The relationship between social support in pregnancy and postnatal depression.

PURPOSE: Lack of social support is considered a potential risk factor for postnatal depression but limited longitudinal evidence is available. Pregnancy, when women have increased contact with healthcare services, may be an opportune time to intervene and help strengthen women's social networks to prevent feelings of depression postnatally, particularly for those at greatest risk. Our study examined the longitudinal relationship between social support in pregnancy and postnatal depression, and whether this is moderated by age or relationship status. METHODS: We analysed data collected from 525 women from a diverse inner-city maternity population in England who were interviewed in pregnancy and again three months postnatally. Women provided sociodemographic information and completed self-report measures of depression (Edinburgh Postnatal Depression Scale) and social support (Social Provisions Scale). RESULTS: Less social support in pregnancy was associated with postnatal depression, after adjusting for sociodemographic confounders and antenatal depression (Coef. = - 0.05; 95% CI - 0.10 to - 0.01; p = 0.02). There was weak evidence of a moderating effect of relationship status. Subgroup analysis showed a stronger relationship between social support in pregnancy and postnatal depression for women who were not living with a partner (Coef. = - 0.11; 95% CI - 0.21 to - 0.01; p = 0.03) than for those who were (Coef. = - 0.03; 95% CI - 0.09 to 0.02; p = 0.28). Sensitivity analysis using multiple imputations to account for missing data confirmed the main results. CONCLUSIONS: Interventions that target social support in pregnancy have the potential to reduce depression postnatally. Future research should explore in greater detail which women would benefit most from which type of social support.

Mums Alone: Exploring the Role of Isolation and Loneliness in the Narratives of Women Diagnosed with Perinatal Depression.

In this study, we explore the role that isolation and loneliness play in the narratives of women diagnosed with perinatal depression. Isolation and loneliness are increasingly seen as risk factors for depression, including in the perinatal period, but little is known about whether, and in what ways, women themselves associate isolation or loneliness with perinatal distress. Based on the thematic analysis of semi-structured interviews with fourteen mothers in England, we found that women often connected feelings of depression during and after pregnancy to feeling dislocated from their previous identities and relationships. Women felt lost, confined to their homes, and often unsupported by their partners and families. However, fears of being judged to be inadequate mothers made it difficult for women to make authentic connections with others or to express negative feelings, increasing isolation and depression. We drew on the intersectionality theory to illustrate how the intersect between motherhood and other aspects of women's identities (being young, single, deprived and/or from an ethnic minority) could leave some women particularly isolated and marginalised. Our conclusions emphasise the need to challenge social constructions of the good/bad mother, advocate for social change to lessen pressures on mothers, and develop support that addresses women's interpersonal contexts and social networks.

Nitroheterocyclic drug resistance mechanisms in Trypanosoma brucei.

OBJECTIVES: The objective of this study was to identify the mechanisms of resistance to nifurtimox and fexinidazole in African trypanosomes. METHODS: Bloodstream-form Trypanosoma brucei were selected for resistance to nifurtimox and fexinidazole by stepwise exposure to increasing drug concentrations. Clones were subjected to WGS to identify putative resistance genes. Transgenic parasites modulating expression of genes of interest were generated and drug susceptibility phenotypes determined. RESULTS: Nifurtimox-resistant (NfxR) and fexinidazole-resistant (FxR) parasites shared reciprocal cross-resistance suggestive of a common mechanism of action. Previously, a type I nitroreductase (NTR) has been implicated in nitro drug activation. WGS of resistant clones revealed that NfxR parasites had lost >100 kb from one copy of chromosome 7, rendering them hemizygous for NTR as well as over 30 other genes. FxR parasites retained both copies of NTR, but lost >70 kb downstream of one NTR allele, decreasing NTR transcription by half. A single knockout line of NTR displayed 1.6- and 1.9-fold resistance to nifurtimox and fexinidazole, respectively. Since NfxR and FxR parasites are ∼6- and 20-fold resistant to nifurtimox and fexinidazole, respectively, additional factors must be involved. Overexpression and knockout studies ruled out a role for a putative oxidoreductase (Tb927.7.7410) and a hypothetical gene (Tb927.1.1050), previously identified in a genome-scale RNAi screen. CONCLUSIONS: NTR was confirmed as a key resistance determinant, either by loss of one gene copy or loss of gene expression. Further work is required to identify which of the many dozens of SNPs identified in the drug-resistant cell lines contribute to the overall resistance phenotype.

Cross-resistance to nitro drugs and implications for treatment of human African trypanosomiasis.

The success of nifurtimox-eflornithine combination therapy (NECT) for the treatment of human African trypanosomiasis (HAT) has renewed interest in the potential of nitro drugs as chemotherapeutics. In order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites. Following selection in vitro by exposure to increasing concentrations of nifurtimox, Trypanosoma brucei brucei nifurtimox-resistant clones designated NfxR1 and NfxR2 were generated. Both cell lines were found to be 8-fold less sensitive to nifurtimox than parental cells and demonstrated cross-resistance to a number of other nitro drugs, most notably the clinical trial candidate fexinidazole (approximately 27-fold more resistant than parental cells). Studies of mice confirmed that the generation of nifurtimox resistance in these parasites did not compromise virulence, and NfxR1 remained resistant to both nifurtimox and fexinidazole in vivo. In the case of fexinidazole, drug metabolism and pharmacokinetic studies indicate that the parent drug is rapidly metabolized to the sulfoxide and sulfone form of this compound. These metabolites retained trypanocidal activity but were less effective in nifurtimox-resistant lines. Significantly, trypanosomes selected for resistance to fexinidazole were 10-fold more resistant to nifurtimox than parental cells. This reciprocal cross-resistance has important implications for the therapeutic use of nifurtimox in a clinical setting and highlights a potential danger in the use of fexinidazole as a monotherapy.