Challenges of variant reinterpretation: Opinions of stakeholders and need for guidelines.

PURPOSE: The knowledge used to classify genetic variants is continually evolving, and the classification can change on the basis of newly available data. Although up-to-date variant classification is essential for clinical management, reproductive planning, and identifying at-risk family members, there is no consistent practice across laboratories or clinicians on how or under what circumstances to perform variant reinterpretation. METHODS: We conducted exploratory focus groups (N = 142) and surveys (N = 1753) with stakeholders involved in the process of variant reinterpretation (laboratory directors, clinical geneticists, genetic counselors, nongenetic providers, and patients/parents) to assess opinions on key issues, including initiation of reinterpretation, variants to report, termination of the responsibility to reinterpret, and concerns about consent, cost, and liability. RESULTS: Stakeholders widely agreed that there should be no fixed termination point to the responsibility to reinterpret a previously reported genetic variant. There were significant concerns about liability and lack of agreement about many logistical aspects of variant reinterpretation. CONCLUSION: Our findings suggest a need to (1) develop consensus and (2) create transparency and awareness about the roles and responsibilities of parties involved in variant reinterpretation. These data provide a foundation for developing guidelines on variant reinterpretation that can aid in the development of a low-cost, scalable, and accessible approach.

Co-development of the ENVISAGE-Families programme for parents of children with disabilities: Reflections on a parent-researcher partnership.

INTRODUCTION: In childhood disability research, the involvement of families is essential for optimal outcomes for all participants. ENVISAGE (ENabling VISions And Growing Expectations)-Families is a programme comprising five online workshops for parents of children with neurodevelopmental disorders. The workshops aim to introduce parents to strengths-based perspectives on health and development. The research is based on an integrated Knowledge Translation (iKT) approach, in which knowledge users are involved throughout the research process. This article is co-authored by the ENVISAGE health service researchers (N = 9) and parent partners (N = 3) to describe the process through which we co-developed and implemented the workshops. METHODS: Collaborative auto-ethnography methods, based on a combination of interviews, qualitative surveys, and discussions held to complete the Guidance for Reporting Involvement of Patients and Public-2 tool, were used to describe the co-design process, the benefits gained, and lessons learned. FINDINGS: Parents (n = 118) were involved in developing and implementing the ENVISAGE workshops across the different phases, as partners, collaborators, or participants. Three parents were involved as investigators throughout. We identify seven key ingredients that we believe are necessary for a successful parent-researcher working relationship: (i) consistent communication; (ii) clear roles and expectations; (iii) onboarding and feedback; (iv) flexibility; (v) understanding; (vi) self-reflection; and (vii) funding. CONCLUSION: Patient and family engagement in research is a rapidly growing area of scholarship with new knowledge and tools added every year. As our team embarks on new collaborative studies, we incorporate this knowledge as well as the practical experience we gain from working together.

Knowledge and attitudes about genetic counseling in patients at a major hospital in Addis Ababa, Ethiopia.

Previous work at St. Paul's Hospital Millennium Medical College (SPHMMC) in Addis Ababa, Ethiopia, demonstrated a need for genetic counseling (GC) services, with 4% of pediatric, neonatal intensive care, and prenatal patients identified as having indications for genetic evaluation (Quinonez et al, 2019). The aim of this study was to investigate SPHMMC patients' familiarity with, knowledge of, and attitudes toward GC services. Surveys were adapted from previous work in North America populations (Riesgraf et al, 2015 and Gemmell et al, 2017) and administered to 102 patients, and results were compared to North American populations using Student's t test. 30% of respondents reported at least some familiarity with GC, primarily via the media or healthcare providers. Patients had generally positive attitudes toward GC, reporting they would trust information provided by a genetic counselor and that GC is in line with their values. Knowledge of GC showed similar trends overall when compared to results from North American populations. Our work indicates limited exposure to GC in this population, but generally positive feelings toward GC. Patients' attitudes toward GC were comparable to rural North American populations surveyed using the same tool on most items; however, cultural differences including views on abortions and directiveness of healthcare providers could account for discrepancies and are important considerations when implementing genetic services globally.

Assessment of posterior tongue mobility using lingual-palatal suction: Progress towards a functional definition of ankyloglossia.

BACKGROUND: A functional definition of ankyloglossia has been based on assessment of tongue mobility using the tongue range of motion ratio (TRMR) with the tongue tip extended towards the incisive papilla (TIP). Whereas this measurement has been helpful in assessing for variations in the mobility of the anterior one-third of the tongue (tongue tip and apex), it may be insufficient to adequately assess the mobility of the posterior two-thirds body of the tongue. A commonly used modification is to assess TRMR while the tongue is held in suction against the roof of the mouth in lingual-palatal suction (LPS). OBJECTIVE: This study aims to explore the utility and normative values of TRMR-LPS as an adjunct to functional assessment of tongue mobility using TRMR-TIP. STUDY DESIGN: Cross-sectional cohort study of 611 subjects (ages: 3-83 years) from the general population. METHODS: Measurements of tongue mobility using TRMR were performed with TIP and LPS functional movements. Objective TRMR measurements were compared with subjective self-assessment of resting tongue position, ease or difficulty elevating the tongue tip to the palate, and ease or difficulty elevating the tongue body to the palate. RESULTS: There was a statistically significant association between the objective measures of TRMR-TIP and TRMR-LPS and subjective reports of tongue mobility. LPS measurements were much more highly correlated with differences in elevating the posterior body of the tongue as compared to TIP measurements (R2 0.31 vs 0.05, P < .0001). CONCLUSIONS: This study validates the TRMR-LPS as a useful functional metric for assessment of posterior tongue mobility.

Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.

BACKGROUND: As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate. METHODS: Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES. RESULTS: Overall, 30% of patients who underwent CES had an identified pathogenic mutation. The most common phenotypes were developmental delay (83%), neuromuscular system abnormalities (81%), and multiple congenital anomalies (42%). In all, 67% of patients had a variant of uncertain significance (VUS) or gene of uncertain significance (GUS); 23% had no variants reported. There was a significant difference in the average number of body systems affected among these groups (pathogenic 5.89, VUS 6.0, GUS 6.12, and no variant 4.6; P < 0.00001). Representative cases highlight four ways in which CES is changing clinical pediatric practice. CONCLUSIONS: Patients with identified variants are enriched for multiple organ system involvement. Furthermore, our phenotyping provides broad insights into which patients are most likely to benefit from genetics referral and CES and how those results can help guide clinical practice more generally.

Brief Report: Low-Barrier Buprenorphine Initiation Predicts Treatment Retention Among Latinx and Non-Latinx Primary Care Patients.

BACKGROUND AND OBJECTIVES: Patients are at risk of dropout while waiting for buprenorphine treatment. Study goals are to compare 3-month retention in two different methods to buprenorphine initiation among persons with opioid use disorder. METHODS: We compared 3-month treatment retention rates of low-barrier buprenorphine initiation (i.e., rapid induction) (n =58) or a traditional method of buprenorphine initiation ( n = 45) for persons with opioid use disorder seen at an urban community health center. RESULTS: Logistic regression revealed that low-barrier initiation had 11.11 greater odds of retention compared with traditional methods (p <0.001). Latinx patients benefited more than non-Latinx patients (OR = 14.79, p =.039). DISCUSSION AND CONCLUSIONS: All patients were more likely to be retained using low-barrier initiation. A significantly larger effect on retention among Latinx patients was observed. SCIENTIFIC SIGNIFICANCE: Rapid buprenorphine initiation increases treatment retention which improves treatment outcomes for persons with opioid use disorder. Study findings support a less restrictive services model that is even more effective for Latinx patients. (Am J Addict 2019;28:409-412).

Primary care physicians' understanding and utilization of pediatric exome sequencing results.

Optimizing exome sequencing (ES) utility requires effective communication and collaboration between primary care physicians (PCPs) and genetics healthcare providers (GHP). To explore how PCPs use ES results to coordinate multipart management plans for complex pediatric patients, we assessed result understanding and utilization. Twenty-seven PCPs of pediatric patients with ES results from a genetics clinic completed a mixed methods 45-question survey measuring perceived genetics knowledge, confidence performing genetics tasks, understanding of ES technology and results, and expectations of GHP. Quantitative and qualitative data analysis classified by ES result types generated descriptive statistics, Pearson correlation coefficients, and common themes. Forty-five-percent of PCPs interpreted variant of uncertain significance results as diagnostic (implementing management changes and recommending familial testing). Most PCPs (85%) identified positive ES results impacts, but only 65% indicated ES was beneficial to care. The majority (74%) expected GHP and patients' families to assume follow-up care responsibility and future ES results re-interpretations. Limited knowledge may be a factor, as 59% desired more patient care information from GHP. Our results suggest optimizing continuity of care and collaboration for pediatric patients with ES results requires additional communication between GHP and PCPs, along with continuing genetics education for PCPs aimed at improving genetic literacy.

A recurrent de novo CTBP1 mutation is associated with developmental delay, hypotonia, ataxia, and tooth enamel defects.

Exome sequencing is an effective way to identify genetic causes of etiologically heterogeneous conditions such as developmental delay and intellectual disabilities. Using exome sequencing, we have identified four patients with similar phenotypes of developmental delay, intellectual disability, failure to thrive, hypotonia, ataxia, and tooth enamel defects who all have the same de novo R331W missense variant in C-terminal binding protein 1 (CTBP1). CTBP1 is a transcriptional regulator critical for development by coordinating different regulatory pathways. The R331W variant found in these patients is within the C-terminal portion of the PLDLS (Pro-Leu-Asp-Leu-Ser) binding cleft, which is the domain through which CTBP1, interacts with chromatin-modifying enzymes and mediates chromatin-dependent gene repression pathways. This is the first report of mutations within CTBP1 in association with any human disease.

A systematic review of evidence-based assessment practices by allied health practitioners for children with cerebral palsy.

AIM: The routine use of psychometrically robust assessment tools is integral to best practice. This systematic review aims to determine the extent to which evidence-based assessment tools were used by allied health practitioners for children with cerebral palsy (CP). METHOD: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols 2015 was employed. A search strategy applied the free text terms: 'allied health practitioner', 'assessment', and 'cerebral palsy', and related subject headings to seven databases. Included articles reported assessment practices of occupational therapists, physiotherapists, or speech pathologists working with children with CP aged 0 to 18 years, published from the year 2000. RESULTS: Fourteen articles met the inclusion criteria. Eighty-eight assessment tools were reported, of which 23 were in high use. Of these, three tools focused on gross motor function and had acceptable validity for use with children with CP: Gross Motor Function Measure, Gross Motor Function Classification System, and goniometry. Validated tools to assess other activity components, participation, quality of life, and pain were used infrequently or not at all. INTERPRETATION: Allied health practitioners used only a few of the available evidence-based assessment tools. Assessment findings in many areas considered important by children and families were rarely documented using validated assessment tools.

Child Maltreatment, Trauma, and Physical Health Outcomes: The Role of Abuse Type and Placement Moves on Health Conditions and Service Use for Youth in Foster Care.

OBJECTIVE: The purpose of the study was to investigate the relations between abuse types, non-maltreatment-related trauma, and health service utilization in a sample of youth in foster care with and without chronic medical conditions. METHOD: A total of 213 youth, aged 8-21 years, provided self-report of general trauma and abuse exposure. Medicaid claims for each child were collected from official state databases. RESULTS: Exposure to sexual abuse, neglect, or general trauma but not exposure to physical abuse or psychological abuse increased the rates of medical visits, while only general trauma increased medical hospitalizations. CONCLUSIONS: Trauma types are not equally predictive of health care utilization for youth with chronic health conditions.

Sustained transmission over two decades of a previously unrecognised MPT64 negative Mycobacterium tuberculosis strain in Queensland, Australia: a whole genome sequencing study.

Background: MPT64 is a key protein used for Mycobacterium tuberculosis (MTB) complex strain identification. We describe protracted transmission of an MPT64 negative MTB strain in Queensland, Australia, and explore genomic factors related to its successful spread. Methods: All MPT64 negative strains identified between 2002 and 2022 by the Queensland Mycobacteria Reference Laboratory, and an additional 2 isolates from New South Wales (NSW), were whole genome sequenced. Bayesian modelling and phylogeographical analyses were used to assess their evolutionary history and transmission dynamics. Protein structural modelling to understand the putative functional effects of the mutated gene coding for MPT64 protein was performed. Findings: Forty-three MPT64 negative isolates were sequenced, belonging to a single MTB cluster of Lineage 4.1.1.1 strains. Combined with a UK dataset of the same lineage, molecular dating estimated 1990 (95% HPD 1987-1993) as the likely time of strain introduction into Australia. Although the strain has spread over a wide geographic area and new cases linked to the cluster continue to arise, phylodynamic analysis suggest the outbreak peaked around 2003. All MPT64 negative strains had a frame shift mutation (delAT, p.Val216fs) within the MPT64 gene, which confers two major structural rearrangements at the C-terminus of the protein. Interpretation: This study uncovered the origins of an MPT64 negative MTB outbreak in Australia, providing a richer understanding of its biology and transmission dynamics, as well as guidance for clinical diagnosis and public health action. The potential spread of MPT64 negative strains undermines the diagnostic utility of the MPT64 immunochromatographic test. Funding: This study was funded from an operational budget provided to the Queensland Mycobacterium Reference Laboratory by Pathology Queensland, Queensland Department of Health.

Risk of measles transmission on aeroplanes: Australian experience 2007-2011.

OBJECTIVE: To quantify the risk of transmission of measles associated with infectious people who travelled on aeroplane flights to or within Australia. DESIGN, SETTING AND SUBJECTS: Data were obtained from state and territory health authorities on all measles notifications from January 2007 to June 2011 for people who were likely to have been infectious or infected while travelling on aeroplanes in Australia. RESULTS: Forty-five infectious people travelled on aeroplanes. Twenty secondary infections occurred in people on seven of 49 flights (14%; 95% CI, 6%-29%), comprising 19% (95% CI, 8%-40%) of the 36 international flights and none of 13 (95% CI, 0-28%) domestic flights that carried infectious people. Secondary infections occurred in nine people who were seated within two rows of the index case and in 11 people who were seated outside of two rows. Secondary transmission was more likely to occur with younger index cases (P = 0.025) and when there were multiple infectious people travelling (P = 0.018). About a third(15/49) of flight manifests were available to health authorities within 5 days oftravel. CONCLUSION: Despite secondary measles transmission occurring on 19% of international flights carrying infectious people, risk was not clearly related to seating proximity, and contact tracing was ineffective, especially given delays in diagnosis, notification and accessing flight manifests. We recommend that direct contact tracing to identify susceptible people exposed to people infected with measles on aeroplane flights should not be undertaken routinely, and other strategies should be considered.

A five-year analysis of latent tuberculosis infection in Queensland, 2016-2020.

Background Australia is aiming to reach tuberculosis pre-elimination targets by 2035. As a low-incidence setting, control efforts will increasingly rely on the management of latent tuberculosis infection (LTBI). We undertook this descriptive analysis to assess the recent trends of LTBI testing in Queensland. Methods Our objective was to describe the features of LTBI testing in Queensland, and to estimate the range of possible annual notifications were it to be made a notifiable condition. We collated both state-wide and region-specific data on tuberculin skin testing (TST) and interferon gamma release assays (IGRA) conducted in Queensland during the five-year period 1 January 2016 - 31 December 2020. We used reports on Medicare-funded TST and IGRA testing in Queensland, as well as tuberculosis notification data, to understand the representativeness of our data and to derive state-wide estimates. Results We analysed 3,899 public TST, 5,463 private TST, 37,802 public pathology IGRA, and 31,656 private pathology IGRA results. The median age of people tested was 31 years; 57% of those tested were female. From our data sources, an annual average of 1,067 positive IGRA and 354 positive TST results occurred in Queensland. Building on this minimum value, we estimate possible latent tuberculosis notifications in Queensland could range from 2,901 to 6,995 per annum. Private laboratory TSTs are estimated to contribute the lowest number of potential notifications (range: 170-340), followed by private laboratory IGRA testing (range: 354-922), public laboratory IGRA testing (range: 706-1,138), and public setting TSTs (range: 1,671-4,595). Conclusion If LTBI were to be made notifiable, these estimates would place it among the ten most notified conditions in Queensland. This has implications for potential surveillance methods and goals, and their associated system and resource requirements.

Additive effect of TAp63 deficiency on the adrenocortical dysplasia (acd) phenotype.

Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutation exhibiting caudal truncation, vertebral segmentation defects, hydronephrosis, limb hypoplasia, and perinatal lethality. Acd encodes TPP1, a component of the shelterin complex that maintains telomere integrity, and consequently acd mutant mice have telomere dysfunction and genomic instability. We previously showed that apoptosis is the primary mechanism causing the acd skeletal phenotype, and that p53 deficiency rescues the skeletal defects of the acd phenotype but has no effect on the perinatal lethality. The Trp63 gene encodes multiple isoforms, which play a role in proliferation, apoptosis, and stem/progenitor cell maintenance. Different p63 isoforms exhibit both proapoptotic (TAp63) and antiapoptotic (ΔNp63) functions. We hypothesized that deficiency of proapoptotic TAp63 isoforms might rescue the acd skeletal phenotype, similar to our previous observations with deficiency of p53. Mice heterozygous for a null allele of TAp63 were crossed to heterozygous acd mice to determine the effect of TAp63 deficiency on the acd mutant phenotype. In contrast to our results with the acd × p53 cross, skeletal anomalies were not rescued by deficiency of TAp63. In fact, the limb and vertebral anomalies observed in double-mutant embryos were more severe than those of embryos with the acd mutation alone, demonstrating a dose-dependent effect. These studies suggest that TAp63 isoforms do not facilitate p53-like apoptosis during development in response to acd-mediated telomere dysfunction and are consistent with the proposed roles of TAp63 in maintaining genomic stability.

Steering towards collaborative assessment: a qualitative study of parents' experiences of evidence-based assessment practices for their child with cerebral palsy.

PURPOSE: To understand parents' experiences of evidence-based assessment by health professionals for their child with cerebral palsy. METHODS: A qualitative interpretive description study was undertaken. Primary carers of children with cerebral palsy (aged 3-18 years) from south-eastern Australia were invited to participate. Face-to-face interviews were held using a semi-structured topic guide and data analyzed inductively. Credibility was ensured through: journal reflections; co-author review; audit trail; and, participant member-checking. RESULTS: Fourteen parents of children with cerebral palsy, representing Gross Motor Functional Classification System levels I-V, participated. Six themes emerged: (1) Protection; (2) Positively Framed; (3) Bridging the Gap; (4) Involvement; (5) Finding Worth; and (6) Trust. Central to parents' experience was protection of their child's identity and personal self. Assessment can be emotionally confronting, at any stage. Representing the child positively and highlighting possibilities was deemed essential. Parents' involvement ranged from being overlooked spectators to being instigators of assessment. Evidence-based assessment was worthwhile when relevant to parents' direction and family context. The researchers' interpretive description generated a schema and metaphor-the Steering Wheel for Collaborative Assessment. CONCLUSIONS: A strengths-based approach to diagnosis and assessment is essential. The resulting interpretive description may assist health professionals align evidence-based assessment practices with family-centred care.Implications for rehabilitationParents of children who have cerebral palsy describe having to protect their child's identity and representation, and their own personal well-being, through evidence-based assessment and diagnostic processes.Involving parents in the process of evidence-based assessment and adopting a strengths-based approach is essential.The interpretive description developed-the Steering Wheel for Collaborative Assessment-may assist health professionals to implement evidence-based assessment tools in ways consistent with family-centred care principles.

Structural racism and reflections from Latinx heavy drinkers: Impact on mental health and alcohol use.

BACKGROUND: Discrimination and social inequity increase risk for alcohol use disorders among Latinxs. An alcohol intervention trial that led to significant reductions in alcohol-related consequences also produced significant reductions in mental health symptoms for Latinx heavy drinkers. In the current qualitative study, we explore this trial's mental health effect by examining participants' perspectives on the social context of immigration, i.e., structural barriers, and associations among the immigrant experience, stigma, depressive/anxiety symptomatology, and alcohol consumption. METHODS: Study participants were eligible if they completed the clinical trial, exhibited levels of depressive and anxiety symptoms that exceeded the range for clinical depression (≥18, CES-D) and anxiety (≥12, BAI) at baseline, and demonstrated significant declines in depression and anxiety symptoms 12 months following their completion of the trial. The study coded 24 participant transcripts using ATLAS.ti and thematic analysis. RESULTS: Participants reported their responses to structural barriers (e.g., a lack of educational supports, difficulties accessing safety net programs). Reported experiences of exclusion and discrimination were associated with depressive and anxiety symptoms. Stigmatization processes included feeling isolated and contributed to poor mental health. Participants reported drinking to cope with low mood. CONCLUSIONS: Structural barriers are exclusionary because they limit full participation and communicate who does/does not belong along race/ethnic lines, i.e., structural racism. Feeling stigmatized for being different was associated with feelings of anxiety and depression among our immigrant participants. Future interventions must focus on stressors associated with the constraints of being an immigrant. Understanding how structural barriers and structural racism impact health behavior can enrich the design and impact of interventions for socially disadvantaged Latinx individuals.

The introduction of genetic counseling in Ethiopia: Results of a training workshop and lessons learned.

BACKGROUND: Over the past two decades non-communicable diseases (NCDs) have steadily increased as a cause of worldwide disability and mortality with a concomitant decrease in disease burden from communicable, maternal, neonatal and nutritional conditions. Congenital anomalies, the most common NCD affecting children, have recently become the fifth leading cause of under-five mortality worldwide, ahead of other conditions such as malaria, neonatal sepsis and malnutrition. Genetic counseling has been shown to be an effective method to decrease the impact of congenital anomalies and genetic conditions but is absent in almost all sub-Saharan Africa countries. To address this need for counseling services we designed and implemented the first broad-based genetic counseling curriculum in Ethiopia, launching it at St. Paul's Millennium Medical College (SPHMMC) in Addis Ababa, Ethiopia. METHODS: The curriculum, created by Michigan Medicine and SPHMMC specialists, consisted of medical knowledge and genetic counseling content and was delivered to two cohorts of nurses. Curriculum evaluation consisted of satisfaction surveys and pre- and post-assessments covering medical knowledge and genetic counseling content. Following Cohort 1 training, the curriculum was modified to increase the medical knowledge material and decrease Western genetic counseling principles material. RESULTS: Both cohorts reported high levels of satisfaction but felt the workshop was too short. No significant improvements in assessment scores were seen for Cohort 1 in terms of total scores and medical knowledge and genetic counseling-specific questions. Following curriculum modification, improvements were seen in Cohort 2 with an increase in total assessment scores from 63% to 73% (p = 0.043), with medical knowledge-specific questions increasing from 57% to 79% (p = 0.01) with no significant change in genetic counseling-specific scores. Multiple logistic, financial, cultural and systems-specific barriers were identified with recommendations for their consideration presented. CONCLUSION: Genetics medical knowledge of Ethiopian nurses increased significantly following curriculum delivery though difficulty was encountered with Western genetic counseling material.

Caudal regression in adrenocortical dysplasia (acd) mice is caused by telomere dysfunction with subsequent p53-dependent apoptosis.

Adrenocortical dysplasia (acd) is a spontaneous autosomal recessive mouse mutation that exhibits a pleiotropic phenotype with perinatal lethality. Mutant acd embryos have caudal truncation, vertebral segmentation defects, hydronephrosis, and limb hypoplasia, resembling humans with Caudal Regression syndrome. Acd encodes Tpp1, a component of the shelterin complex that maintains telomere integrity, and consequently acd mutant mice have telomere dysfunction and genomic instability. While the association between genomic instability and cancer is well documented, the association between genomic instability and birth defects is unexplored. To determine the relationship between telomere dysfunction and embryonic malformations, we investigated mechanisms leading to the caudal dysgenesis phenotype of acd mutant embryos. We report that the caudal truncation is caused primarily by apoptosis, not altered cell proliferation. We show that the apoptosis and consequent skeletal malformations in acd mutants are dependent upon the p53 pathway by genetic rescue of the limb hypoplasia and vertebral anomalies with p53 null mice. Furthermore, rescue of the acd phenotype by p53 deficiency is a dosage-sensitive process, as acd/acd, p53(-/-) double mutants exhibit preaxial polydactyly. These findings demonstrate that caudal dysgenesis in acd embryos is secondary to p53-dependent apoptosis. Importantly, this study reinforces a significant link between genomic instability and birth defects.

Management of isoniazid-monoresistant tuberculosis (Hr-TB) in Queensland, Australia: a retrospective case series.

OBJECTIVES: Drug-resistance represents a major threat in the fight against tuberculosis. Globally, isoniazid-monoresistant tuberculosis (Hr-TB) is twice as common as multidrug/rifampicin-resistant (MDR/RR)-TB. Recently updated WHO guidelines now recommend treatment of Hr-TB with rifampicin, ethambutol, pyrazinamide and levofloxacin for at least six months. Our primary objective was to define the frequency, treatment and outcomes for Hr-TB in Queensland, Australia. We also sought to determine the frequency of fluoroquinolone use and whether its inclusion improved outcomes. METHODS: Retrospective case series of tuberculosis notifications in Queensland between 2000 and 2017 with at least low-level isoniazid resistance and preserved susceptibility to other first-line oral agents. RESULTS: Hr-TB was identified in 7.2% of all notifications. Where outcomes were assessable (163/198), 76.1% were treated with first-line agents only and 11.0% received at least six months of a fluoroquinolone-containing regimen (consistent with recent WHO guidelines). Favourable outcomes were achieved in 95.7%, comparable to fully susceptible disease (94.9%). Inclusion of a fluoroquinolone did not significantly improve outcomes compared with a regimen containing first-line agents only, although these cases were more likely to have high-level resistance. Previous treatment made an unfavourable outcome more likely. CONCLUSIONS: Hr-TB is prevalent in Queensland. Treatment outcomes in our cohort were comparable to fully susceptible disease. The current WHO-recommended regimen did not confer advantage over an appropriately constructed regimen containing first-line agents only. Our findings suggest that, in a well-resourced setting with good programmatic management, the addition of a fluoroquinolone may not substantially improve outcomes - potentially allowing these agents to be reserved for more extensively resistant disease.