Accepted Manuscript Sudden Infant Death Syndrome and Abnormal Metabolism of Thiamin Derrick Lonsdale PII: DOI: Reference:

S0306-9877(15)00352-7 http://dx.doi.org/10.1016/j.mehy.2015.09.009 YMEHY 8044

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Medical Hypotheses

Received Date: Accepted Date:

17 June 2015 9 September 2015

Please cite this article as: D. Lonsdale, Sudden Infant Death Syndrome and Abnormal Metabolism of Thiamin, Medical Hypotheses (2015), doi: http://dx.doi.org/10.1016/j.mehy.2015.09.009

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SUDDEN INFANT DEATH SYNDROME AND ABNORMAL METABOLISM OF THIAMIN

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Derrick Lonsdale MB BS, FAAP, FACN Associate Emeritus, Cleveland Clinic Foundation Cleveland, Ohio

Thiamin, magnesium, pseudo-hypoxia, sudden infant death

Derrick Lonsdale MB BS 28575 Westlake Village Dr. A 106 Westlake OH 44145 Tel 440-471-4852 [email protected]

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ABSTRACT Although it has been generally accepted that moving the infant from the prone to the supine position has solved the problem of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

sudden infant death syndrome (SIDS), it has been hypothesized that this is an insufficient explanation and that a mixture of genetic risk, some form of stressful incident and marginal brain metabolism is proportionately required. It is suggested that each of these three variables, with dominance in one or more of them, act together in the common etiology. Much has been written about the association of thiamin and magnesium but the finding of extremely high concentrations of serum thiamin in SIDs victims has largely caused rejection of thiamin as being involved in the etiology. The publication of abnormal brainstem auditory evoked potentials strongly suggests that there are electrochemical changes in the brainstem affecting the mechanisms of automatic breathing and the control of cardiac rhythm. The brainstem, cerebellum and limbic system of the brain are known to be highly sensitive to thiamin deficiency (pseudo-hypoxia) and the

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pathophysiology is similar to a mild continued deprivation of oxygen. Little attention has been paid to the complex metabolism of thiamin. Dietary thiamin requires the cooperation of the SLC19 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

family of thiamin transporters for its absorption into cells and recent information has shown that transporter SNPs may be relatively common and can be expected to increase genetic risk. Thiamin must be phosphorylated to

synthesize thiamin

pyrophosphate (TPP), well established in its vital action in glucose metabolism. TPP is also a cofactor for the enzyme 2-hydroxyacylCoA lyase (HACL1) in the peroxisome, emphasizing its importance in alpha oxidation and plasmalogen synthesis in cell membrane physiology. The importance of thiamine triphosphate (TTP) in energy metabolism is still largely unknown. Thiamin metabolism has been implicated in hyperemesis gravidarum and iatrogenic Wernicke encephalopathy has been reported when the patient is treated with hyperalimentation, in spite of the pharmaceutical doses of thiamin in the intravenous fluid. Defective glucose metabolism, the vital fuel for energy synthesis, particularly in

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brain,must affect the developing fetus and the pattern of subsequent neonatal health.

Sudden death in an apparently

healthy infant, occurring at 3 to 4 months, has long been known 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

to result from feeding the infant with thiamin deficient breast milk. The early investigators of the cause of beriberi considered that this form of sudden death was pathognomonic of the infantile form of the disease.

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INTRODUCTION Many theories have been proposed for the etiology of the sudden infant death syndrome (SIDS). Severely premature infants are at risk because of incomplete development of life supporting 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

systems[1]. The neurotrophin brain-derived neurotrophic factor, required for the appropriate development of the central respiratory network, has been implicated [2].

Laryngeal

inflammation has been found in some cases of SIDS [3]. Neuroanatomical and functional changes in the inferior colliculus have been reported[4]. Guidelines for preventive care have been published[5-7].

The underlying mechanism has still not been

described. Thiamin deficiency As long ago as 1944, the clinical description of sudden death in breastfed infants of thiamin deficient Chinese mothers was reported as infantile beriberi. During the Japanese invasion of Hong Kong the rice ration to the mothers was severely restrictedand this form of sudden death disappeared, only to

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reappear again when ad lib rice was restored after the Japanese left the colony. The epidemiology of this kind of sudden death in 3 to 4 month old infants, often considered to be the healthiest in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

the family, was so similar to “cot death” as it was then described in England, that Fehily proposed thiamin deficiency as its cause [8]. A very important etiological clue lies in the fact that sudden infant death disappeared when rice rationing was instituted in the mothers. Beriberi still occurred in infants breast fed by their starving mothersbut it was less acute and the clinical presentation was completely different. It was this kind of information that led Read and his group in Australia to study the relationship of thiamin deficiency as the underlying cause of SIDS [9]. These investigators had found an unexpectedly high incidence of thiamin deficiency in groups of mothers and infants by the measurement of erythrocyte transketolase, selected for apparent health. The incidence of thiamin deficiency was high in “near-miss” SIDS infants and their mothers and in siblings of SIDS. The thiamin deficient infants had

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a high familial incidence of SIDS deaths. They stated that apparently thriving infants with thiamin deficiency can sometimes die unexpectedly and that thiamin status deserved more 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

attention in clinical practice and research [10]. They also reported a wide range of clinical findings in 58 near-miss SIDS infants [11] Interest arising from these studies was quickly refuted.

Post

mortem heart blood aspirates from 24 consecutive SIDS victims revealed no differences in an erythrocyte transketolase activity with those in infants dying from other causes[12]. In 1982 it was reported that serum thiamin concentrations in 233 infants dying from SIDS were significantly higher than those found in 46 infants dying from other explicable causes [13]. Subsequently thiamin serum levels from 12,613 infants showed a five-fold increase in SIDS victims as compared with controls. The author stated that the interpretation of thiamin screening data required further detailed investigation [14]. Thiamin deficiency and sudden death again received some comment in 1990 [15] and infantile beriberi

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was recognized as the main cause of death, accounting for 40% of all infant mortality in a refugee population in Thailand [16].

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

Magnesium dependent metabolism in SIDS The biochemical relationship between thiamin and magnesium is well known and the clinical effects of deficiency of one overlaps the other, each or both collectively being responsible for many symptoms [17].

Even though magnesium is by far the least

abundant serum electrolyte in serum, it is extremely important, together with thiamin for the metabolism of many enzymes that govern energy metabolism. Its absorption into cells depends on a large number of variables, absence of even one leading to its deficiency [18]. In 1992 it was hypothesized that SIDS occurred as a shock-like event in a stressed infant with congenital or acquired magnesium deficiency with respect to calcium or with genetically determined high magnesium requirements [19]. The same author cited cases linking respiratory distress syndrome and SIDS with magnesium deficiency shock [20].

At peak incidence of SIDS

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between two and four months the vitreous magnesium concentration is high and there is little change despite the extremes in dietary magnesium [21]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

It was concluded that

magnesium deficiency was at least one major unifying factor that explained increased SIDS in the prone sleeping infants, a position that stressed the infant [22]. Gestational magnesium deficiency results in suboptimal growth and development of the fetus and reduced survival in the infant [23]. Durlach and associates also claimed magnesium deficiency in the etiology of SIDS[24-26] and it has been shown to produce an inflammatory lung reactionin mice that suggested a similar mechanism in SIDS [27].

Brainstem Auditory Evoked Potential (BAEP) Although a number of papers were published more than 30 years ago on BAEP studies in SIDS, there has been little interest in recent years.

Fifteen infants at risk for sudden infant death

syndrome by clinical criteria were tested by BAEP. All of them demonstrated abnormalities on two or more of the seven criteria

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employed to assess results[28]. Thirty six infants identified as infant apnea syndrome (IAS) and 25 controls with comparable age distribution were evaluated by BAEP. Fifteen IAS patients had 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

bilateral abnormalities. Of 21 IAS patients with unilateral abnormalities, 17 of them had abnormalities on the left side. Significant differences between normal controls and IAS infantswere found for peak latencies I, III and V and amplitude III [29]. BAEP responses were recorded from 63 near-miss SIDS infants, 26 siblings of SIDS and 67 control infants between 0 and 30 weeks post-term. The majority of BAEP records from both groups of infants had normal form and inter-peak intervals. The distributions of V-IIn intervals for both groups of at risk infants were significantly different compared with those of control infants. The authors concluded that although BAEP is not suitable for identifying infants at risk of SIDS, they suggested that maturation of the overall neural processing in the brainstem may be delayed[30].

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The Three Circles of Health [17] It has been hypothesized that SIDS requires a genetic risk factor, coupled with some form of stress and marginal malnutrition, 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

either in the infant, the mother, or both [31].

Genetics

TABLE 1 here Table 1 presents the results of genomic analysis on six adolescent subjects, all of whom were suffering from postural orthostatic hypotension syndrome (POTS). Subjects 1 and 2 acquired POTS immediately after receiving HPV vaccine and were then found to have

an

abnormal

erythrocyte

transketolase

thiamin

pyrophosphate effect (TPPE), proving thiamin deficiency. Subject 3 also had thiamine deficient POTS but had not received the vaccine. Subjects 4-6 had the genomic analysis, but had not been tested with the erythrocyte transketolase test. The interest lies in the fact that the SNPs were found in the SLC family of thiamin

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transporters. This small number of cases suggests that POTSis early beriberi from dietary thiamin deficiency or that a stress factor such as a vaccine can precipitate the symptoms in an 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

individual who is in a state of asymptomatic marginal malnutrition prior to the vaccination [17]. It is only relatively recently that inherited defects in thiamin uptake, activation and the attachment of the active cofactor to target enzymes have been described [32].

Despite normal

thiamin serum levels, a patient with atrophic beriberi responded quickly to intramuscular thiamin treatment. He was found to have 37 mutations, 29 in SLC19A2, 6 in SLC19A3, and 2 in SLC 25A19 [33]. Genotyping of two single-nucleotide polymorphisms (SNPs) in genes of importance for respiratory control was studied in SIDS. For rs701265 in P2RY1, homozygous G carriers were significantly more frequent in the control group. The authors concluded that allele G provides a protective effect in events of ventilatory stress and recommended further studies to further investigate

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functional polymorphisms in the genes involved in respiratory control [34].

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

Stress The individual histories of SIDS often indicate that the mother had noticed rhinorrhea in the infant the night before the discovery of his death the next morning, raising a sense of guilt that a trivial infection had been ignored.

A leading hypothesis is that an

abnormality in the brainstem of infants who succumb to SIDS either causes or predisposes to failure to respond appropriately to an exogenous stressor, such as a cold causing virus. The dorsal motor nucleus of the vagus is an autonomic nucleus in which abnormalities have regularly been identified in SIDS research, suggesting compromise of the infant’s ability to respond to stress such as hypoxia [35]. There is also growing consensus that SIDS requires the intersection of multiple risk factors that might result in failure of the infant to overcome cardio-respiratory challenges [36]. The progressive increase in SIDS in England and Wales

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between 1951 and 1988 seemed to be related to the increasing use of fire retardants in cot mattresses [37], perhaps acting as a stressor in an otherwise metabolically compromised infant. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

Thiamin metabolism Several lines of reasoning in regard to thiamin metabolism need to be considered. First, it is clear that breast feeding by mothers with dietary thiamin deficiency gives rise to infancy death identical to the epidemiology of modern SIDS [8]. A fivefold increase in serum thiamin focuses attention on the vitamin again [13,14]. This kind of observation, found so repeatedly in infants dying from SIDS can hardly be ignored and requires explanation. BAEP observations, suggesting electrochemical changes in brainstem metabolism [29], together with the recent evidence of SNPs in thiamin transporters [32,33] might point to thiamin as the common denominator. The feces of a three-month-old boy with infant botulism contained Clostridium botulinum serotype A2 that carries the thiaminase I gene and produced thiaminase I. He

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quickly and favorably responded to thiamin supplementation [38].Clostridium botulinum type B was detected in the intestinal contents of a suddenly deceased 11-week old infant [39]. In 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

studies analyzing infants who died from SIDS, botulism bacteria or toxin were found in up to 20% of cases [40]. Of 57 SIDS cases free botulism toxin was found in nine and bacterial forms were detected in six [41].Among the proteins involved in thiamin metabolism, thiamin transporters, thiamin pyrophosphokinase and thiamin triphosphatase have been characterized at the molecular level, in contrast to thiamin mono- and diphosphatases whose specificities remain to be proven [42]. Thiamin triphosphate was discovered over 60 years ago.

Long thought to be

neuroactive, its presence in most cell types suggests a more general role, but this has not yet been defined [43]. The roles of thiamin include neuronal communication, immune system activation, signaling, maintenance processes in cells and tissues, and cell-membrane dynamics [44]. The discovery of thiamin pyrophosphate as a cofactor for the enzyme 2-hydroxyacyl-CoA

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lyase (HACL1) in peroxisomes must eventually add considerable complexity to the clinical effects of thiamin deficiency [45]. Transport of TPP into peroxisomes appears to be dependent on 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

HACL1 import without the requirement of a specific solute transporter [46,47].It appears to be well established that thiamin deficiency, reported 70 years ago, is a cause of sudden infant death with an epidemiology identical to that of modern SIDS. It is hypothesized that, because of new information, abnormal thiamin metabolism can produce the same effect and needs to be reconsidered for potential preventive action. For example, the very high levels of thiamin in the serum of infants dying from SIDS might have been unphosphorylated thiamin derived from diet and may reflect gestational maternal nutrition or some form genetic risk involving phosphorylation.

of

The expression and

activity of thiamine triphosphatase appears to correlate with the degree of cell differentiation. adenosine

thiamin

differentiated

fast

Thiamin triphosphate and

triphosphate growing

cells,

were

found

suggesting

in a

poorly hitherto

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unsuspected link between these compounds and cell division or differentiation [48]. Baseline erythrocyte transketolase activity (TKA) can be normal in the presence of thiamin pyrophosphate 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

(TPP) deficiency. It is only depressed with severe and prolonged deficiency or because of genetically determined reasons. The next part of the test to define whether acceleration of the baseline activity can be achieved by the in vitro addition of TPP, known as the thiamin pyrophosphate effect (TPPE) is mandatory. [49].This makes the finding of normal erythrocyte transketolase activity without the TPPE in post mortem SIDS blood samples suspect [12]. Thiamin triphosphate is still an unknown entity and its deficiency was detected in the phrenic nerve of some cases of SIDS [50]. Finding normal concentrations of magnesium in the vitreous does nothing to exclude its deficiency. It is well known that serum magnesiumand thiamin can be normal in the presence of their respective deficiencies. components.

They are both intracellular

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Dysautonomia Autonomic dysfunction has been identified in threatened SIDS [35]. Changes in cytological composition in the carotid body have 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

been described. Exposure to tobacco smoke, substances of abuse, hyperoxia, continuous and intermittent hypoxia, that increase the risk of SIDS, are also known to affect carotid body functional and structural maturation adversely, suggesting the role of arterial chemoreceptors in SIDS [51].

Prolonged QT interval A prolongedQT interval was noted in 30.7% of a group of patients with familial dysautonomia, a disease in which sudden death remains the cause of death in up to 43% of patients [52]. Compared with matched control infants, QTc intervals were increased in future SIDS victims. Such a prolongation could be related to the autonomic dysfunction already reported in these patients [53]. Children with congenital central hypoventilation syndrome have cardiovascular symptoms consistent with the

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autonomic nervous system dysregulation phenotypeand a prolonged QTc interval that did not vary by genotype. Among three childrenwho had prolonged r-r intervals, two died suddenly 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

[54]. The prolonged QTc interval may be considered to be a biomarker for detecting alterations in sympathovagal balance [55].

Sudden nocturnal death in sleep occurs in substantial

numbers among young men in Southeast Asia and is associated with a prolonged QTc interval and poor thiamin status.

The

authors suggest that thiamin deficiency may be a cause of the prolonged QT interval and sudden death [56]. Night terrors, a signature event in this disease and known in the Philippines as Bangungut has been shown to be associated with cardiac conduction defects and severe autonomic discharge in many of the victims[57]. This disease, known in the West as “dead-in-bed syndrome” mainly affects young type 1 diabetes patients [58], a disease in which thiamin metabolism is implicated [59] and in which autonomic neuropathy is common. Thiamin deficiency beriberi is a prototype for dysautonomia in its early stages [17].

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Hypoxia and pseudohypoxia A recently proposed classification of sudden unexpected infant 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

death incorporates consideration of possible asphyxia, a reliable marker for which has yet to be identified. An attempt was made to use the presence of nucleated red blood cells in infants as a marker. There was a significant increase in ex-premature babies and a trend toward higher levels in infants born to smoking mothers, both being at potential risk for SIDS [60]. Lesions from hypoxia in the brain are similar to those produced by thiamin deficiency (pseudo-hypoxia)[61].

Both hypoxia and thiamin

deficiency (TD) resulted in an increase in the expression of the thiamin transporter SLC 19A3 and TD induced HIF-1alphamediated gene expression similar to that observed in hypoxic stress [62]

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Thiamin derivatives

Figure 1 here 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

The potential role of thiamin and its derivatives in modern nutrition has been published [63]. Thiamin tetrahydrofurfuryl disulfide (TTFD) is the synthetic equivalent of allithiamin, the naturally occurring derivative found in garlic.

Although its

physiologic action is the same as water soluble thiamin salts, TTFD has the advantage of being absorbed into cells without the need for thiamin transporters. Being a disulfide, it is reduced nonenzymatically at the cell membrane, enabling the open ring thiamin molecule to pass through the lipid barrier in the cell membrane. Hence it is sometimes known as fat soluble thiamin [64]. Clinical benefit from the use of TTFD was backed by BAEP studies in four infants with infant apnea syndrome [65]. In an uncontrolled trial published as a pilot study, some clinical benefit was observed in a small group of autistic children [66]. TTFD

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given to rats attenuated the decrease in ATP content in the skeletal muscle caused by forced swimming with a weight load and exerted anti-fatigue effects by improving energy metabolism 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

during physical fatigue [67]. It increased whole brain thiamin concentrations in mice and the authors suggested that its use during early development deserved clinical trials [68].

Hypothesis: SIDS is preventable Obviously, any form of prevention would be a great boon to anxious mothers. Evidence has been presented that threatened SIDS is a logical diagnosis based on non-specific symptoms. If there is a history of SIDS in the family and the infant is unusually fussy, such symptoms would strengthen the possibility. The first step would be to apply one of the commercially available cardiorespiratory monitors that can readily be used in the home. Based on preliminary information, an additional step might be to obtain genomic evidence of relevant SNPs. It is particularly important to note that infantile beriberi disappeared in Hong Kong when

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carbohydrate calories were reduced. As long ago as 1936, Peters reported the so-called catatorulin effect when glucose was added to brain cells derived from thiamin deficient pigeons. Respiration 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49

in the thiamin deficient cells was no different than that in thiamin sufficient cells until glucose was added [69]. Dietary sugar restriction can be very therapeutic [17] and sweetened fluids are frequently offered to infants. Thiamin tetrahydrofurfuryl disulfide (TTFD) has no known toxicity, is absorbed into cells non enzymatically and does not require transporters, thus bypassing their necessity. It could be given as a supplement with impunity. Its clinical benefits and results of animal studies have been described [64-68]. There appears to be a need for updating the evidence derived from BAEP studies with their normalization after administration of TTFD if abnormalities are found to be present.

The same thing would apply by

correction if the cardio-respiratory monitor was providing repeated evidence of apnea or bradycardia.

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Conflict of interest: There are no conflicts of interest

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If

FIGURE 1 Formula of two disulfide derivatives of thiamin

TABLE 1 SNPs recorded from six adolescents, all of whom had postural orthostatic hypotension syndrome (POTS). (See text) Subject Gardasil

POTS

TPPE

SLC19A2

SLC 19 A3

SLC25A19

1 2

Yes Yes

Yes Yes

49% 48%

5 9

14 16

1 6

3 4 5 6

No Yes Yes Yes

Yes Yes Yes Yes

25% -

9 5 5 9

16 17 8 15

6 0 0 6