Removal of pregnancy categories and likelihood of prescribing: a randomized trial.

OBJECTIVES: To assess the degree to which removal of FDA' Pregnancy Categories (PC) of medications (A, B, C, and D) from labeling, affects the likelihood that providers will prescribe those medications. METHODS: Over a one-year period a convenience sample of providers was recruited into a randomized, survey-based, study. Two versions of the survey were randomly distributed; version 1 presented clinical vignettes, drug information, and PC, while version 2, presented the identical information without the PC. Respondents were asked to estimate their likelihood of prescribing the drug. A mixed linear model was constructed, with likelihood of prescription as the dependent variable, treated as interval-scaled. RESULTS: Out of 169 surveys given out, 162 (96%) were returned. Simple effects analysis showed that the presence of PC letter significantly affected the decision to prescribe category B (p<0.001) and C drugs (p=0.008) but not the A or D. Participants were significantly less likely to prescribe class B and C drugs when the letters were not available for review. These findings remained significant even when controlling for covariates (p=0.001). CONCLUSIONS: When a PC letter is absent on labeling, physicians were less likely to use category B and C drugs, the most common medications prescribed in pregnancy.

A highly potent maytansinoid analogue and its use as a cytotoxic therapeutic agent in gold nanoparticles for the treatment of hepatocellular carcinoma.

Gold nanoparticles are promising drug delivery agents with the potential to deliver chemotherapeutic agents to tumour sites. The highly cytotoxic maytansinoid tubulin inhibitor DM1 has been attached to gold nanoparticles and shows tumour growth inhibition in mouse models of hepatocellular carcinoma. Attempting to improve the stability of the gold-cytotoxin bond led to the design and synthesis of novel maytansinoids with improved potency in cell viability assays and improved in vivo tolerability compared to the DM1 analogues. These novel maytansines may also have applications in other methods of drug delivery, for example as the cytotoxic component of antibody drug conjugates.

Moment subset sums over finite fields.

The k-subset sum problem over finite fields is a classical NP-complete problem. Motivated by coding theory applications, a more complex problem is the higher m-th moment k-subset sum problem over finite fields. We show that there is a deterministic polynomial time algorithm for the m-th moment k-subset sum problem over finite fields for each fixed m when the evaluation set is the image set of a monomial or Dickson polynomial of any degree n. In the classical case m=1, this recovers previous results of Nguyen-Wang (the case m=1, p>2) [24] and the results of Choe-Choe (the case m=1, p=2) [3].

DM1 Loaded Ultrasmall Gold Nanoparticles Display Significant Efficacy and Improved Tolerability in Murine Models of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide with poor prognosis and limited options for treatment. Life expectancy after diagnosis is short; the currently available treatments are not well tolerated and have limited clinical benefit. There is a clear unmet clinical need for the development of new treatments. In this study, ultrasmall, 2 nm gold core nanoparticles (MidaCore) conjugated with the potent maytansine analogue DM1 (MTC-100038) were assessed as a systemic nanomedicine for the treatment of hepatocellular carcinoma. The platform improved overall tolerability of DM1, permitting ∼3-fold higher levels of drug to be administered compared to free drug. Dose for dose, MTC-100038 also facilitated delivery of ∼2.0-fold higher ( p = 0.039) levels of DM1 to the tumor compared to free DM1. MTC-100038 produced significant efficacy (tumor growth index ∼102%; p = <0.0001), in several murine xenograft models of HCC, and was superior to both free DM1 and the current standard of care, sorafenib. Furthermore, MTC-100038 displayed potent (nM) in vitro activity in various HCC primary patient derived cell lines and across various other different cancer cell types. These data demonstrate the potential of MidaCore nanoparticles to enhance tumor delivery of cytotoxic drugs and indicate MTC-100038 is worthy of further investigation as a potential treatment for HCC and other cancer types.

Race, Income, and Disease Outcomes in Juvenile Dermatomyositis.

OBJECTIVE: To determine the relationships among race, income, and disease outcomes in children with juvenile dermatomyositis (JDM). STUDY DESIGN: Data from 438 subjects with JDM enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Legacy Registry were analyzed. Demographic data included age, sex, race, annual family income, and insurance status. Clinical outcomes included muscle strength, presence of rash, calcinosis, weakness, physical function, and quality of life measures. Disease outcomes were compared based on race and income. RESULTS: Minority subjects were significantly more likely to have low annual family income and significantly worse scores on measures of physical function, disease activity, and quality of life measures. Subjects with lower annual family income had worse scores on measures of physical function, disease activity, and quality of life scores, as well as weakness. Black subjects were more likely to have calcinosis. Despite these differences in outcome measures, there were no significant differences among the racial groups in time to diagnosis or duration of disease. Using calcinosis as a marker of disease morbidity, black race, annual family income <$50 000 per year, negative antinuclear antibody, and delay in diagnosis >12 months were associated with calcinosis. CONCLUSION: Minority race and lower family income are associated with worse morbidity and outcomes in subjects with JDM. Calcinosis was more common in black subjects. Further studies are needed to examine these associations in more detail, to support efforts to address health disparities in subjects with JDM and improve disease outcomes.

Deprived, but not depraved: Prosocial behavior is an adaptive response to lower socioeconomic status.

Individuals of lower socioeconomic status (SES) display increased attentiveness to others and greater prosocial behavior compared to individuals of higher SES. We situate these effects within Pepper & Nettle's contextually appropriate response framework of SES. We argue that increased prosocial behavior is a contextually adaptive response for lower-SES individuals that serves to increase control over their more threatening social environments.

Sexually transmitted infections in children as a marker of child sexual abuse and direction of future research.

PURPOSE OF REVIEW: This review considers recent evidence on sexually transmitted infections (STIs) as a marker of child sexual abuse (CSA), when diagnosed after the neonatal period. It also aims to identify if there are specific areas where additional research is required. RECENT FINDINGS: An evidence-based systematic review using strict inclusion criteria shows that CSA is a major cause of STIs in children. In children 12 years and below, 36-83% of Neisseria gonorrhoeae and 75-94% of Chlamydia trachomatis infections are due to CSA; for children 14 years and younger, 31-58% of anogenital warts are due to CSA. In child genital sampling, genital human papillomavirus (HPV) types were more common in those considered abused (13.7%) than nonabused (1.3%). HPV typing of genital warts in children were all of genital type 6. Subsequent research, into N. gonorrhoeae, C. trachomatis, Trichomonas vaginalis and syphilis in children including ophthalmic infection, found that 13 of 15 cases were confirmed/likely due to CSA. Recent data indicate that bacterial vaginosis and Mycoplasma genitalium are related to sexual activity in adults but did not assess children. SUMMARY: STIs in children under 13-14 years may indicate CSA. Genital HPV types are associated with CSA. Research is required of sufficient standard to contribute to the evidence base.

Comparing WTP values of different types of QALY gain elicited from the general public.

BACKGROUND: The appropriate thresholds for decisions on the cost-effectiveness of medical interventions remain controversial, especially in 'end-of-life' situations. Evidence of the values placed on different types of health gain by the general public is limited. METHODS: Across nine European countries, 17,657 people were presented with different hypothetical health scenarios each involving a gain of one quality adjusted life year (QALY) and asked about their willingness to pay (WTP) for that gain. The questions included quality of life (QoL) enhancing and life extending health gains, and a scenario where respondents faced imminent, premature death. RESULTS: The mean WTP values for a one-QALY gain composed of QoL improvements were modest (PPP$11,000). When comparing QALY gains obtained in the near future, the valuation of life extension exceeded the valuation of QoL enhancing gains (mean WTP PPP$19,000 for a scenario in which a coma is avoided). The mean WTP values were higher still when respondents faced imminent, premature death (PPP$29,000). CONCLUSIONS: Evidence from the largest survey on the value of health gains by the general public indicated a higher value for life extending gains compared with QoL enhancing gains. A further modest premium may be indicated for life extension when facing imminent, premature death.

Multiple polymer architectures of human polyhomeotic homolog 3 sterile alpha motif.

The self-association of sterile alpha motifs (SAMs) into a helical polymer architecture is a critical functional component of many different and diverse array of proteins. For the Drosophila Polycomb group (PcG) protein Polyhomeotic (Ph), its SAM polymerization serves as the structural foundation to cluster multiple PcG complexes, helping to maintain a silenced chromatin state. Ph SAM shares 64% sequence identity with its human ortholog, PHC3 SAM, and both SAMs polymerize. However, in the context of their larger protein regions, PHC3 SAM forms longer polymers compared with Ph SAM. Motivated to establish the precise structural basis for the differences, if any, between Ph and PHC3 SAM, we determined the crystal structure of the PHC3 SAM polymer. PHC3 SAM uses the same SAM-SAM interaction as the Ph SAM sixfold repeat polymer. Yet, PHC3 SAM polymerizes using just five SAMs per turn of the helical polymer rather than the typical six per turn observed for all SAM polymers reported to date. Structural analysis suggested that malleability of the PHC3 SAM would allow formation of not just the fivefold repeat structure but also possibly others. Indeed, a second PHC3 SAM polymer in a different crystal form forms a sixfold repeat polymer. These results suggest that the polymers formed by PHC3 SAM, and likely others, are dynamic. The functional consequence of the variable PHC3 SAM polymers may be to create different chromatin architectures.

Uptake of the HPV vaccination programme in England: a cross-sectional survey of young women attending sexual health services.

OBJECTIVES: The U.K. human papilloma virus (HPV) vaccination programme requires 80% uptake to have a significant impact on cervical cancer rates. Uptake in the first three years of the programme was 66%. We report the results of a cross-sectional survey of young women attending sexual health services (SHS) in England, reviewing HPV vaccination uptake and prevalence of HPV-related risk factors. METHODS: An anonymous questionnaire surveyed women aged 13-19 attending 19 hospital-based and 13 community-based SHS across England, March-August 2011. Data were analysed using multiple logistic regression. RESULTS: 2247 questionnaires were completed. Compared with national data, respondents had higher smoking rates (48% vs. 14% of 15 year olds), coitarche under-16 (52% vs. 38%), previous sexually transmitted infections (STIs) (25% vs. 4%) and a higher proportion not in education, employment or training (NEETs) (8% vs. 2% of 16 year olds). Seventy-four per cent had been offered the vaccination, with significantly lower offer rates in London, non-white ethnicities, 17-19 year olds, NEETs, smokers and those with previous STIs (all p<0.05 in multivariate analysis). Sixty-five per cent of those offered, completed, with significantly lower completion rates in London, non-white ethnicities, 17-19 year olds, NEETs, smokers and those with previous STIs (all p<0.05 in multivariate analysis). Overall completion rate was 47%. CONCLUSIONS: We observed lower vaccination offer and completion rates and higher prevalence of HPV-related risk factors compared with national data. The highest risk individuals were the least likely to have been offered or to have completed the course. This survey highlights an opportunity for primary prevention by routinely offering the HPV vaccine to eligible women attending SHS.

The presentation, assessment, pathogenesis, and treatment of calcinosis in juvenile dermatomyositis.

Calcinosis is one of the hallmark sequelae of juvenile dermatomyositis (JDM), and despite recent progress in the therapy of JDM, dystrophic calcification still occurs in approximately one third of patients. This review discusses our current, albeit limited, understanding of risk factors for the development of calcinosis in JDM, as well as approaches to assessment, and current views on its pathogenesis. Anecdotal approaches to treating calcinosis associated with JDM, including both anti-inflammatory therapies and agents aimed at inhibiting the deposition of calcium hydroxyapatite, are reviewed. An improved understanding of the pathogenesis of calcinosis, the establishment of standardized measurement tools to assess calcinosis, and randomized controlled trials employing more sensitive outcome measures are needed to develop efficacious therapies for this often disabling complication.

Childhood Arthritis and Rheumatology Research Alliance Biologic DMARD Consensus Treatment Plans for Refractory Moderately Severe Juvenile Dermatomyositis.

OBJECTIVE: The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease-modifying antirheumatic drugs (bDMARDs). METHODS: The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Research Committee used case-based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM. RESULTS: Four bDMARD CTPs were proposed: TNF-alpha inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67/72]) as well as for patient characteristics, assessments, outcome measures, and follow up. By weighted average, respondents indicated that they would most likely use rituximab followed by abatacept, TNF-alpha inhibitor, and tocilizumab. CONCLUSION: CTPs for the use of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry-based prospective comparative effectiveness studies.

The growth-suppressive function of the polycomb group protein polyhomeotic is mediated by polymerization of its sterile alpha motif (SAM) domain.

Polyhomeotic (Ph), a member of the Polycomb Group (PcG), is a gene silencer critical for proper development. We present a previously unrecognized way of controlling Ph function through modulation of its sterile alpha motif (SAM) polymerization leading to the identification of a novel target for tuning the activities of proteins. SAM domain containing proteins have been shown to require SAM polymerization for proper function. However, the role of the Ph SAM polymer in PcG-mediated gene silencing was uncertain. Here, we first show that Ph SAM polymerization is indeed required for its gene silencing function. Interestingly, the unstructured linker sequence N-terminal to Ph SAM can shorten the length of polymers compared with when Ph SAM is individually isolated. Substituting the native linker with a random, unstructured sequence (RLink) can still limit polymerization, but not as well as the native linker. Consequently, the increased polymeric Ph RLink exhibits better gene silencing ability. In the Drosophila wing disc, Ph RLink expression suppresses growth compared with no effect for wild-type Ph, and opposite to the overgrowth phenotype observed for polymer-deficient Ph mutants. These data provide the first demonstration that the inherent activity of a protein containing a polymeric SAM can be enhanced by increasing SAM polymerization. Because the SAM linker had not been previously considered important for the function of SAM-containing proteins, our finding opens numerous opportunities to manipulate linker sequences of hundreds of polymeric SAM proteins to regulate a diverse array of intracellular functions.

Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease.

Hereditary hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, leading to hypertonia and apnea episodes. Missense, nonsense, frameshift, splice site mutations, and large deletions in the human glycine receptor α1 subunit gene (GLRA1) are the major known cause of this disorder. However, mutations are also found in the genes encoding the glycine receptor ß subunit (GLRB) and the presynaptic Na(+)/Cl(-)-dependent glycine transporter GlyT2 (SLC6A5). In this study, systematic DNA sequencing of SLC6A5 in 93 new unrelated human hyperekplexia patients revealed 20 sequence variants in 17 index cases presenting with homozygous or compound heterozygous recessive inheritance. Five apparently unrelated cases had the truncating mutation R439X. Genotype-phenotype analysis revealed a high rate of neonatal apneas and learning difficulties associated with SLC6A5 mutations. From the 20 SLC6A5 sequence variants, we investigated glycine uptake for 16 novel mutations, confirming that all were defective in glycine transport. Although the most common mechanism of disrupting GlyT2 function is protein truncation, new pathogenic mechanisms included splice site mutations and missense mutations affecting residues implicated in Cl(-) binding, conformational changes mediated by extracellular loop 4, and cation-π interactions. Detailed electrophysiology of mutation A275T revealed that this substitution results in a voltage-sensitive decrease in glycine transport caused by lower Na(+) affinity. This study firmly establishes the combination of missense, nonsense, frameshift, and splice site mutations in the GlyT2 gene as the second major cause of startle disease.

Implementing the supportive supervision intervention for registered nurses in a long-term care home: a feasibility study.

BACKGROUND: This pilot study was conducted in response to the call in 2009 by the International Association of Gerontology and Geriatrics to focus on effective leadership structures in nursing homes and to develop leadership capacity. Few researchers have evaluated interventions aimed at enhancing the leadership ability of registered nurses in long-term care. AIM: The aim of the pilot study was to test the feasibility of a three-part supportive supervisory intervention to improve supervisory skills of registered nurses in long-term care. METHODS: A repeated measures group design was used. Quantitative data were collected from healthcare aides, licensed practical nurses (i.e., supervised staff), and registered nurses (i.e., supervisors). Focus groups with care managers and supervisors examined perceptions of the intervention. RESULTS: There were nonsignificant changes in both the registered nurse supervisors' job satisfaction and the supervised staff's perception of their supervisors' support. Supervised staff scores indicated an increase in the use of research utilization but did not reflect an increase in job satisfaction. Focus group discussions revealed that the supervisors and care managers perceived the workshop to be valuable; however, the weekly self-reflection, coaching, and mentoring components of the intervention were rare and inconsistent. CONCLUSIONS: While the primary outcomes were not influenced by the Supportive Supervision Intervention, further effort is required to understand how best to enhance the supportive supervisory skills of RNs. Examples of how to improve the possibility of a successful intervention are advanced. IMPLICATIONS: Effective supervisory skills among registered nurses are crucial for improving the quality of care in long-term care homes. Registered nurses are receptive to interventions that will enhance their roles as supervisors.

Pre-Clinical Development of an Adenovirus Vector Based RSV and Shingles Vaccine Candidate.

Respiratory syncytial virus (RSV) infection and shingles are two viral diseases that affect older adults, and a combined vaccine to protect against both could be beneficial. RSV infection causes hospitalisations and significant morbidity in both children and adults and can be fatal in the elderly. The RSV fusion (F) envelope glycoprotein induces a strong RSV-neutralising antibody response and is the target of protective immunity in the first RSV vaccine for older adults, recently approved by the FDA. An initial childhood infection with the varicella zoster virus (VZV) results in chickenpox disease, but reactivation in older adults can cause shingles. This reactivation in sensory and autonomic neurons is characterized by a skin-blistering rash that can be accompanied by prolonged pain. The approved protein-in-adjuvant shingles vaccine induces VZV glycoprotein E (gE)-fspecific antibody and CD4+ T cell responses and is highly effective. Here we report the evaluation of RSV/shingles combination vaccine candidates based on non-replicating chimpanzee adenovirus (ChAd) vectors. We confirmed the cellular and humoral immunogenicity of the vaccine vectors in mice using T cell and antibody assays. We also carried out an RSV challenge study in cotton rats which demonstrated protective efficacy following a homologous prime-boost regimen with our preferred vaccine candidate.

Treatment escalation patterns to start biologics in refractory moderate juvenile dermatomyositis among members of the Childhood Arthritis and Rheumatology Research Alliance.

BACKGROUND: Despite new and better treatments for juvenile dermatomyositis (JDM), not all patients with moderate severity disease respond adequately to first-line therapy. Those with refractory disease remain at higher risk for disease and glucocorticoid-related complications. Biologic disease-modifying antirheumatic drugs (DMARDs) have become part of the arsenal of treatments for JDM. However, prospective comparative studies of commonly used biologics are lacking. METHODS: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM biologics workgroup met in 2019 and produced a survey assessing current treatment escalation practices for JDM, including preferences regarding use of biologic treatments. The cases and questions were developed using a consensus framework, requiring 80% agreement for consensus. The survey was completed online in 2020 by CARRA members interested in JDM. Survey results were analyzed among all respondents and according to years of experience. Chi-square or Fisher's exact test was used to compare the distribution of responses to each survey question. RESULTS: One hundred twenty-one CARRA members responded to the survey (denominators vary for each question). Of the respondents, 88% were pediatric rheumatologists, 85% practiced in the United States, and 43% had over 10 years of experience. For a patient with moderately severe JDM refractory to methotrexate, glucocorticoids, and IVIG, approximately 80% of respondents indicated that they would initiate a biologic after failing 1-2 non-biologic DMARDs. Trials of methotrexate and mycophenolate were considered necessary by 96% and 60% of respondents, respectively, before initiating a biologic. By weighed average, rituximab was the preferred biologic over abatacept, tocilizumab, and infliximab. Over 50% of respondents would start a biologic by 4 months from diagnosis for patients with refractory moderately severe JDM. There were no notable differences in treatment practices between respondents by years of experience. CONCLUSION: Most respondents favored starting a biologic earlier in disease course after trialing up to two conventional DMARDs, specifically including methotrexate. There was a clear preference for rituximab. However, there remains a dearth of prospective data comparing biologics in refractory JDM. These findings underscore the need for biologic consensus treatment plans (CTPs) for refractory JDM, which will ultimately facilitate comparative effectiveness studies and inform treatment practices.

2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

Human polyhomeotic homolog 3 (PHC3) sterile alpha motif (SAM) linker allows open-ended polymerization of PHC3 SAM.

Sterile alpha motifs (SAMs) are frequently found in eukaryotic genomes. An intriguing property of many SAMs is their ability to self-associate, forming an open-ended polymer structure whose formation has been shown to be essential for the function of the protein. What remains largely unresolved is how polymerization is controlled. Previously, we had determined that the stretch of unstructured residues N-terminal to the SAM of a Drosophila protein called polyhomeotic (Ph), a member of the polycomb group (PcG) of gene silencers, plays a key role in controlling Ph SAM polymerization. Ph SAM with its native linker created shorter polymers compared to Ph SAM attached to either a random linker or no linker. Here, we show that the SAM linker for the human Ph ortholog, polyhomeotic homolog 3 (PHC3), also controls PHC3 SAM polymerization but does so in the opposite fashion. PHC3 SAM with its native linker allows longer polymers to form compared to when attached to a random linker. Attaching the PHC3 SAM linker to Ph SAM also resulted in extending Ph SAM polymerization. Moreover, in the context of full-length Ph protein, replacing the SAM linker with PHC3 SAM linker, intended to create longer polymers, resulted in greater repressive ability for the chimera compared to wild-type Ph. These findings show that polymeric SAM linkers evolved to modulate a wide dynamic range of SAM polymerization abilities and suggest that rationally manipulating the function of SAM containing proteins through controlling their SAM polymerization may be possible.