Update on multi‐gene panel testing and communication of genetic test results

With technological advances, multi‐gene panel testing has become increasingly used to identify patients at risk for hereditary breast cancer (HBC). There are currently evidence‐based interventions and breast cancer screening strategies that exist for cancer prevention and early detection among patients with HBC. Moreover, in addition to the personal impact of identifying HBC, this information may be shared with at‐risk family members to amplify the benefits of testing and subsequent care among those at high risk. Opportunities and challenges with the utilization of updated multi‐gene panel testing for HBC, including: (a) tumor sequencing with germline consequences; (b) genetic counseling implications; and (c) strategies to improve the communication of genetic test results to family members will be reviewed. With the advances and expansion of genetic testing, all health care providers need to be updated on both the importance and complexities of HBC counseling and testing, in order to optimize patient care.     

High HIV and active tuberculosis prevalence and increased mortality risk in adults with symptoms of TB: a systematic review and meta‐analyses

Introduction

HIV and tuberculosis (TB) remain leading causes of preventable death in low‐ and middle‐income countries (LMICs). The World Health Organization (WHO) recommends HIV testing for all individuals with TB symptoms, but implementation has been suboptimal. We conducted a systematic literature review and meta‐analyses to estimate HIV and TB prevalence, and short‐term (two to six months) mortality, among adults with TB symptoms at community‐ and facility level.

Methods

We searched Embase, Global Health and MEDLINE databases, and reviewed conference abstracts for studies reporting simultaneous HIV and TB screening of adults in LMICs published between January 2003 and December 2017. Meta‐analyses were performed to estimate prevalence of HIV, undiagnosed TB and mortality risk at different health system levels.

Results

Sixty‐two studies including 260,792 symptomatic adults were identified, mostly from Africa and Asia. Median HIV prevalence was 19.2% (IQR: 8.3% to 40.4%) at community level, 55.7% (IQR: 20.9% to 71.2%) at primary care level and 80.7% (IQR: 73.8% to 84.6%) at hospital level. Median TB prevalence was 6.9% (IQR: 3.3% to 8.4%) at community, 20.5% (IQR: 11.7% to 46.4%) at primary care and 36.4% (IQR: 22.9% to 40.9%) at hospital level. Median short‐term mortality was 22.6% (IQR: 15.6% to 27.7%) among inpatients, 3.1% (IQR: 1.2% to 4.2%) at primary care and 1.6% (95% CI: 0.45 to 4.13, n = 1 study) at community level.

Conclusions

Adults with TB symptoms have extremely high prevalence of HIV infection, even when identified through community surveys. TB prevalence and mortality increased substantially at primary care and inpatient level respectively. Strategies to expand symptom‐based TB screening combined with HIV and TB testing for all symptomatic individuals should be of the highest priority for both disease programmes in LMICs with generalized HIV epidemics. Interventions to reduce short‐term mortality are urgently needed.

     

Brucella microti‐like prevalence in French farms producing frogs

In the last 10 years, many atypical novel members of Brucella species have been reported, including several Brucella inopinata‐like strains in wild‐caught and “exotic” amphibians from various continents. In 2017, a strain of Brucella was isolated for the first time in animals from a French farm producing frogs—Pelophylax ridibundus—for human consumption and identified as B. microti‐like. Following this first isolation, investigations were performed in this farm as well as in the farm of the research unit that provided the domestic frog strain to estimate the prevalence of B. microti‐like infection and its presence in the surrounding environment. Farming practices were investigated and samples including frogs at different development stages, surface tank swabs, water, feed and soil were analysed by real‐time PCR and bacteriological methods. High B. microti‐like prevalence values (higher than 90%) were obtained in frog samples in the commercial farm, and its presence was highlighted in the environmental samples except feed. In the research unit farm, B. microti‐like species was also isolated and detected in frog and environmental samples. These results show that B. microti‐like organisms are able to colonize amphibians and persist in their environment. Its presence could constitute a possible risk for consumers and workers proving the importance of assessing the zoonotic and pathogenic potentials of these new and atypical Brucella species.     

Single port laparoscopic ileocaecal resection for Crohn's disease: a multicentre comparison with multi‐port laparoscopy

Aim

Single port (SP) ileocaecal resection (ICR) is an established technique but there are no large studies comparing SP and multi‐port (MP) laparoscopic surgery in Crohn's disease (CD). The aim of this study was to compare postoperative pain scores and analgesia requirements after SP and MP laparoscopic ICR for CD.

Method

This was a retrospective study of patients undergoing SP or MP ICR for CD in three tertiary referral centres from February 1999 to October 2014. Baseline characteristics (age, sex, body mass index and indication for surgery) were compared. Primary end‐points were postoperative pain scores, analgesia requirements and short‐term postoperative outcomes.

Results

SP ICR (n = 101) and MP ICR (n = 156) patients were included in the study. Visual analogue scale scores were significantly lower after SP ICR on postoperative day 1 (P = 0.016) and day 2 (P = 0.04). Analgesia requirements were significantly reduced on postoperative day 2 in the SP group compared with the MP group (P = 0.007). Duration of surgery, conversion to open surgery and stoma rates were comparable between the two groups. Surgery was more complex in terms of additional procedures when MP was adopted (P = 0.001). There were no differences in postoperative complication rates, postoperative food intake, length of stay and readmissions.

Conclusion

These data suggest that in comparison to standard laparoscopic surgery SP ICR might be less painful and patients might require less opioid analgesia.     

Evaluation of a flexible bronchoscope prototype designed for bronchoscopy during mechanical ventilation: a proof‐of‐concept study

Bronchoscopy during mechanical ventilation of patients' lungs significantly affects ventilation because of partial obstruction of the tracheal tube, and may thus be omitted in the most severely ill patients. It has not previously been possible to reduce the external diameter of the bronchoscope without reducing the diameter of the suction channel, thus reducing the suctioning capacity of the device. We believed that a better‐designed bronchoscope could improve the safety of bronchoscopy in patients whose lungs were ventilated. We designed a flexible bronchoscope prototype with a drumstick‐shaped head consisting of a long, thin proximal portion; a short and large distal portion for camera docking; and a large suction channel throughout the length of the device. The aims of our study were to test the impact of our prototype on mechanical ventilation when inserted into the tracheal tube, and to assess suctioning capacity. We first tested the efficiency of the suction channel, and demonstrated that the suction flow of the prototype was similar to that of conventional adult bronchoscopes. We next evaluated the consequences of bronchoscopy when using the prototype on minute ventilation and intrathoracic pressures during mechanical ventilation: firstly, in vitro using a breathing simulator; and secondly, in vivo using a porcine model of pulmonary ventilation. The insertion of adult bronchoscopes into the tracheal tube immediately impaired the protective ventilation strategy employed, whereas the prototype preserved it. For the first time, we have developed an innovative flexible bronchoscope designed for bronchoscopy during invasive mechanical ventilation, that both preserved the protective ventilation strategy, and enabled efficient suction flow.     

Single nucleotide polymorphisms in Renalase and KCNQ1 genes and female infertility: A cross‐sectional study in Pakistan

A global increase in the incidence of subfertility is observed, and research suggests strong genetic influences that might restrict fertility directly or indirectly. It therefore becomes important to rule out the existence of genetic causes and counsel infertile couples before offering “Advanced Infertility Treatment Techniques.” This cross‐sectional study aimed to explore the association of KCNQ1 (rs2237895) and Renalase (rs2576178 and rs10887800) single nucleotide polymorphisms with different causes of infertility by analysing 508 fertile and 164 infertile women. Gene variant (AC/CC) of KCNQ1 rs2237895 showed a slight difference in the endometriosis group compared to the fertile group (p = .049), with the C allele showing a significant association with infertility overall (OR = 1.42 [1.100–1.833]; p < .0069). The variant AG/GG of Renalase rs2576178 was significantly associated with overall infertility (OR = 2.266; p < .001), with a strong G allele association with unexplained infertility OR = 2.796 (p = .002) that remained significant after adjusting for age and body mass index. Similarly, Renalase rs10887800 AG/GG and G allele showed significant association with both infertility due to polycystic ovarian syndrome and unexplained infertility. Expression of single nucleotide polymorphism rs2237895 and rs2576178 in both KCNQ1 and Renalase genes might be responsible for altering reproductive potential, hence leading to infertility in women.     

The effect of two cognitive aid designs on team functioning during intra‐operative anaphylaxis emergencies: a multi‐centre simulation study

This multi‐centre repeated measures study was undertaken to determine how contrasting designs of cognitive aids affect team performance during simulated intra‐operative anaphylaxis crises. A total of 24 teams consisting of a consultant anaesthetist, an anaesthetic trainee and anaesthetic assistant managed three simulated intra‐operative anaphylaxis emergencies. Each team was assigned at random to a counterbalanced order of: no cognitive aid; a linear cognitive aid; and a branched cognitive aid, and scored for team functioning. Scores were significantly higher with a linear compared with either a branched version of the cognitive aid or no cognitive aid for ‘Team Overall Behavioural Performance’, difference between study groups (F‐value) 5.8, p = 0.01. Aggregate scores were higher with the linear compared with the branched aid design (p = 0.03). Cognitive aids improve co‐ordination of the team's activities and support team members to verbalise their actions. A linear design of cognitive aid improves team functioning more than a branched design.     

Kisspeptin and attributes of infertile males and females: A cross‐sectional study in a subset of Pakistani population

Kisspeptin, a peptide hormone, plays a pivotal role in fertility and neuroendocrine regulation of hypothalamo–pituitary–gonadal axis. Increased kisspeptin and reproductive hormones are responsible for fertility in male and females. This study aimed to explore the role of kisspeptin on hypothalamo–pituitary–gonadal axis by comparing the levels of kisspeptin in fertile and infertile subjects and identifying single nucleotide polymorphisms (SNPs) of KISS1 gene in exon 2 and exon 3 of infertile male and female cohorts. A cross‐sectional study was carried out on 80 males (44 infertile and 36 fertile) and 88 females (44 in each group). Significantly high levels of kisspeptin (KP), follicle‐stimulating hormone (FSH), luteinizing hormone and testosterone were observed in fertile male and female subjects except low FSH levels in comparison with infertile female subjects. One polymorphism in exon 2 (E1225K [G/A 3673]) and three in exon 3 (P1945A [C/G 5833]; Insertion of T at 6075; G2026G [C/G 6078]) in infertile group were detected, with low KP and hormonal levels. Male subjects had abnormal sperm parameters and unsuccessful attempt of intracytoplasmic sperm injection in females. Expression of SNP in exon 2 and exon 3 of KISS1 could be responsible for alteration in release of reproductive hormones and gonadal functions, hence causing infertility.     

The cost‐effectiveness and budgetary impact of a dolutegravir‐based regimen as first‐line treatment of HIV infection in India

Introduction

Dolutegravir (DTG)‐based antiretroviral therapy (ART) is recommended for first‐line HIV treatment in the US and Europe. Efavirenz (EFV)‐based regimens remain the standard of care (SOC) in India. We examined the clinical and economic impact of DTG‐based first‐line ART in the setting of India's recent guidelines change to treating all patients with HIV infection regardless of CD4 count.

Methods

We used a microsimulation of HIV disease, the Cost‐Effectiveness of Preventing AIDS Complications (CEPAC)‐International model, to project outcomes in ART‐naive patients under two strategies: (1) SOC: EFV/tenofovir disoproxil fumarate (TDF)/lamivudine (3TC); and (2) DTG: DTG + TDF/3TC. Regimen‐specific inputs, including virologic suppression at 48 weeks (SOC: 82% vs. DTG: 90%) and annual costs ($98 vs. $102), were informed by clinical trial data and other sources and varied widely in sensitivity analysis. We compared incremental cost‐effectiveness ratios (ICERs), measured in $/year of life saved (YLS), to India's per capita gross domestic product ($1600 in 2015). We compared the budget impact and HIV transmission effects of the two strategies for the estimated 444,000 and 916,000 patients likely to initiate ART in India over the next 2 and 5 years.

Results

Compared to SOC, DTG improved 5‐year survival from 76.7% to 83.0%, increased life expectancy from 22.0 to 24.8 years (14.0 to 15.5 years, discounted), averted 13,000 transmitted HIV infections over 5 years, increased discounted lifetime care costs from $3040 to $3240, and resulted in a lifetime ICER of $130/YLS, less than 10% of India's per capita GDP in 2015. DTG maintained an ICER below 50% of India's per capita GDP as long as the annual three‐drug regimen cost was ≤$180/year. Over a 2‐ or 5‐year horizon, total undiscounted outlays for HIV‐related care were virtually the same for both strategies.

Conclusions

A generic DTG‐based regimen is likely to be cost‐effective and should be recommended for initial therapy of HIV infection in India.

     

Weekend effect on early allograft outcome after kidney transplantation‐ a multi‐centre cohort study

Weekend surgery may be associated with a higher risk of early complications, but the effect of the timing of kidney transplant surgery on early allograft outcome remains uncertain. The aim of this study is to evaluate whether the association between weekend transplant surgery and allograft failure was modified by prevalent vascular disease. Using data from the Australia and New Zealand Dialysis and Transplant registry, we examined the association between weekend status and 90‐day and 1‐year allograft failure in deceased donor transplant recipients between 1994–2012. Two‐way interaction between vascular disease and weekend status was examined. Of 6622 recipients, 1868 (28.2%) received transplants during weekends. Compared with weekday transplants, weekend transplants were associated with an adjusted hazard ratio (HR) for 90‐day and 1‐year allograft failure of 0.99 (0.78–1.25; P = 0.917) and 0.93 (0.76–1.13, P = 0.468), respectively. There was a significant interaction between prevalent vascular disease and weekend status for 90‐day allograft failure (P_interaction = 0.008) but not at 1‐year, such that patients with vascular disease were more likely to experience 90‐day allograft failure if transplanted on weekend (versus weekdays), particularly failures secondary to vascular complications. Timing of transplantation does not impact on allograft outcome, although those with vascular disease may benefit from more intensive post‐transplant follow‐up for potential vascular complications.     

Early Onset Breast Cancer in a Registry‐based Sample of African‐American Women: BRCA Mutation Prevalence,and Other Personal and System‐level Clinical Characteristics

Young Black women are disproportionately afflicted with breast cancer, a proportion of which may be due to BRCA1 and BRCA2 (BRCA) gene mutations. In a sample of Black women with early onset breast cancer, we evaluated BRCA mutations and explored personal and system‐level clinical characteristics. Black women diagnosed with invasive breast cancer (age ≤50) were recruited through the state cancer registry. Participants completed a questionnaire, genetic counseling and BRCA testing. Of the 48 women who consented to study participation, 46 provided a usable biologic specimen for BRCA testing. The overall prevalence of BRCA mutations and variants of uncertain significance (VUS) in participants was 6.5% and 34.8%, respectively. Of these, only 14 were referred for genetic counseling prior to study enrollment. Overall, those participants who chose to undergo bilateral mastectomy had a higher number of relatives with breast and ovarian cancer (p = 0.024) and a higher household income (p = 0.009). BRCA mutation prevalence and the high prevalence of VUS in participants are consistent with prior studies. Furthermore, clinical factors such as family history and financial means may influence type of surgery recommended and chosen, at both the provider and patient level, respectively. Finally, the limited number of patients referred for genetic counseling prior to surgical treatment for breast cancer may represent a missed clinical opportunity to inform surgical decisions.     

Primary sepsis in a university hospital in northern Sweden: a retrospective study

BACKGROUND: Severe sepsis and septic shock are associated with high mortality rates. Data on sepsis outcome from Scandinavian countries are sparse. The aim of this study was to examine the length of stay (LOS) in the ICU, ICU mortality and costs of care for adult patients with primary sepsis in a university hospital in northern Sweden. METHODS: We performed a retrospective data analysis of records of 92 patients admitted over a 3-year period, under the diagnosis of sepsis or urosepsis. Demographic data, admission category, APACHE II score, aetiology and severity of sepsis, ICU LOS, mortality and TISS were analyzed. RESULTS: Eighty-one adult patients were identified by standard definitions as suffering from sepsis. The median ICU length of stay was 4.2 days, 6 days for survivors and 2.1 days for non-survivors. Thirteen out of 20 deaths occurred within the first 3 days after admission. Overall ICU mortality rate was 24.7% while the ICU mortality for patients with septic shock was 57.7%. The mean costs of care for patients with sepsis were 3139 Euros day(-1) and the cost of care per patient surviving sepsis was 38,494 Euros. CONCLUSION: The incidence of primary sepsis in our ICU was low. Previous reports on high mortality in association with severe sepsis and septic shock are valid also at our hospital. The ICU-LOS was shorter than previously reported, while our costs of care were in the same range as stated by others. This retrospective analysis is valid for interpretation of the applicability of currently available sepsis therapies.