be particularly important for correct and efficient folding of the precursor. CONCLUSIONS: These findings are consistent with the malfolding/toxicity hypothesis underlying the pathogenesis of adFNDI. Moreover, they illustrate the value of genetic analysis in all patients who develop idiopathic diabetes insipidus in childhood, even if no other family members are affected.