The study protocol: COVID-19 awareness and perception among dentists in the Russian Federation.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has spread rapidly worldwide since it has been first identified in November 2018. It is transmissible via air droplets from infected individuals. Close contact between dentists and patients has aggravated the pandemic situation in Russia. It is necessary to reduce the risk of spreading COVID-19 during dental appointments by adhering to the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommendations. SUBJECTS AND METHODS: Questionnaires were developed to assess levels of COVID-19 infection and preventive measures in private and state-funded dental practices in Moscow and other cities in Russia. Two questionnaires were developed to assess the COVID-19 situation among dental professionals and their patients. The first, for dentists, included four domains: demographic data, signs, and symptoms of COVID-19 experienced by dentists, personal protective measures taken by dentists, and presence or absence of dental practice during the pandemic. For dentists' patients, the second included domains regarding their health status after their dental appointment. 1,500 questionnaires were sent to different cities and regions of Russia; 1,011 questionnaires (67.4%) were returned. We used statistical observation (monitoring) and clustering to analyze the data. The x2 was used to check the significance level. RESULTS: We found a direct relationship between those patients who contracted COVID-19 after dental treatment by those dentists who did not follow recommended measures in the dental clinic. However, patients were less likely to become infected after dental treatment by those dentists who followed the measures, such as the disinfection of surfaces and dental equipment several times a day, the wearing of medical masks by all patients, and the airing of the dental office after each patient for 10 minutes. CONCLUSIONS: Dentists wearing an FFP2 or FFP3 respirator, as well as a sterile disposable microfiber medical gown, prevented their patients from becoming infected with COVID-19 at dental appointments and, as a result, the spread of the virus. A key aspect of this study is its knowledge regarding preventive measures against COVID-19. The findings of this study can potentially help in formulating strategies to reduce the prevalence of COVID-19.

Yield of clinically reportable genetic variants in unselected cerebral palsy by whole genome sequencing.

Cerebral palsy (CP) is the most common cause of childhood physical disability, with incidence between 1/500 and 1/700 births in the developed world. Despite increasing evidence for a major contribution of genetics to CP aetiology, genetic testing is currently not performed systematically. We assessed the diagnostic rate of genome sequencing (GS) in a clinically unselected cohort of 150 singleton CP patients, with CP confirmed at >4 years of age. Clinical grade GS was performed on the proband and variants were filtered, and classified according to American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines. Variants classified as pathogenic or likely pathogenic (P/LP) were further assessed for their contribution to CP. In total, 24.7% of individuals carried a P/LP variant(s) causing or increasing risk of CP, with 4.7% resolved by copy number variant analysis and 20% carrying single nucleotide or indel variants. A further 34.7% carried one or more rare, high impact variants of uncertain significance (VUS) in variation intolerant genes. Variants were identified in a heterogeneous group of genes, including genes associated with hereditary spastic paraplegia, clotting and thrombophilic disorders, small vessel disease, and other neurodevelopmental disorders. Approximately 1/2 of individuals were classified as likely to benefit from changed clinical management as a result of genetic findings. In addition, no significant association between genetic findings and clinical factors was detectable in this cohort, suggesting that systematic sequencing of CP will be required to avoid missed diagnoses.

[Use of fixed individual micro-implant supported orthodontic appliance in children with bilateral cleft lip and palate]. / Primenenie nes"emnykh individual'nykh ortodonticheskikh apparatov s oporoi na mikroimplantatakh u detei s dvustoronnei rasshchelinoi guby i neba.

Congenital malformations of the maxillofacial region are significant, not completely decisive, medical and social problems. Recent literature data indicate a trend towards improvement. PURPOSE OF THE STUDY: Improving the effectiveness of treatment of children with bilateral orthodontic and surgical training. MATERIAL AND METHODS: Under the supervision were 80 children with cleft lip and palate, with an age of up to 3 years. Of these 56 patients, 28 patients are the 2nd group prepared for surgery according to the developed technique. RESULTS: Preoperative orthodontic preparation of 28 children with bilateral cleft and an indicator that 22 (78.6%) patients should not have fully achieved results between the interhuman and fragmentary alveolar process of the upper jaw. In the second group of patients, 27 (96.4%) patients showed a normal ratio of the intermaxillary bone and lateral fragments. CONCLUSION: The use of the developed orthodontic design with active elements and mini implants in 96.4% of cases requires the presence of pre-spiral orthodontic preparation, normalization of the position of the intercellular bone and shape, followed by primary chelorinoplastics and in relation to additional uranoplastics, as well as the periodic stages of rehabilitation of patients with bilateral cleft lip and achieved thereby a stable aesthetic and functional result.

Targeted resequencing identifies genes with recurrent variation in cerebral palsy.

A growing body of evidence points to a considerable and heterogeneous genetic aetiology of cerebral palsy (CP). To identify recurrently variant CP genes, we designed a custom gene panel of 112 candidate genes. We tested 366 clinically unselected singleton cases with CP, including 271 cases not previously examined using next-generation sequencing technologies. Overall, 5.2% of the naïve cases (14/271) harboured a genetic variant of clinical significance in a known disease gene, with a further 4.8% of individuals (13/271) having a variant in a candidate gene classified as intolerant to variation. In the aggregate cohort of individuals from this study and our previous genomic investigations, six recurrently hit genes contributed at least 4% of disease burden to CP: COL4A1, TUBA1A, AGAP1, L1CAM, MAOB and KIF1A. Significance of Rare VAriants (SORVA) burden analysis identified four genes with a genome-wide significant burden of variants, AGAP1, ERLIN1, ZDHHC9 and PROC, of which we functionally assessed AGAP1 using a zebrafish model. Our investigations reinforce that CP is a heterogeneous neurodevelopmental disorder with known as well as novel genetic determinants.

Muscle ciliary neurotrophic factor receptor α helps maintain choline acetyltransferase levels in denervated motor neurons following peripheral nerve lesion.

Systemic ciliary neurotrophic factor (CNTF) administration protects motor neurons from denervating diseases and lesions but produces non-neuromuscular side effects. Therefore, CNTF related therapeutics will need to specifically target motor neuron protective receptor mechanisms. Expression of the essential ligand binding subunit of the CNTF receptor, CNTF receptor α (CNTFRα), is induced in skeletal muscle by denervating lesion and in human denervating diseases. We show here, with muscle-specific in vivo genetic disruption, that muscle CNTFRα makes an essential/non-redundant contribution to maintaining choline acetyltransferase levels in denervated motor neurons following nerve crush, suggesting the muscle CNTFRα induction is an endogenous denervation-induced neuroprotective response that could be enhanced to treat nerve lesion and denervating diseases. Notably, unlike motor neuron gene expression, skeletal muscle gene expression can be specifically targeted with human gene therapy vectors already approved for market.

Muscle ciliary neurotrophic factor receptor α contributes to motor neuron STAT3 activation following peripheral nerve lesion.

Expression of the ciliary neurotrophic factor (CNTF) receptor essential ligand binding subunit, CNTF receptor α (CNTFRα), is induced in motor neurons and skeletal muscle following peripheral nerve lesion. We previously found muscle CNTFRα promotes motor neuron axon regeneration post-lesion. Both nerve lesion and CNTF administration activate motor neuron signal transducer and activator of transcription 3 (STAT3), a transcription factor implicated in axon growth, suggesting CNTF receptors may contribute to the lesion-induced STAT3 activation. However, many receptor types signal through STAT3, and if CNTF receptors contribute, motor neuron receptors seemed most likely to regulate motor neuron STAT3. To determine the role played by muscle CNTFRα, we used in vivo, muscle-specific CNTFRα depletion in mice and report here that this selectively impairs the second phase, sustained motor neuron STAT3 activation post-lesion. Thus, muscle CNTFRα makes an essential contribution to motor neuron STAT3 activation during axon regeneration and may thereby promote axon regeneration through such signaling. We also report CNTFRα quantitative PCR suggesting involvement of many denervated muscle types, as well as muscle damaged at the lesion site. The present data add to the evidence suggesting that enhancing muscle CNTFRα expression may promote motor neuron regeneration in trauma and disease.

The emerging genetic landscape of cerebral palsy.

Cerebral palsy (CP) is a broad clinical descriptor that encompasses a heterogeneous group of nonprogressive neurodevelopmental disabilities affecting movement and posture. While linked by the presence of damage to the developing brain, the etiology of CP is likely varied and the clinical outcomes are diverse. There is now a large body of evidence supporting a significant role for genetics in causation of CP. An increasing number of studies have identified likely causative genetic variants in families with CP, as well as in individual sporadic cases. Next-generation sequencing is now aiding clinicians in making specific molecular diagnoses, providing future opportunities for tailored treatments and for informed reproductive decisions.

Adult ciliary neurotrophic factor receptors help maintain facial motor neuron choline acetyltransferase expression in vivo following nerve crush.

Exogenous ciliary neurotrophic factor (CNTF) administration promotes the survival of motor neurons in a wide range of models. It also increases the expression of the critical neurotransmitter enzyme choline acetyltransferase (ChAT) by in vitro motor neurons, likely independent of its effects on their survival. We have used the adult mouse facial nerve crush model and adult-onset conditional disruption of the CNTF receptor α (CNTFRα) gene to directly examine the in vivo roles played by endogenous CNTF receptors in adult motor neuron survival and ChAT maintenance, independent of developmental functions. We have previously shown that adult activation of the CreER gene construct in floxed CNTFRα mice depletes this essential receptor subunit in a large subset of motor neurons (and all skeletal muscle, as shown in this study) but has no effect on the survival of intact or lesioned motor neurons, indicating that these adult CNTF receptors play no essential survival role in this model, in contrast to their essential role during embryonic development. Here we show that this same CNTFRα depletion does not affect ChAT labeling in nonlesioned motor neurons, but it significantly increases the loss of ChAT following nerve crush. The data suggest that, although neither motor neuron nor muscle CNTF receptors play a significant, nonredundant role in the maintenance of ChAT in intact adult motor neurons, the receptors become essential for ChAT maintenance when the motor neurons are challenged by nerve crush. Therefore, the data suggest that the receptors act as a critical component of an endogenous neuroprotective mechanism. J. Comp. Neurol. 525:1206-1215, 2017. © 2016 Wiley Periodicals, Inc.

Muscle and motor neuron ciliary neurotrophic factor receptor α together maintain adult motor neuron axons in vivo.

The molecular mechanisms maintaining adult motor innervation are comparatively unexplored relative to those involved during development. In addition to the fundamental neuroscience question, this area has important clinical ramifications given that loss of neuromuscular contact is thought to underlie several adult onset human neuromuscular diseases including amyotrophic lateral sclerosis. Indirect evidence suggests that ciliary neurotrophic factor (CNTF) receptors may contribute to adult motor neuron axon maintenance. To directly address this in vivo, we used adult onset mouse genetic disruption techniques to deplete motor neuron and muscle CNTF receptor α (CNTFRα), the essential ligand binding subunit of the receptor, and incorporated reporters labelling affected motor neuron axons and terminals. The combined depletion of motor neuron and muscle CNTFRα produced a large loss of motor neuron terminals and retrograde labelling of motor neurons with FluoroGold indicated axon die-back well beyond muscle, together revealing an essential role for CNTFRα in adult motor axon maintenance. In contrast, selective depletion of motor neuron CNTFRα did not affect motor innervation. These data, along with our previous work indicating no effect of muscle specific CNTFRα depletion on motor innervation, suggest that motor neuron and muscle CNTFRα function in concert to maintain motor neuron axons. The data also raise the possibility of motor neuron and/or muscle CNTFRα as therapeutic targets for adult neuromuscular denervating diseases.

Whole-exome sequencing points to considerable genetic heterogeneity of cerebral palsy.

Cerebral palsy (CP) is a common, clinically heterogeneous group of disorders affecting movement and posture. Its prevalence has changed little in 50 years and the causes remain largely unknown. The genetic contribution to CP causation has been predicted to be ~2%. We performed whole-exome sequencing of 183 cases with CP including both parents (98 cases) or one parent (67 cases) and 18 singleton cases (no parental DNA). We identified and validated 61 de novo protein-altering variants in 43 out of 98 (44%) case-parent trios. Initial prioritization of variants for causality was by mutation type, whether they were known or predicted to be deleterious and whether they occurred in known disease genes whose clinical spectrum overlaps CP. Further, prioritization used two multidimensional frameworks-the Residual Variation Intolerance Score and the Combined Annotation-dependent Depletion score. Ten de novo mutations in three previously identified disease genes (TUBA1A (n=2), SCN8A (n=1) and KDM5C (n=1)) and in six novel candidate CP genes (AGAP1, JHDM1D, MAST1, NAA35, RFX2 and WIPI2) were predicted to be potentially pathogenic for CP. In addition, we identified four predicted pathogenic, hemizygous variants on chromosome X in two known disease genes, L1CAM and PAK3, and in two novel candidate CP genes, CD99L2 and TENM1. In total, 14% of CP cases, by strict criteria, had a potentially disease-causing gene variant. Half were in novel genes. The genetic heterogeneity highlights the complexity of the genetic contribution to CP. Function and pathway studies are required to establish the causative role of these putative pathogenic CP genes.

The contribution of ciliary neurotrophic factor receptors to adult motor neuron survival in vivo is specific to insult type and distinct from that for embryonic motor neurons.

Exogenous ciliary neurotrophic factor (CNTF) promotes motor neuron (MN) survival following trauma and in genetic models of MN disease. Unconditional disruption of the mouse CNTF receptor α (CNTFRα) gene leads to MN loss, demonstrating a developmental role for endogenous CNTF receptor signaling. These data also suggest that CNTF receptors may promote adult MN survival and that appropriately manipulating the receptors could effectively treat adult MN disorders. This effort would greatly benefit from a better understanding of the roles played by CNTF receptors in adult MNs. We have previously found that adult onset disruption of CNTFRα in facial MNs of "floxed CNTFRα" mice by AAV-Cre vector injection leads to significantly more MN loss than in identically treated controls. While indicating that CNTF receptors can promote adult MN survival, the data did not distinguish between potential roles in MN maintenance versus roles in protecting MNs from the injection associated trauma or the toxicity of the chronic Cre recombinase (Cre) produced by the AAV-Cre. Here we used an inducible Cre gene construct to produce adult-onset CNTFRα disruption in facial MNs without the traumatic and toxic effects of the AAV-Cre procedure. The MNs survive without CNTFRα, even when challenged by facial nerve crush or the injection-associated trauma, thereby suggesting, in conjunction with our previous study, that endogenous CNTF receptor signaling can protect MNs against toxic insult, such as that produced by chronic Cre. The data also indicate that in vivo CNTF receptors play very different roles in adult and embryonic MNs.

Muscle ciliary neurotrophic factor receptor α promotes axonal regeneration and functional recovery following peripheral nerve lesion.

Ciliary neurotrophic factor (CNTF) administration maintains, protects, and promotes the regeneration of both motor neurons (MNs) and skeletal muscle in a wide variety of models. Expression of CNTF receptor α (CNTFRα), an essential CNTF receptor component, is greatly increased in skeletal muscle following neuromuscular insult. Together the data suggest that muscle CNTFRα may contribute to neuromuscular maintenance, protection, and/or regeneration in vivo. To directly address the role of muscle CNTFRα, we selectively-depleted it in vivo by using a "floxed" CNTFRα mouse line and a gene construct (mlc1f-Cre) that drives the expression of Cre specifically in skeletal muscle. The resulting mice were challenged with sciatic nerve crush. Counting of nerve axons and retrograde tracing of MNs indicated that muscle CNTFRα contributes to MN axonal regeneration across the lesion site. Walking track analysis indicated that muscle CNTFRα is also required for normal recovery of motor function. However, the same muscle CNTFRα depletion unexpectedly had no detected effect on the maintenance or regeneration of the muscle itself, even though exogenous CNTF has been shown to affect these functions. Similarly, MN survival and lesion-induced terminal sprouting were unaffected. Therefore, muscle CNTFRα is an interesting new example of a muscle growth factor receptor that, in vivo under physiological conditions, contributes much more to neuronal regeneration than to the maintenance or regeneration of the muscle itself. This novel form of muscle-neuron interaction also has implications in the therapeutic targeting of the neuromuscular system in MN disorders and following nerve injury. J. Comp. Neurol. 521: 2947-2965, 2013. © 2013 Wiley Periodicals, Inc.

Ciliary neurotrophic factor receptor regulation of adult forebrain neurogenesis.

Appropriately targeted manipulation of endogenous neural stem progenitor (NSP) cells may contribute to therapies for trauma, stroke, and neurodegenerative disease. A prerequisite to such therapies is a better understanding of the mechanisms regulating adult NSP cells in vivo. Indirect data suggest that endogenous ciliary neurotrophic factor (CNTF) receptor signaling may inhibit neuronal differentiation of NSP cells. We challenged subventricular zone (SVZ) cells in vivo with low concentrations of CNTF to anatomically characterize cells containing functional CNTF receptors. We found that type B "stem" cells are highly responsive, whereas type C "transit-amplifying" cells and type A neuroblasts are remarkably unresponsive, as are GFAP(+) astrocytes found outside the SVZ. CNTF was identified in a subset of type B cells that label with acute BrdU administration. Disruption of in vivo CNTF receptor signaling in SVZ NSP cells, with a "floxed" CNTF receptor α (CNTFRα) mouse line and a gene construct driving Cre recombinase (Cre) expression in NSP cells, led to increases in SVZ-associated neuroblasts and new olfactory bulb neurons, as well as a neuron subtype-specific, adult-onset increase in olfactory bulb neuron populations. Adult-onset receptor disruption in SVZ NSP cells with a recombinant adeno-associated virus (AAV-Cre) also led to increased neurogenesis. However, the maintenance of type B cell populations was apparently unaffected by the receptor disruption. Together, the data suggest that endogenous CNTF receptor signaling in type B stem cells inhibits adult neurogenesis, and further suggest that the regulation may occur in a neuron subtype-specific manner.

Quality of life and the role of menopausal hormone therapy.

The quality of life of countless menopausal women world-wide has been significantly diminished following the sensationalist reporting of the Women's Health Initiative (WHI) and the resulting 50% or more decline in the use of hormone replacement therapy (HRT) over the subsequent 10 years. Quality of life is difficult to measure as there are so many contributing factors and a large number of different instruments, some of which assess general health and only a few which specifically include symptoms related to menopause. HRT improves quality of life of symptomatic menopausal women and some studies of the effects of HRT provide reliable evidence on quality of life other than reduction in vasomotor symptoms. Until there is a better understanding of the minimal risks of HRT for the majority of women, too many will continue to suffer a reduced quality of life unnecessarily.

Evidence-based assessment of the impact of the WHI on women's health.

Following the announcement of the first results of the Women's Health Initiative (WHI) to the media in 2002, prior to their scientific publication, the resulting panic headlines had an immediate and lasting negative effect on use of menopausal hormone replacement therapy (HRT) around the world. Rates of use dropped by 40-80%. Symptomatic women then sought multiple alternative therapies but the majority of these have no greater effect than the effect seen from placebo in well-conducted trials of HRT. Some of these therapies have risks. Although anecdotally most menopause practitioners after 2002 can attest to having to counsel large numbers of women with debilitating menopausal symptoms who were too frightened to consider HRT, it is difficult to document loss of health-related quality of life in large population studies as they were not conducted. Similarly, the positive or negative effects of the marked decline in HRT on long-term morbidities and mortality have yet to be fully assessed. Recent studies have shown an increase in postmenopausal fractures and in some, but not all, populations a small temporary decline in breast cancer. Cardiovascular outcomes may not be apparent for another decade. Short-term, randomized, placebo-controlled trials confirm that HRT is the only therapy that effectively improves health-related quality of life in symptomatic women through a reduction in vasomotor and urogenital symptoms, joint pains and insomnia, while improving sexuality. The results of the re-analyses of the WHI data and new data from other studies do not justify the continuing negative attitude to HRT in symptomatic women who start HRT near menopause.

Future long-term trials of postmenopausal hormone replacement therapy - what is possible and what is the optimal protocol and regimen?

The ideal long-term, randomized, placebo-controlled trial of hormone replacement therapy (HRT) from near menopause for up to 30 years to assess major morbidity and mortality is impractical because of high cost, participant retention, therapy compliance, and continuity of research staff and funding. Also the trial regimen may become outdated. It is nihilistic to demand such a long-term trial before endorsing HRT. However, medium-term trials using surrogate measures for long-term morbidity and mortality are possible and two are near completion. If these studies have been able to maintain reasonable participant retention, therapy compliance and minimal breach of protocol, they will set standards for trials of new HRT regimens. This paper discusses lessons learnt from past attempts at long-term trials and suggests the currently optimal protocol and cost of assessing new HRT regimens to optimize potential benefits and minimize adverse effects. A 5-7-year randomized, placebo-controlled trial of a flexible transdermal estrogen regimen ± either a selective estrogen receptor modulator, e.g. bazedoxifene, or micronized progesterone is discussed. Mild to moderately symptomatic women, 1-4 years post menopause, can be recruited via general practice and group meetings. Future trials should be funded by independent agencies and are high priority in women's health.

The anorectic effect of CNTF does not require action in leptin-responsive neurons.

Leptin resistance is a feature of obesity that poses a significant therapeutic challenge. Any treatment that is effective to reduce body weight in obese patients must overcome or circumvent leptin resistance, which promotes the maintenance of excess body fat in obese individuals. Ciliary neurotrophic factor (CNTF) is unique in its ability to reduce food intake and body weight in obese, leptin-resistant humans and rodents. Although attempts to use CNTF as an obesity therapy failed due to the development of neutralizing antibodies to the drug, efforts to understand mechanisms for CNTF's anorectic effects provide an opportunity to develop new drugs for leptin-resistant individuals. CNTF and leptin share several structural, anatomic, and signaling properties, but it is not understood whether or how the two cytokines might interact to affect energy balance. Here, we conditionally deleted the CNTF receptor (CNTFR) subunit, CNTFRα, in cells expressing leptin receptors. We found that CNTFR signaling in leptin-responsive neurons is not required for endogenous maintenance of energy balance and is not required for the anorectic response to exogenous administration of a CNTF agonist. These results indicate that despite anatomical overlap for CNTF and leptin action, CNTF appears to act within a distinct neuronal population to elicit its potent anorectic effect.

Menopausal hot flushes and night sweats: where are we now?

OBJECTIVE: An overview of the current knowledge on the etiology and treatment of vasomotor symptoms in postmenopausal women. MATERIALS AND METHODS: Acknowledged experts in the field contributed a brief assessment of their areas of interest which were combined and edited into the final manuscript. RESULTS: Women around the world experience vasomotor symptoms as they enter and complete the menopause transition. Vasomotor symptoms, specifically hot flushes, are caused by a narrowing of the thermoneutral zone in the brain. This effect, although related to estrogen withdrawal, is most likely related to changes in central nervous system neurotransmitters. Peripheral vascular reactivity is also altered in symptomatic women. Estrogen replacement therapy is the most effective treatment for hot flushes. Of the other interventions investigated, selective serotonin and selective norepinephrine reuptake inhibitors and gabapentin show efficacy greater than placebo. Objective monitoring of hot flushes indicates a robust improvement with hormone replacement therapy but little to no change with placebo. These data suggest that the subjective assessment of responses to therapy for vasomotor symptom results in inaccurate data. Hot flushes have recently been associated with increased cardiovascular risks and a lower incidence of breast cancer, but these data require confirmation. CONCLUSIONS: Vasomotor symptoms are experienced by women of all ethnic groups. They are caused by changes in the central nervous system associated with estrogen withdrawal and are best treated with estrogen replacement therapy. Objective monitoring of hot flushes indicates that placebo has little to no effect on their improvement. Subjective assessments of hot flushes in clinical trials may be inaccurate based on objective measurement of the frequency of hot flushes. Based on preliminary reports, women experiencing hot flushes have an increased risk of cardiovascular disease and a reduced incidence of breast cancer.

HRT in difficult circumstances: are there any absolute contraindications?

Many traditional contraindications to hormone replacement therapy (HRT) are based on the theoretical potential for these hormones to worsen a disease process and are rarely based on supporting data. This review addresses the available data and lack of data that make the prescription of HRT difficult in a variety of common morbidities. In each circumstance, it is assumed that conservative evidence-based therapies have been tried and that menopausal symptoms remain debilitating and are reducing quality of life. Tailoring of the product, dose, route and regimen may avoid some of the theoretical risks of HRT in particular women or conditions and guidelines are given for each co-morbidity. Specifically, it is discussed that tailored HRT may be used without strong evidence of a deleterious effect after ovarian cancer, endometrial cancer, most other gynecological cancers, bowel cancer, melanoma, a family history of breast cancer, benign breast disease, in carriers of BRACA mutations, after breast cancer if adjuvant therapy is not being used, past thromboembolism, varicose veins, fibroids and past endometriosis. Relative contraindications are existing cardiovascular and cerebrovascular disease and breast cancer being treated with adjuvant therapies. Consultation with other carers and written consent are recommended in all these difficult circumstances, but no condition is an absolute contraindication to HRT if potential risk is understood, if HRT is effective in symptom control and if quality of remaining life is paramount.