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GeneTether Therapeutics Publishes Paper on Novel Recombination Products in the CFTR Gene – TheNewswire.ca

Posted: May 15, 2022 at 2:35 am

San Lorenzo, California TheNewswire - May 11, 2022 - GeneTether Therapeutics Inc. (GeneTether or the Company) (CSE:GTTX), an innovative genetic medicines company focused on creating best-in-class gene editing therapies based on its proprietary GeneTether platform, announces a new paper co-authored by R. Geoffrey Sargent, GeneTether CSO, and colleagues from The University of California, San Francisco, The University of Texas, Health Science Center at Houston (UTHealth Houston), Kumamoto University, University of Pavia, and University of Vermont College of Medicine.

The paper entitled Seamless Gene Correction in the Human Cystic Fibrosis Transmembrane Conductance Regulator Locus by Vector Replacement and Vector Insertion Events, published online in the peer-reviewed journal Frontiers in Genome Editing, describes novel homology directed recombination (HDR) products and the subsequent derivation of seamless gene correction of the W1282X CFTR mutation in human induced pluripotent stem cells. The corresponding senior author is R. Geoffrey Sargent, PhD, CSO at GeneTether; and the first, and co-corresponding, author is Shingo Suzuki, PhD, research instructor at The Brown Foundation Institute of Molecular Medicine in McGovern Medical School at UTHealth Houston.

The paper demonstrates a class of HDR products that appear to be often overlooked in experiments using the CRISPR/Cas9 nuclease. One of the goals of gene editing is to make seamless corrections of mutant genes to restore the normal or wild type DNA sequence without errors including undesired mutations or inadvertent DNA sequence changes. The most frequent approach for HDR gene corrections is to replace the target mutation with the normal DNA sequences, a process sometimes referred to as vector replacement events. The research in the paper demonstrates that for some DNA repair, templates used to replace target mutations results in the duplication of the target gene sequences. These are often referred to as vector insertion events which have the potential to allow creation of multiple cell lines, containing different DNA edits, starting from one parental cell line.

If we go back to classic HDR gene editing, before CRISPR/Cas, Transcription Activator-Like Effector Nucleases (TALENs), and Zinc Finger Nucleases (ZFN), vector insertion events were well-known and shown to occur in organisms from yeast to human cell lines. Indeed, under certain circumstances, vector insertion events can occur more frequently than vector replacement events. In the paper, we show that vector insertion events frequently occur using CRISPR/Cas9 treated human-induced pluripotent stem cells. We have now observed these events in other human iPS cell lines and at other genes, commented Dr. Sargent. This expands the toolkit of ways to modify genes in cells to study disease and for developing new therapeutic approaches. I am excited to utilize these HDR vector insertion products in our GeneTether platform development.

About GeneTether

Founded by EGB Ventures founder and managing partner, William J. Garner, M.D., and veteran gene editing researcher, R. Geoffrey Sargent, Ph.D., GeneTether is focused on developing its disruptive proprietary platform technology to significantly increase the efficiency of DNA insertion into the genome for gene correction and complementation strategies. The Companys wholly-owned platform technology uses a proprietary method to tether donor DNA templates to the genome editing complex, making the template readily available for use during the genome editing repair stage. The Company is leveraging its platform technology to develop curative therapies for the treatment of rare genetic diseases. GeneTethers proof of concept study demonstrated an approximately 7x higher gene editing efficiency as compared to the same gene editing payload without application of GeneTethers technology.

For more information, visitwww.genetether.com.

Contact:

Geoffrey Sargent, CSO

(833) 294-4363 ext. 3

geoff@genetether.com

Forward-Looking Disclaimer

This news release contains statements that constitute "forward-looking statements." Such forward looking statements involve known and unknown risks, uncertainties and other factors that may cause GeneTethers actual results, performance or achievements, or developments in the industry to differ materially from the anticipated results, performance or achievements expressed or implied by such forward-looking statements. Forward looking statements are statements that are not historical facts and are generally, but not always, identified by the words "expects," "plans," "anticipates," "believes," "intends," "estimates," "projects," "potential" and similar expressions, or that events or conditions "will," "would," "may," "could" or "should" occur. Forward-looking statements in this news release include the expectation that the Company will utilize HDR vector insertion products in its GeneTether platform development and all other statements that are not statements of historical fact.

Although GeneTether believes the forward-looking information contained in this news release is reasonable based on information available on the date hereof, by their nature forward-looking statements involve known and unknown risks, uncertainties and other factors which may cause our actual results, performance or achievements, or other future events, to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. By their nature, these statements involve a variety of assumptions, known and unknown risks and uncertainties and other factors, which may cause actual results, levels of activity and achievements to differ materially from those expressed or implied by such statements. Examples of such assumptions, risks and uncertainties include, without limitation, those set forth under the heading Risk Factors in the Companys final prospectus dated March 21, 2022.

The forward-looking information contained in this news release represents the expectations of the Company as of the date of this news release and, accordingly, is subject to change after such date. Readers should not place undue importance on forward-looking information and should not rely upon this information as of any other date. While the Company may elect to, it does not undertake to update this information at any particular time except as required in accordance with applicable laws.

Neither the Canadian Securities Exchange nor its Regulation Service has approved nor disapproved the contents of this news release.

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GeneTether Therapeutics Publishes Paper on Novel Recombination Products in the CFTR Gene - TheNewswire.ca

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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation – Nature.com

Posted: May 15, 2022 at 2:33 am

  1. Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation  Nature.com
  2. A Nutritious Diet May Reduce Diabetes Risk, Regardless of Genetics  Verywell Health
  3. Worldwide analysis 'a major step' in understanding genetics of type 2 diabetes  Medical Economics
  4. Huge study of diverse populations advances understanding of type 2 diabetes  Science Daily
  5. CCMB research shows population- specific genetic susceptibility to Type-2 Diabetes  The Hindu
  6. View Full Coverage on Google News

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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation - Nature.com

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Genetic and chemotherapeutic influences on germline hypermutation – Nature.com

Posted: May 15, 2022 at 2:33 am

DNM filtering in 100,000 Genomes Project

We analysed DNMs called in 13,949 parentoffspring trios from 12,609 families from the rare disease programme of the 100,000 Genomes Project. The rare disease cohort includes individuals with a wide array of diseases, including neurodevelopmental disorders, cardiovascular disorders, renal and urinary tract disorders, ophthalmological disorders, tumour syndromes, ciliopathies and others. These are described in more detail in previous publications60,61. The cohort was whole-genome sequenced at around 35 coverage and variant calling for these families was performed through the Genomics England rare disease analysis pipeline. The details of sequencing and variant calling have been previously described61. DNMs were called by the Genomics England Bioinformatics team using the Platypus variant caller62. These were selected to optimize various properties, including the number of DNMs per person being approximately what we would expect, the distribution of the VAF of the DNMs to be centred around 0.5 and the true positive rate of DNMs to be sufficiently high as calculated from examining IGV plots. The filters applied were as follows:

Genotype is heterozygous in child (1/0) and homozygous in both parents (0/0).

Child read depth (RD)>20, mother RD>20, father RD>20.

Remove variants with >1 alternative read in either parent.

VAF>0.3 and VAF<0.7 for child.

Remove SNVs within 20bp of each other. Although this is probably removing true MNVs, the error mode was very high for clustered mutations.

Removed DNMs if child RD>98 (ref. 14).

Removed DNMs that fell within known segmental duplication regions as defined by the UCSC (http://humanparalogy.gs.washington.edu/build37/data/GRCh37GenomicSuperDup.tab).

Removed DNMs that fell in highly repetitive regions (http://humanparalogy.gs.washington.edu/build37/data/GRCh37simpleRepeat.txt).

For DNM calls that fell on the X chromosome, these slightly modified filters were used:

For DNMs that fell in PAR regions, the filters were unchanged from the autosomal calls apart from allowing for both heterozygous (1/0) and hemizygous (1) calls in males.

For DNMs that fell in non-PAR regions the following filters were used:

For males: RD>20 in child, RD>20 in mother, no RD filter on father.

For males: the genotype must be hemizygous (1) in child and homozygous in mother (0/0).

For females: RD>20 in child, RD>20 in mother, RD>10 in father.

To identify individuals with hypermutation in the DDD study, we started with exome-sequencing data from the DDD study of families with a child with a severe, undiagnosed developmental disorder. The recruitment of these families has been described previously63: families were recruited at 24 clinical genetics centres within the UK National Health Service and the Republic of Ireland. Families gave informed consent to participate, and the study was approved by the UK Research Ethics Committee (10/H0305/83, granted by the Cambridge South Research Ethics Committee, and GEN/284/12, granted by the Republic of Ireland Research Ethics Committee). Sequence alignment and variant calling of SNVs and indels were conducted as previously described. DNMs were called using DeNovoGear and filtered as described previously12,64. The analysis in this paper was conducted on a subset (7,930 parentoffspring trios) of the full current cohort, which was not available at the start of this research.

In the DDD study, we identified 9 individuals out of 7,930 parentoffspring trios with an increased number of exome DNMs after accounting for parental age (7-17 exome DNMs compared to an expected number of ~2). These were subsequently submitted along with their parents for PCR-free whole-genome sequencing at >30x mean coverage using Illumina 150bp paired end reads and in house WSI sequencing pipelines. Reads were mapped with bwa (v0.7.15)65. DNMs were called from these trios using DeNovoGear64 and were filtered as follows:

Child RD>10, mother RD>10, father RD>10.

Alternative allele RD in child of >2.

Filtered on strand bias across parents and child (p-value>0.001, Fishers exact test).

Removed DNMs that fell within known segmental duplication regions as defined by the UCSC (http://humanparalogy.gs.washington.edu/build37/data/GRCh37GenomicSuperDup.tab).

Removed DNMs that fell in highly repetitive regions (http://humanparalogy.gs.washington.edu/build37/data/GRCh37simpleRepeat.txt).

Allele frequency in gnomAD<0.01.

VAF<0.1 for both parents.

Removed mutations if both parents have >1 read supporting the alternative allele.

Test to see whether VAF in the child is significantly greater than the error rate at that site as defined by error sites estimated using Shearwater66.

Posterior probability from DeNovoGear>0.00781 (refs. 12,64).

Removed DNMs if the child RD>200.

After applying these filters, this resulted in 1,367 DNMs. All of these DNMs were inspected in the Integrative Genome Viewer67 and removed if they appeared to be false-positives. This resulted in a final set of 916 DNMs across the 9 trios. One out of the nine had 277 dnSNVs genome wide, whereas the others had expected numbers (median, 81 dnSNVs).

To phase the DNMs in both 100kGP and DDD, we used a custom script that used the following read-based approach to phase a DNM. This first searches for heterozygous variants within 500bp of the DNM that was able to be phased to a parent (so not heterozygous in both parents and offspring). We next examined the reads or read pairs that included both the variant and the DNM and counted how many times we observed the DNM on the same haplotype of each parent. If the DNM appeared exclusively on the same haplotype as a single parent then that was determined to originate from that parent. We discarded DNMs that had conflicting evidence from both parents. This code is available on GitHub (https://github.com/queenjobo/PhaseMyDeNovo).

To assess the effect of parental age on germline-mutation rate, we ran the following regressions on autosomal DNMs. These and subsequent statistical analyses were performed primarily in R (v.4.0.1). On all (unphased) DNMs, we ran two separate regressions for SNVs and indels. We chose a negative binomial generalized linear model (GLM) here as the Poisson was found to be overdispersed. We fitted the following model using a negative Binomial GLM with an identity link where Y is the number of DNMs for an individual:

E(Y)=0+1paternal age+2maternal age

For the phased DNMs we fit the following two models using a negative binomial GLM with an identity link where Ymaternal is the number of maternally derived DNMs and Ypaternal is the number of paternally derived DNMs:

E(Ypaternal)=0+1paternal age

E(Ymaternal)=0+1maternal age

To identify individuals with hypermutation in the 100kGP cohort, we first wanted to regress out the effect of parental age as described in the parental age analysis. We then looked at the distribution of the studentized residuals and then, assuming these followed a t distribution with N3 degrees of freedom, calculated a t-test P value for each individual. We took the same approach for the number of indels except, in this case, Y would be the number of de novo indels.

We identified 21 individuals out of 12,471 parentoffspring trios with a significantly increased number of dnSNVs genome wide (P<0.05/12,471tests). We performed multiple quality control analyses, which included examining the mutations in the Integrative Genomics Browser for these individuals to examine DNM calling accuracy, looking at the relative position of the DNMs across the genome and examining the mutational spectra of the DNMs to identify any well-known sequencing error mutation types. We identified 12 that were not truly hypermutated. The majority of false-positives (10) were due to a parental somatic deletion in the blood, increasing the number of apparent DNMs (Supplementary Fig. 7). These individuals had some of the highest numbers of DNMs called (up to 1,379 DNMs per individual). For each of these 10 individuals, the DNM calls all clustered to a specific region in a single chromosome. In this same corresponding region in the parent, we observed a loss of heterozygosity when calculating the heterozygous/homozygous ratio. Moreover, many of these calls appeared to be low-level mosaic in that same parent. This type of event has previously been shown to create artifacts in CNV calls and is referred to as a loss of transmitted allele event68. The remaining two false-positives were due to bad data quality in either the offspring or one of the parents leading to poor DNM calls. The large number of DNMs in these false-positive individuals also led to significant underdispersion in the model so, after removing these 12 individuals, we reran the regression model and subsequently identified 11 individuals who appeared to have true hypermutation (P<0.05/12,459tests).

Mutational signatures were extracted from maternally and paternally phased autosomal DNMs, 24 controls (randomly selected), 25 individuals (father with a cancer diagnosis before conception), 27 individuals (mother with a cancer diagnosis before conception) and 12 individuals with hypermutation that we identified. All DNMs were lifted over to GRCh37 before signature extraction (100kGP samples are a mix of GRCh37 and GRCh38) and, through the liftover process, a small number of 100kGP DNMs were lost (0.09% overall, 2 DNMs were lost across all of the individuals with hypermutation). The mutation counts for all of the samples are shown in Supplementary Table 1. This was performed using SigProfiler (v.1.0.17) and these signatures were extracted and subsequently mapped on to COSMIC mutational signatures (COSMIC v.91, Mutational Signature v.3.1)19,40. SigProfiler defaults to selecting a solution with higher specificity than sensitivity. A solution with 4 de novo signatures was chosen as optimal by SigProfiler for the 12 individuals with germline-hypermutated genomes. Another stable solution with five de novo signatures was also manually deconvoluted, which has been considered as the final solution. The mutation probability for mutational signature SBSHYP is shown in Supplementary Table 3.

We compared the extracted signatures from these individuals with hypermutation with a compilation of previously identified signatures caused by environmental mutagens from the literature. The environmental signatures were compiled from refs. 24,51,52. Comparison was calculated as the cosine similarity between the different signatures.

We compiled a list of DNA-repair genes that were taken from an updated version of the table in ref. 69 (https://www.mdanderson.org/documents/Labs/Wood-Laboratory/human-dna-repair-genes.html). These can be found in Supplementary Table 4. These are annotated with the pathways that they are involved with (such as nucleotide-excision repair, mismatch repair). A rare variant is defined as those with an allele frequency of <0.001 for heterozygous variants and those with an allele frequency of <0.01 for homozygous variants in both the 1000 Genomes as well as across the 100kGP cohort.

The A135T variant of MPG was generated by site-directed mutagenesis and confirmed by sequencing both strands. The catalytic domain of WT and A135T MPG was expressed in BL21(DE3) Rosetta2 Escherichia coli and purified as described for the full-length protein70. Protein concentration was determined by absorbance at 280nm. Active concentration was determined by electrophoretic mobility shift assay with 5-FAM-labelled pyrolidine-DNA48 (Extended Data Fig. 8). Glycosylase assays were performed with 50mM NaMOPS, pH7.3, 172mM potassium acetate, 1mM DTT, 1mM EDTA, 0.1mgml1 BSA at 37C. For single-turnover glycosylase activity, a 5'-FAM-labelled duplex was annealed by heating to 95C and slowly cooling to 4C (Extended Data Fig. 9). DNA substrate concentration was varied between 10nM and 50nM, and MPG concentration was maintained in at least twofold excess over DNA from 25nM to 10,000nM. Samples taken at timepoints were quenched in 0.2M NaOH, heated to 70C for 12.5min, then mixed with formamide/EDTA loading buffer and analysed by 15% denaturing polyacrylamide gel electrophoresis. Fluorescence was quantified using the Typhoon 5 imager and ImageQuant software (GE). The fraction of product was fit by a single exponential equation to determine the observed single-turnover rate constant (kobs). For Hx excision, the concentration dependence was fit by the equation kobs=kmax[E]/(K1/2+[E]), where K1/2 is the concentration at which half the maximal rate constant (kmax) was obtained and [E] is the concentration of enzyme. It was not possible to measure the K1/2 for A excision using a fluorescence-based assay owing to extremely tight binding71. Multiple turnover glycosylase assays were performed with 5nM MPG and 1040-fold excess of substrate (Extended Data Fig. 8).

To estimate the fraction of germline mutation variance explained by several factors, we fit the following negative binomial GLMs with an identity link. Data quality is likely to correlate with the number of DNMs detected so, to reduce this variation, we used a subset of the 100kGP dataset that had been filtered on some base quality control metrics by the Bioinformatics team at GEL:

We then included the following variables to try to capture as much of the residual measurement error which may also be impacting DNM calling. In brackets are the corresponding variable names used in the models below:

Mean coverage for the child, mother and father (child mean RD, mother mean RD, father mean RD)

Proportion of aligned reads for the child, mother and father (child prop aligned, mother prop aligned, father prop aligned)

Number of SNVs called for child, mother and father (child snvs, mother snvs, father snvs)

Median VAF of DNMs called in child (median VAF)

Median Bayes Factor as outputted by Platypus for DNMs called in the child. This is a metric of DNM quality (median BF).

The first model only included parental age:

E(Y)=0+1paternal age+2maternal age

The second model also included data quality variables as described above:

$$begin{array}{cc}E(Y),= & {beta }_{0}+{beta }_{1}{rm{paternal; age}}+{beta }_{2}{rm{maternal; age}}\ & +{beta }_{3}{rm{child; mean; RD}}+{beta }_{4}{rm{mother; mean; RD}}\ & +{beta }_{5}{rm{father; mean; RD}}+{beta }_{6}{rm{child; prop; aligned}}\ & +{beta }_{7}{rm{mother; prop; aligned}}+{beta }_{8}{rm{father; prop; aligned}}\ & +{beta }_{9}{rm{childs; nvs}}+{beta }_{10}{rm{mother; snvs}}+{beta }_{11}{rm{father; snvs}}\ & +{beta }_{12}{rm{median; VAF}}+{beta }_{13}{rm{median; BF}}end{array}$$

The third model included a variable for excess mutations in the 11 confirmed individuals with hypermutation (hm excess) in the 100kGP dataset. This variable was the total number of mutations subtracted by the median number of DNMs in the cohort (65), Yhypermutatedmedian(Y) for these 11 individuals and 0 for all other individuals.

$$begin{array}{cc}E(Y),= & {beta }_{0}+{beta }_{1}{rm{paternal; age}}+{beta }_{2}{rm{maternal; age}}\ & +{beta }_{3}{rm{child; mean; RD}}+{beta }_{4}{rm{mother; mean; RD}}\ & +{beta }_{5},{rm{father; mean; RD}}+{beta }_{6}{rm{child; prop; aligned}}\ & +{beta }_{7}{rm{mother; prop; aligned}}+{beta }_{8}{rm{father; prop; aligned}}\ & +{beta }_{9}{rm{child; snvs}}+{beta }_{10}{rm{mother; snvs}}+{beta }_{11}{rm{father; snvs}}\ & +{beta }_{12}{rm{median; VAF}}+{beta }_{13}{rm{median; BF}}+{beta }_{14}{rm{hm; excess}}end{array}$$

The fraction of variance (F) explained after accounting for Poisson variance in the mutation rate was calculated in a similar way to in ref. 1 using the following formula:

$$F={rm{pseudo}},{R}^{2}frac{1-underline{Y}}{{rm{Var}}(Y)}$$

McFaddens pseudo R2 was used here as a negative binomial GLM was fitted. We repeated these analyses fitting an ordinary least squares regression, as was done in ref. 1, using the R2 and got comparable results. To calculate a 95% confidence interval, we used a bootstrapping approach. We sampled with a replacement 1,000 times and extracted the 2.5% and 97.5% percentiles.

We fit eight separate regressions to assess the contribution of rare variants in DNA-repair genes (compiled as described previously). These were across three different sets of genes: variants in all DNA-repair genes, variants in a subset of DNA-repair genes that are known to be associated with base-excision repair, MMR, NER or a DNA polymerase, and variants within this subset that have also been associated with a cancer phenotype. For this, we downloaded all ClinVar entries as of October 2019 and searched for germline pathogenic or likely pathogenic variants annotated with cancer55. We tested both all non-synonymous variants and just PTVs for each set. To assess the contribution of each of these sets, we created two binary variables per set indicating a presence or absence of a maternal or paternal variant for each individual, and then ran a negative binomial regression for each subset including these as independent variables along with hypermutation status, parental age and quality-control metrics as described in the previous section.

We downsampled from the full cohort to examine how the estimates of the fraction of variance in the numberof DNMs explained by paternal age varied with sample number. We first simulated a random sample as follows 10,000 times:

Randomly sample 78 trios (the number of trios in ref. 1.)

Fit ordinary least squares of E(Y)=0+1paternal age.

Estimated the fraction of variance (F) as described in ref. 1.

We found that the median fraction explained was 0.77, with a s.d. of 0.13 and with 95% of simulations fallings between 0.51 and 1.00.

To identify parents who had received a cancer diagnosis before the conception of their child, we examined the admitted patient care hospital episode statistics of these parents. There were no hospital episode statistics available before 1997, and many individuals did not have any records until after the birth of the child. To ensure that comparisons were not biased by this, we first subset to parents who had at least one episode statistic recorded at least two years before the childs year of birth. Two years before the childs birth was our best approximation for before conception without the exact child date of birth. This resulted in 2,891 fathers and 5,508 mothers. From this set we then extracted all entries with ICD10 codes with a C prefix, which corresponds to malignant neoplasms, and Z85, which corresponds to a personal history of malignant neoplasm. We defined a parent as having a cancer diagnosis before conception if they had any of these codes recorded 2 years before the childs year of birth. We also extracted all entries with ICD10 code Z511, which codes for an encounter for antineoplastic chemotherapy and immunotherapy.

Two fathers of individuals with hypermutation who we suspect had chemotherapy before conception did not meet these criteria as the father of GEL_5 received chemotherapy for treatment for systemic lupus erythematosus and not cancer and, for the father of GEL_8, the hospital record personal history of malignant neoplasm was entered after the conception of the child (Supplementary Table 5).

To compare the number of dnSNVs between the group of individuals with parents with and without cancer diagnoses, we used a Wilcoxon test on the residuals from the negative binomial regression on dnSNVs correcting for parental age, hypermutation status and data quality. To look at the effect of maternal cancer on dnSNVs, we matched these individuals on maternal and paternal age with sampling replacement with 20 controls for each of the 27 individuals. We found a significant increase in DNMs (74 compared to 65 median dnSNVs, P=0.001, Wilcoxon Test).

For this analysis, we started with the same subset of the 100kGP dataset that had been filtered as described in the analysis of the impact of rare variants in DNA-repair genes across the cohort (see above). To ensure variant quality, we subsetted to variants that have been observed in genomes from gnomAD (v.3)72. These were then filtered by ancestry to parentoffspring trios where both the parents and child mapped on to the 1000 Genomes GBR subpopulations. The first 10 principal components were subsequently included in the heritability analyses. To remove cryptic relatedness, we removed individuals with an estimated relatedness of >0.025 (using GCTA grm-cutoff, 0.025). This resulted in a set of 6,352 fathers and 6,329 mothers. The phenotype in this analysis was defined as the residual from the negative binomial regression of the number of DNMs after accounting for parental age, hypermutation status and several data quality variables, as described when estimating the fraction of DNM count variation explained (see above). To estimate heritability, we ran GCTA GREML-LDMS on two linkage disequilibrium stratifications and three MAF bins (0.0010.01, 0.010.05, 0.051)56. For mothers, this was run with the --reml-no-constrain option because it would otherwise not converge (Supplementary Table 9).

Further information on research design is available in theNature Research Reporting Summary linked to this paper.

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Genetic and chemotherapeutic influences on germline hypermutation - Nature.com

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PrecisionLife and Sano Genetics partnership will help identify treatments for long COVID – PharmaTimes

Posted: May 15, 2022 at 2:33 am

The project will analyse risks from Sano Genetics data from 3,000 UK adults suffering from long COVID

PrecisionLife has announced a partnership with Sano Genetics a genetic research platform enabling patients to participate in ethical research projects. It is hoped that the move will accelerate the understanding of long-term COVID-19 impacts.

The project will analyse Sano Genetics data from 3,000 UK adults suffering from long COVID symptoms, using PrecisionLifes proprietary combinatorial analytics platform to identify risk-factors and potential drug targets.

It is estimated that 5-30% of COVID-19 patients will go on to have long-term complications and with over 500 million people worldwide confirmed as having been infected the need for better diagnostics and treatments is of utmost importance.

Under the terms of the collaboration, Sano Genetics will provide access to its long COVID patient population dataset to PrecisionLife for analysis.

Dr Patrick Short, CEO and co-founder of Sano Genetics, said: Learning to live with COVID-19 and manage its health consequences has long term public health and economic implications. An estimated 1.7 million people in the UK have reported experiences of long COVID, with symptoms lasting longer than four weeks.

Understanding how our genetics influence our response to COVID-19 is key to better protecting vulnerable people and developing effective treatments. PrecisionLifes analysis of Sano Genetics data will enable this deep biological understanding.

Dr Steve Gardner, CEO of PrecisionLife, explained: Long COVID is a major public health issue. Most sufferers have no clear path for engaging with the healthcare system, as diagnosis is uncertain and the complex symptoms and causes of the disease are not yet fully understood. In our 2020 study, we noted a range of cardiovascular, immunological and neurological changes in COVID-19 patients, and want to understand whether these are transient or permanent.

"We are confident that this study into the long-term effects of SARS-CoV-2 infection, working in partnership with Sano Genetics, will deliver valuable insights to enable a better understanding of long COVID vulnerabilities and ultimately ensure that personalised treatments are directed towards those patients that need them most, he added.

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PrecisionLife and Sano Genetics partnership will help identify treatments for long COVID - PharmaTimes

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Can genetics be part of the ADHD puzzle? – Southernminn.com

Posted: May 15, 2022 at 2:33 am

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Can genetics be part of the ADHD puzzle? - Southernminn.com

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S&W Seed (SANW) and Trigall Genetics Enter Discussions to Combine Wheat Efforts in Australia – StreetInsider.com

Posted: May 15, 2022 at 2:33 am

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Trigall Genetics, the world leader in transgenic wheat, and S&W Seed Company (Nasdaq: SANW), a leading middle-market agricultural company, have entered preliminary, nonbinding discussions to potentially combine wheat operations through the creation of Trigall Australia, a wheat breeding company. The combination would harness S&W's Australian footprint and the capabilities of both Bioceres Crop Solutions (Nasdaq: BIOX) and Florimond Desprez, co-owners of Trigall Genetics.

Trigall Genetics is the world leader in transgenic wheat thanks to the development of its drought-tolerance HB4 EcoWheat technology and a leader in conventional wheat breeding in Argentina. Trigall Genetics aims to expand its activities into regions where farmers face climate change challenges and, more specifically, drought. With a harvest of more than 32 million tons of wheat, Australia is a priority development geography for Trigall Genetics, where the effects of climate change are ever more pressing.

S&W Seed Company currently conducts wheat breeding activities in Australia, counting wheat within its crop portfolio alongside sorghum, alfalfa, and various pasture crops. To ensure the most successful development of its wheat variety portfolio, S&W seeks to benefit from the expertise of an international wheat breeder such as Florimond Desprez. Florimond Desprez historically breeds wheat in Greater Europe, North Africa, and Latin America.

Trigall Australia activities would be based in New South Wales and would aim first at developing wheat varieties for all Australian regions and uses, all the while supporting Australian cereal farmers. Trigall Australia would be expected to be the favoured platform for Bioceres Crop Solutions and Florimond Desprez to develop their activities in Australia, be it crop productivity solutions or alternative breeding activities for crops such as barley, durum wheat, potato, or pulses. All Australian wheat breeding activities of S&W would be owned and operated by Trigall Australia.

Franois Desprez, president of Trigall Genetics and Florimond Desprez declares: "As a cereals and pulses breeder, we are very excited with this opportunity which could potentially allow us to step into a major wheat country in the world and reinforces the fruitful cooperation that exists between Bioceres Crop Solutions and Florimond Desprez since 2013."

Federico Trucco, vice-president of Trigall Genetics and CEO of Bioceres Crop Solutions comments: "This investment would be a very important step in our strategy to bring HB4 EcoWheat to farmers in every corner of the world. Australia is not only a leading participant of the global wheat value chain, but it is also a geography that is chronically affected by severe drought events, a condition we seek to mitigate with our drought tolerance technology. Partnering with S&W would allow us to make this opportunity a near-term reality."

Mark Wong, CEO of S&W Seed comments: "We believe this joint venture could significantly strengthen S&W's position in wheat, enabling us to benefit from the worldwide exposure the combined entity provides. Further, it would allow us to focus our efforts internally on our key centers of value. We look forward to further exploring the benefits this unique partnership would enable."

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Pink pigeons need a "genetic rescue" to survive extinction – Earth.com

Posted: May 15, 2022 at 2:33 am

In a new study, experts report that a boost in the number of pink pigeons in recent decades will not be enough to save the species from a high risk of extinction.

An international team of researchers led by the University of East Anglia worked with organizations in Mauritius to investigate the impacts of what ultimately became a genetic bottleneck across the wild population of pink pigeons.

Across Mauritius, an island nation in the Indian Ocean, there was a rapid collapse in numbers of the pink pigeon in the late 1980s. The decline worsened until there were only 12 birds surviving in the wild.

Since then, conservation efforts by the Mauritian Wildlife Foundation, the Durrell Wildlife Conservation Trust, and the Government of Mauritius National Parks and Conservation Service paid off. The number of wild pink pigeons reached around 500 birds.

The experts analyzed genetic samples that were collected from 175 pink pigeons over nearly two decades, as conservation efforts took place. Based on the analysis of the DNA, the experts found some disappointing news.

The researchers discovered that, despite an increase in population, the pink pigeon now has a high genetic load of bad mutations. They explained that these mutations put the birds at considerable risk of extinction in the wild within 100 years without continued conservation actions.

By studying the genome of a recovered species that was once critically endangered, we can learn how to help other species to bounce back from a population collapse, said study co-lead author Professor Cock van Oosterhout.

During the pigeons population bottleneck, the gene pool lost a lot of variation, and many bad mutations increased in frequency. This genetic load still poses a severe threat, even though the population has recovered in numbers.

The problem is that all individuals are somehow related to each other. They are the descendants of the few ancestors that managed to survive the bottleneck. Hence, it becomes virtually impossible to stop inbreeding, and this exposes these bad mutations. In turn, this can increase the mortality rate, and it could cause the population to collapse again.

The researchers warn that genetic rescue is needed to recover lost genetic variation caused by inbreeding and to reduce the effects of the harmful mutations. This could be achieved by releasing captive-bred birds from UK and EU zoos, they said.

A captive population of pink pigeons in the Gerald Durrell Endemic Wildlife Sanctuary in Mauritius, jointly managed by the Mauritian Wildlife Foundation and the National Parks and Conservation Service, was established in the 1970s, said Professor Jim Groombridge from the University of Kent.

This was used to breed birds for release into the wild, which boosted population numbers. The team also restored habitat by controlling introduced species and provided supplementary food as part of a field programme of intensive conservation management, which further increased the free-living population.

We didnt know how many bad mutations the population carried initially, before the bottleneck, said co-author Dr. Hernan Morales from University of Copenhagen. We first had to simulate the ancestral population to find out how many bad mutations could have evolved. We then checked this data with data on inbreeding depression data from zoo populations of the pink pigeon.

The researchers compared pedigree and fitness data to that of more than 1,000 birds at the Jersey Zoo. The analysis showed that the pink pigeon carried a high genetic load of 15 lethal equivalents.

The computer simulations clearly show that just boosting numbers isnt enough, said Dr. Morales. The population also needs genetic rescue from more genetically diverse birds bred in European zoos. These birds are not as closely related, and they can help to reduce the level of inbreeding. However, there is a risk that we could introduce other bad mutations from the zoo population into the wild.

According to study co-author Sam Speak, the team is now analyzing the genome of the pink pigeon from zoo populations in the UK, trying to locate these bad mutations. We can do this now using bioinformatics tools developed for studying human genetics and the genomes of other model bird species such as the chicken.

By using conservation genomics, future reintroduction programmes can avoid releasing individuals with high genetic load, said Speak. This would help reduce inbreeding and improve the long-term recovery of threatened species such as the pink pigeon.

The study is published in the journal Conservation Biology.

By Chrissy Sexton, Earth.com Staff Writer

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BrainStorm Strengthens Executive Team with Key Appointments in R&D and Legal USA – English – USA – English – PR Newswire

Posted: May 15, 2022 at 2:32 am

Netta Blondheim-Shraga, PhD Appointed as VP R&DAntalPearl-Lendner, Adv. Appointed as Chief Legal Counsel

NEW YORK, May 12, 2022 /PRNewswire/ --BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of cellular therapies for neurodegenerative diseases, announced two senior management appointments. Netta Blondheim Shraga, PhD has been appointed as VP, Research & Development, and AntalPearl-Lendner, Adv. has been appointed to the newly created position of Chief Legal Counsel. Both will report directly to Chaim Lebovits, CEO.

"We are thrilled to welcome Netta and Antal, each of whom brings valuable experience in their respective areas of R&D and Legal Affairs," said Chaim Lebovits, Chief Executive Officer of BrainStorm. "As we prepare the company for growth, it is important that we continue to build out our senior executive team and attract professionals with the appropriate skillsets. We look forward to leveraging their backgrounds as we execute on our mission to bring autologous cell therapies to patients with debilitating neurodegenerative diseases."

Dr. Blondheim-Shraga will be responsible for advancing the company's pipeline and steering the R&D team towards significant breakthroughs in the field of cell therapy and development of novel solutions to positively impact patients' health. Dr. Blondheim-Shraga joins BrainStorm with over 14 years of translational research experience in academic, biotech and pharma settings, having led teams in Israel, USA and China, combining scientific, entrepreneurial and management skills. Prior to joining BrainStorm, she was Project Leader on the Academic Affairs team at Teva Pharmaceuticals, Israel. In this role, she managed a portfolio of diverse and highly impactful strategic scientific collaborations with Teva's academic partners and managed Teva's involvement in several international consortia. Prior to Teva, she was Study Director and Senior Scientist at CrownBio, San Diego, CA. Earlier in her career, she was a Senior Scientist at Lifemap Sciences LTD in Tel-Aviv and served as Scientific Advisor to ImmunoHiTech LTD, Ramat Hasharon, Israel for several years. Dr. Blondheim-Shraga received a PhD from the Faculty of Medicine, Bar-Ilan University, Safed, Israel, an MSc Med from The Faculty of Medicine, Tel Aviv University, Israel and a BSc Med from The Faculty of Medicine, Hebrew University Jerusalem, Israel.

AntalPearl-Lendner, Adv. is an experienced bilingual attorney with a proven track record in legal and business development capacities. Prior to joining Brainstorm, Ms. Pearl-Lendner spent 8 years at Mizrahi-Tefahot Bankin Israel where her responsibilities included spearheading bank-wide complex projects, negotiating large scale international contracts and providing ongoing advice regarding the international activities of the bank. Before her tenure at the bank, she worked at GE Capital in Chicago and Connecticut, USA, where she served in GE's premier commercial leadership program, working in business development, strategy & analytics. Earlier in her career, Ms. Pearl-Lendner was an Associate Attorney in the international department of Caspi & Co. Advocates & Notaries in Tel Aviv, Israel. In this role she represented clients in M&A transactions and led due diligence processes for investments ranging from $5M to $350M. Ms. Pearl-Lendner received an MBA from the MIT Sloan School of Management in Cambridge, Massachusetts and an LLB from Tel Aviv University.

AboutBrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwn technology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug designation status from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has completed a Phase 3 pivotal trial in ALS (NCT03280056); this trial investigated the safety and efficacy of repeat-administration of autologous MSC-NTF cells and was supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). BrainStorm completed under an investigational new drug application a Phase 2 open-label multicenter trial (NCT03799718) of autologous MSC-NTF cells in progressive multiple sclerosis (MS) and was supported by a grant from the National MS Society (NMSS).

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future clinical trial enrollment and data, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may," "should," "would," "could," "will," "expect,""likely," "believe," "plan," "estimate," "predict," "potential," and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, prospects for future regulatory approval of BrainStorm's NurOwn treatment candidate, the success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our products and services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwn treatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture and commercialize the NurOwn treatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation; the impacts of the COVID-19 pandemic on our clinical trials, supply chain, and operations; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations, and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance, or achievements.

CONTACTS

Investor Relations:John MullalyLifeSci Advisors, LLCPhone: +1 617-429-3548 [emailprotected]

Media:Uri Yablonka[emailprotected]

SOURCE BrainStorm Cell Therapeutics Inc.

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BrainStorm Strengthens Executive Team with Key Appointments in R&D and Legal USA - English - USA - English - PR Newswire

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The One Doctor You Dont Have But Likely Need – TravelAwaits

Posted: May 15, 2022 at 2:30 am

Many retirees are concerned with staying physically and mentally healthy. As we age, our risk for diseases and injuries begins to increase. This is where integrative medicine can come into play.

As a primary care doctor and Osteopathic Physician (D.O.), I found looking for the root cause of illness and possible prevention much more challenging and rewarding than just diagnosing and medicating. Imagine if we can decrease breast cancer rates because of what we eat, how we reduce stress, and taking a look at advanced biomarkers and genetic testing. What if we can reverse diabetes and lower the risk of heart attacks and strokes and dementia? This is what gets me excited. Talking with my patients about alternative methods like using a sauna for 15-20 minutes four times a week is much more exciting than writing another diabetic script.

The term integrative medicine was born from combining the practice of so-called conventional medicine and complementary medicine. Conventional medicine is what most doctors practice. This is also called traditional Western medicine. Adding outside-the-box treatments such as chiropractic care, acupuncture, and other lifestyle recommendations like improving diet, supplements, herbs, exercise, stress management, and functional specialty labs results in the actual integration of the two disciplines. And we need both.

In some cases, especially those that are true emergencies, traditional medicine is lifesaving. But, in some cases, another prescription, procedure, or surgery is not going to help. One of the largest movements of integrative medicine in the United States is called Functional Medicine. Functional Medicine at its basic definition looks at the root cause of illness. While we look to undo the damage of the presenting complaints, doctors might integrate using traditional and complementary medicine to achieve healing. It makes sense. Look for why you have a problem and work backward. This contrasts the traditional medical diagnosis of a problem and writing a script to help.

You should look for where they received their integrative certificate. One of the most challenging programs is the Institute of Functional Medicine program. Its generally 3 additional years of study. Providers also have to take a board exam and present an actual patient case to be reviewed as part of the board examination. Once completed, they receive their certificate.

Another good idea is to read up on why someone is an integrative doctor. If they offer a free consultation, sign up and interview them. See if they have any reviews on their websites or if you can contact any of their current patients.

Pro Tip: Another consideration with an integrative doctor is how long they have been in practice. My suggestion is to find someone with 5 or more years of experience.

Integrative medicine is not covered because insurance companies cannot compensate properly for longer visit times or specialized and individualized medical and lifestyle care. This takes time. That is not how the traditional medical model was created. Insurance companies also dont recognize specialty blood work and other labs.

When you have a complex problem, a 10-minute office visit is not going to solve it. Integrative medicine takes time and is very complex. It is strategic in its approach. For example, if you have a medical condition called small intestinal bacterial overgrowth (SIBO) and have mold exposure, the questions become Which medical problem do you treat first? and How do you keep a patient from getting sick while treating?

Pro Tip: Have an HSA or FSA? Even though integrative medicine isnt covered by insurance, we take FSA and HSA payments. After every visit, a patient will receive an after-visit summary/receipt/invoice that they can turn into their insurance for potential partial reimbursement. Also, if prescribed by a doctor, we can fill out an insurance form allowing supplements to also be covered either with insurance or FSA/HSA funds.

There is no one answer to this question. But I can tell you why most of my patients see me. They are tired of being told everything is normal when they dont feel normal. They are looking for alternatives to hormone replacement therapy in the form of BHRT (bioidentical hormone replacement therapy).

My patients are also looking for someone who can help them become and stay healthy. Intuitively, you know that lifestyle medicine is important but you need someone to put it all together for you. You might be looking for the right diet for your body. You might want to lose weight because you know that even being 15 pounds overweight is causing many problems like diabetes, heart disease, and inflammation.

After an initial consultation with me, my patients receive health coaching, dietician consultation, and stress reduction tips. They learn how to sleep better and understand the importance of having a strong network of support. We also work through the right exercise programs.

I also order advanced medical lab testing for my patients. This is going way beyond and deeper than any traditional labs. Were doing stool studies, advanced mitochondrial studies, micronutrient testing, DNA aging testing, genetic testing, and more to improve lifestyle and function with an ultimate goal of disease prevention, longevity, and vitality.

Most of my patients come to me because they read something online and they get excited that there is a type of doctor out there who can help. Generally, they visit the Institution For Functional Medicine site to find a practitioner near them.

My patients come to me with a variety of issues: the guy who has eczema and is tired of using steroid creams learns gut health could be the root cause, the woman going through perimenopause or menopause who feels like she is going crazy but no one knows how to safely administer bioidentical hormones, the patient who has bloating after every meal and everyone tells her she is fine.

I also have patients who want to be able to put their own suitcases up on the top bin of an airplane well into their 70s and 80s. My patients value being functional. This is important. Not just growing old but growing old and staying functional. These are real patients with real issues who need more than conventional medicine to fix a problem.

I got into functional medicine because I knew there were solutions to all these problems. However, we were not taught how to fix them in medical school. Prescription medications can only do so much. I knew there were other ways to get to the root of the problems and not just mask them. My patients are living healthier, more fulfilling lives as we work toward the best solutions for each of them.

For more from Dr. Basima, consider 8 Ways To Improve Brain Function As We Age.

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Sure Signs You Have Hashimoto’s Disease Like Zoe Saldana Eat This Not That – Eat This, Not That

Posted: May 15, 2022 at 2:30 am

Hashimoto's Disease is an autoimmune disorder that affects the thyroid gland and "The number of people who have Hashimoto's disease in the United States is unknown. However, the disease is the most common cause of hypothyroidism, which affects about 5 in 100 Americans," according to the National Institute of Diabetes and Digestive and Kidney Disease. While it's unclear how many people struggle with Hashimoto's Disease, researchers do know it affects women more than men and Zoe Saldana can attest to that. The Avatar and Guardians of the Galaxy star revealed a few years ago she has the disorder, as do her mother and sister. To learn more about Hashimoto's Disease, Eat This, Not That! Health spoke with Dr. Michael Hirt, a Board Certified Nutrition from Harvard University and Board Certified in Internal Medicine and is with The Center for Integrative Medicine in Tarzana California who explained what to know. Read onand to ensure your health and the health of others, don't miss these Sure Signs You've Already Had COVID.

Dr. Hirt says, "Hashimoto's thyroiditis is a medical condition in which the immune system attacks your thyroid, a butterfly-shaped gland that sits just below your Adam's apple at the front of your neck. Early in the condition, patients may feel very little, but over time as the thyroid gland is destroyed by the immune attack, patients may begin to experience symptoms of insufficient thyroid hormone. These symptoms of low thyroid hormone levels typically include cold intolerance, fatigue, low mood, hair loss, constipation, generalized bloating, a weak voice, and weight gain."

Every cell in your body has a receptor for thyroid hormone. This means that healthy cells require healthy levels of thyroid hormone. Once the destructive process of Hashimoto's has compromised your gland's ability to pump out sufficient thyroid hormone, then patients will begin to experience the negative effects of low thyroid hormone blood levels. Much like the slow dimming of the lights at a movie theater just before the show starts, patients with Hashimoto's may not initially realize that their body is changing. Patients may think that they are tired because they didn't get enough sleep, that they are gaining weight because of their diet, or that they are bloated because of excessive salt consumption. Eventually, most patients will realize that something is very wrong and seek medical attention from their healthcare professional."

Dr. Hirt explains, "A simple blood test can determine the extent of the thyroid hormone deficiency and prescription thyroid hormone is available to replace the lack of hormone from the thyroid gland. (Fun fact: thyroid hormone was the very first prescription drug authorized in the United States, some 150 years ago.)"6254a4d1642c605c54bf1cab17d50f1e

Dr. Hirt lists the following signs to watch out for.

The Mayo Clinic states, "Hashimoto's disease is an autoimmune disorder. The immune system creates antibodies that attack thyroid cells as if they were bacteria, viruses or some other foreign body. The immune system wrongly enlists disease-fighting agents that damage cells and lead to cell death.

What causes the immune system to attack thyroid cells is not clear. The onset of disease may be related to:

According to the Mayo Clinic, "Most people with Hashimoto's disease take medication to treat hypothyroidism. If you have mild hypothyroidism, you may have no treatment but get regular TSH tests to monitor thyroid hormone levels.

T-4 hormone replacement therapy

Hypothyroidism associated with Hashimoto's disease is treated with a synthetic hormone called levothyroxine (Levoxyl, Synthroid, others). The synthetic hormone works like the T-4 hormone naturally produced by the thyroid.

The treatment goal is to restore and maintain adequate T-4 hormone levels and improve symptoms of hypothyroidism. You will need this treatment for the rest of your life." And to protect your life and the lives of others, don't visit any of these 35 Places You're Most Likely to Catch COVID.

Heather Newgen

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Sure Signs You Have Hashimoto's Disease Like Zoe Saldana Eat This Not That - Eat This, Not That

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