Theresa Anne Lawrie

In the wake of the COVID-19 crisis, a need has arisen to prevent and treat two related conditions, COVID-19 vaccine injury and long COVID-19, both of which can trace at least part of their aetiology to the spike protein, which can cause harm through several mechanisms. One significant mechanism of harm is vascular, and it is mediated by the spike protein, a common element of the COVID-19 illness, and it is related to receiving a COVID-19 vaccine. Given the significant number of people experiencing these two related conditions, it is imperative to develop treatment protocols, as well as to consider the diversity of people experiencing long COVID-19 and vaccine injury. This review summarizes the known treatment options for long COVID-19 and vaccine injury, their mechanisms, and their evidentiary basis.

Pharmacovigilance databases are showing evidence of injury in the context of the modified COVID-19 mRNA products. According to recent publications, adverse event reports linked to the mRNA COVID-19 injections largely point to the spike protein as an aetiological agent of adverse events, but we propose that the platform itself may be culpable. To assess the safety of current and future mRNA vaccines, further analysis is needed on the risks due to the platform itself, and not specifically the expressed antigen. If harm can be exclusively and conclusively attributed to the spike protein, then it is possible that future mRNA vaccines expressing other antigens will be safe. If harms are attributable to the platform itself, then regardless of the toxicity, or lack thereof, of the antigen to be expressed, the platform may be inherently unsafe, pending modification. In this work, we examine previous studies of RNA-based delivery by a lipid nanoparticle (LNP) and break down the possible aetiological elements of harm.

In the wake of the Covid-19 crisis, a need has arisen to prevent and treat two related conditions, Covid vaccine injury and long Covid, both of which have a significant vascular component. Therefore, the management of these conditions require the development of strategies to prevent or dissolve blood clots and restore circulatory health. This review summarizes the evidence on strategies that can be applied to treat both long and vaccine injuries based on similar mechanisms of action.

Background: The ECHO trial randomised 7829 women to depot medroxyprogesterone acetate (DMPA-IM), the copper intrauterine device (IUD) and the levonorgestrel (LNG) implant (1:1:1) and found no clear difference in HIV incidence between these three groups. We have previously hypothesized that oligo-amenorrhoea induced by DMPA-IM may have a protective effect on HIV acquisition. The aim of this ancillary study was to assess the effects of DMPA-IM, the IUD and the LNG implant on menstrual symptoms and sexual behavior and to correlate these with HIV acquisition. Methods: At the Effective Care Research Unit (ECRU) in South Africa, of 615 women already randomised to DMPA-IM, the copper IUD and the LNG implant (1:1:1) 552 agreed to participate. Participants completed a 28-day symptom and behavior diary following their one-month ECHO trial visit and returning it at their 3-month follow-up visit. HIV acquisition data were retrieved from ECHO trial records. Results: Of 552 women enrolled on the ancillary study, 390 (70.6%) completed their daily diary; 130, 133, and 127 received DMPA-IM, IUD, and LNG implant, respectively. Thirty-three (5.9%) of these women acquired HIV. Women on the progestin-only contraceptives were more likely to experience amenorrhoea, as expected, and were less likely to have intra-menstrual coitus than IUD users (p < 0.001 for DMPA-IM vs IUD and p = 0.002 for implant vs IUD). Overall coital frequency was highest and condom usage lowest among DMPA-IM users. Intra-menstrual coitus correlated positively, and duration of menstruation correlated negatively, with HIV acquisition, although these effects were not statistically significant (p = 0.09 and p = 0.079, respectively). Conclusions: Findings support the hypothesis that oligo-amenorrhoea and the associated reduced intra-menstrual coitus may mitigate the potential for an increased biological risk of HIV acquisition with DMPA-IM but more evidence is needed. Study registration number PACTR201706001651380

Background: Repurposed medicines may have a role against the SARS-CoV-2 virus. The antiparasitic ivermectin, with antiviral and anti-inflammatory properties, has now been tested in numerous clinical trials. Areas of uncertainty: We assessed the efficacy of ivermectin treatment in reducing mortality, in secondary outcomes, and in chemoprophylaxis, among people with, or at high risk of, COVID-19 infection. Data sources: We searched bibliographic databases up to April 25, 2021. Two review authors sifted for studies, extracted data, and assessed risk of bias. Meta-analyses were conducted and certainty of the evidence was assessed using the GRADE approach and additionally in trial sequential analyses for mortality. Twenty-four randomized controlled trials involving 3406 participants met review inclusion. Therapeutic Advances: Meta-analysis of 15 trials found that ivermectin reduced risk of death compared with no ivermectin (average risk ratio 0.38, 95% confidence interval 0.19–0.73; n = 2438; I² = 49%; moderate-certainty evidence). This result was confirmed in a trial sequential analysis using the same DerSimonian–Laird method that underpinned the unadjusted analysis. This was also robust against a trial sequential analysis using the Biggerstaff–Tweedie method. Low-certainty evidence found that ivermectin prophylaxis reduced COVID-19 infection by an average 86% (95% confidence interval 79%–91%). Secondary outcomes provided less certain evidence. Low-certainty evidence suggested that there may be no benefit with ivermectin for “need for mechanical ventilation,” whereas effect estimates for “improvement” and “deterioration” clearly favored ivermectin use. Severe adverse events were rare among treatment trials and evidence of no difference was assessed as low certainty. Evidence on other secondary outcomes was very low certainty. Conclusions: Moderate-certainty evidence finds that large reductions in COVID-19 deaths are possible using ivermectin. Using ivermectin early in the clinical course may reduce numbers progressing to severe disease. The apparent safety and low cost suggest that ivermectin is likely to have a significant impact on the SARS-CoV-2 pandemic globally.

Background Glioblastoma (GBM) is a highly malignant brain tumour that almost inevitably progresses or recurs after first line standard of care. There is no consensus regarding the best treatment/s to offer people upon disease progression or recurrence. For the purposes of this review, progression and recurrence are considered as one entity. Objectives To evaluate the effectiveness of further treatment/s for first and subsequent progression or recurrence of glioblastoma (GBM) among people who have received the standard of care (Stupp protocol) for primary treatment of the disease; and to prepare a brief economic commentary on the available evidence. Search methods We searched MEDLINE and Embase electronic databases from 2005 to December 2019 and the Cochrane Central Register of Controlled Trials (CENTRAL, in the Cochrane Library; Issue 12, 2019). Economic searches included the National Health Service Economic Evaluation Database (NHS EED) up to 2015 (database closure) and MEDLINE and Embase from 2015 to December 2019. Selection criteria Randomised controlled trials (RCTs) and comparative non‐randomised studies (NRSs) evaluating effectiveness of treatments for progressive/recurrent GBM. Eligible studies included people with progressive or recurrent GBM who had received first line radiotherapy with concomitant and adjuvant temozolomide (TMZ). Data collection and analysis Two review authors independently selected studies and extracted data to a pre‐designed data extraction form. We conducted network meta‐analyses (NMA) and ranked treatments according to effectiveness for each outcome using the random‐effects model and Stata software (version 15). We rated the certainty of evidence using the GRADE approach. Main results We included 42 studies: these comprised 34 randomised controlled trials (RCTs) and 8 non‐randomised studies (NRSs) involving 5236 participants. We judged most RCTs to be at a low risk of bias and NRSs at high risk of bias. Interventions included chemotherapy, re‐operation, re‐irradiation and novel therapies either used alone or in combination. For first recurrence, we included 11 interventions in the network meta‐analysis (NMA) for overall survival (OS), and eight in the NMA for progression‐free survival (PFS). Lomustine (LOM; also known as CCNU) was the most common comparator and was used as the reference treatment. No studies in the NMA evaluated surgery, re‐irradiation, PCV (procarbazine, lomustine, vincristine), TMZ re‐challenge or best supportive care. We could not perform NMA for second or later recurrence due to insufficient data. Quality‐of‐life data were sparse. First recurrence (NMA findings) Median OS across included studies in the NMA ranged from 5.5 to 12.6 months and median progression‐free survival (PFS) ranged from 1.5 months to 4.2 months. We found no high‐certainty evidence that any treatments tested were better than lomustine. These treatments included the following. Bevacizumab plus lomustine: Evidence suggested probably little or no difference in OS between bevacizumab (BEV) combined with lomustine (LOM) and LOM monotherapy (hazard ratio (HR) 0.91, 0.75 to 1.10; moderate‐certainty evidence), although BEV + LOM may improve PFS (HR 0.57, 95% confidence interval (CI) 0.44 to 0.74; low‐certainty evidence). Bevacizumab monotherapy: Low‐certainty evidence suggested there may be little or no difference in OS (HR 1.22, 95% CI 0.84 to 1.76) and PFS (HR 0.90, 95% CI 0.58 to 1.38; low‐certainty evidence) between BEV and LOM monotherapies; more evidence on BEV is needed. Regorafenib (REG): REG may improve OS compared with LOM (HR 0.50, 95% CI 0.33 to 0.76; low‐certainty evidence). Evidence on PFS was very low certainty and more evidence on REG is needed. Temozolomide (TMZ) plus Depatux‐M (ABT414): For OS, low‐certainty evidence suggested that TMZ plus ABT414 may be more effective than LOM (HR 0.66, 95% CI 0.47 to 0.92) and may be more effective than BEV (HR 0.54, 95% CI 0.33 to 0.89; low‐certainty evidence). This may be due to the TMZ component only and more evidence is needed. Fotemustine (FOM): FOM and LOM may have similar effects on OS (HR 0.89, 95% CI 0.51 to 1.57, low‐certainty evidence). Bevacizumab and irinotecan (IRI): Evidence on BEV + irinotecan (IRI) versus LOM for both OS and PFS is very uncertain and there is probably little or no difference between BEV + IRI versus BEV monotherapy (OS: HR 0.95, 95% CI 0.70 to 1.30; moderate‐certainty evidence). When treatments were ranked for OS, FOM ranked first, BEV + LOM second, LOM third, BEV + IRI fourth, and BEV fifth. Ranking does not take into account the certainty of the evidence, which also suggests there may be little or no difference between FOM and LOM. Other treatments Three studies evaluated re‐operation versus no re‐operation, with or without re‐irradiation and chemotherapy, and these suggested possible survival advantages with re‐operation within the context of being able to select suitable candidates for re‐operation. A cannabinoid treatment in the early stages of evaluation, in combination with TMZ, merits further evaluation. Second or later recurrence Limited evidence from three heterogeneous studies suggested that radiotherapy with or without BEV may have a beneficial effect on survival but more evidence is needed. Evidence was insufficient to draw conclusions about the best radiotherapy dosage. Other evidence suggested that there may be little difference in survival with tumour‐treating fields compared with physician's best choice of treatment. We found no reliable evidence on best supportive care. Severe adverse events (SAEs) The BEV+LOM combination was associated with significantly greater risk of SAEs than LOM monotherapy (RR 2.51, 95% CI to 3.66, high‐certainty evidence), and ranked joint worst with cediranib + LOM (RR 2.51, 95% CI 1.29 to 4.90; high‐certainty evidence). LOM ranked best and REG ranked second best. Adding novel treatments to BEV was generally associated with a higher risk of severe adverse events compared with BEV alone. Authors' conclusions For treatment of first recurrence of GBM, among people previously treated with surgery and standard chemoradiotherapy, the combination treatments evaluated did not improve overall survival compared with LOM monotherapy and were often associated with a higher risk of severe adverse events. Limited evidence suggested that re‐operation with or without re‐irradiation and chemotherapy may be suitable for selected candidates. Evidence on second recurrence is sparse. Re‐irradiation with or without bevacizumab may be of value in selected individuals, but more evidence is needed.

Background Brain tumours are recognised as one of the most difficult cancers to diagnose because presenting symptoms, such as headache, cognitive symptoms, and seizures, may be more commonly attributable to other, more benign conditions. Interventions to reduce the time to diagnosis of brain tumours include national awareness initiatives, expedited pathways, and protocols to diagnose brain tumours, based on a person's presenting symptoms and signs; and interventions to reduce waiting times for brain imaging pathways. If such interventions reduce the time to diagnosis, it may make it less likely that people experience clinical deterioration, and different treatment options may be available. Objectives To systematically evaluate evidence on the effectiveness of interventions that may influence: symptomatic participants to present early (shortening the patient interval), thresholds for primary care referral (shortening the primary care interval), and time to imaging diagnosis (shortening the secondary care interval and diagnostic interval). To produce a brief economic commentary, summarising the economic evaluations relevant to these interventions. Search methods For evidence on effectiveness, we searched CENTRAL, MEDLINE, and Embase from January 2000 to January 2020; Clinicaltrials.gov to May 2020, and conference proceedings from 2014 to 2018. For economic evidence, we searched the UK National Health Services Economic Evaluation Database from 2000 to December 2014. Selection criteria We planned to include studies evaluating any active intervention that may influence the diagnostic pathway, e.g. clinical guidelines, direct access imaging, public health campaigns, educational initiatives, and other interventions that might lead to early identification of primary brain tumours. We planned to include randomised and non‐randomised comparative studies. Included studies would include people of any age, with a presentation that might suggest a brain tumour. Data collection and analysis Two review authors independently assessed titles identified by the search strategy, and the full texts of potentially eligible studies. We resolved discrepancies through discussion or, if required, by consulting another review author. Main results We did not identify any studies for inclusion in this review. We excluded 115 studies. The main reason for exclusion of potentially eligible intervention studies was their study design, due to a lack of control groups. We found no economic evidence to inform a brief economic commentary on this topic. Authors' conclusions In this version of the review, we did not identify any studies that met the review inclusion criteria for either effectiveness or cost‐effectiveness. Therefore, there is no evidence from good quality studies on the best strategies to reduce the time to diagnosis of brain tumours, despite the prioritisation of research on early diagnosis by the James Lind Alliance in 2015. This review highlights the need for research in this area.

Optimal maternal nutrition, including adequate intake of essential vitamins and minerals, is important for fetal development and longer term impacts on the child’s health. Although pregnant women are considered to be at increased risk of micronutrient deficiencies due to increased maternal and fetal nutritional needs, there is some debate around how best to achieve an optimal diet with adequate and balanced intakes of the necessary nutrients during the antenatal period and before pregnancy.1 The most common micronutrient deficiency in pregnancy that is known to impact maternal health is iron deficiency, due to increased iron demands. Iron deficiency is a common cause of anaemia, which is estimated to affect 40% of pregnancies globally, highest in South-East Asia (49%), Africa (46%) and the Eastern Mediterranean (41%) and lower prevalence in Western Pacific (33%), the Americas (26%) and Europe (27%).2 Thus, iron supplementation has been recommended by WHO for all women during pregnancy since the 1950s. Current global nutrition targets call for a 50% reduction in anaemia among women of reproductive age by 2025, and the prevalence of anaemia in women aged 15–49 years, by pregnancy status, has now been proposed as an indicator for Sustainable Development Goal 2.3 In addition to routine iron and folic acid (IFA) supplementation, various other interventions have been proposed to increase the micronutrient intake before and during pregnancy, including food-based approaches.

Background: Increasingly, WHO recommendations are defined by context-specific factors and WHO is developing strategies to ensure that recommendations are successfully adapted and implemented at country level. This manuscript describes the development of a toolkit to support governments to adapt the WHO recommendations on antenatal care (ANC) for a positive pregnancy experience for their context in a systematic manner. Methods: The toolkit was developed in three steps. It was created with input from methodologists and regional implementation experts (Step 1) followed by a user-testing phase (Step 2), implemented during country stakeholder meetings. User testing consisted of stakeholder interviews that were transcribed, and data was categorised according to the content analysis method. Suggestions for toolkit improvement and issues identified during the interviews were assessed as serious, moderately serious or minor/cosmetic. Results: A total of 22 stakeholders – comprising five Ministry of Health (MoH) consultants, four MoH policy-makers, and 13 advisors/implementers – from Burkina Faso, India, Rwanda and Zambia participated in user-testing interviews during stakeholder meetings held in each country between August 2018 and February 2019. Most stakeholders had a medical or nursing background and half were women. Overall, responses to the toolkit were positive, with all stakeholders finding it useful and desirable. User testing interviews highlighted four serious, four moderately serious and five minor/cosmetic issues to be managed. These were addressed in the final step (Step 3), an updated version of the WHO ANC Recommendations Adaptation Toolkit, comprised of two main components – a baseline assessment tool with spreadsheets for data entry and a Slidedoc^®, a dual-purpose document for reading and presentation, outlining the qualitative data that shaped the women-centred perspective of the guidelines, accompanied by an instruction manual detailing the components’ use. Conclusions: The WHO ANC Recommendations Adaptation Toolkit was developed to support countries to systematically adapt the WHO ANC recommendations for country contexts. Using this approach, similar tools can be developed to support guideline implementation across different health domains and the continuum of care.