Previous longitudinal studies indicate that hearing loss and cognitive impairment are associated in non-tonal language-speaking older adults. This study aimed to investigate whether there is a longitudinal association between hearing loss and cognitive decline in older adults who speak a tonal language.Chinese-speaking older adults aged 60 years and above were recruited for baseline and 12 month follow-up measurements. All participants completed a pure tone audiometric hearing test, Hearing Impaired-Montreal Cognitive Assessment Test (HI-MoCA), and a Computerized Neuropsychological Test Battery (CANTAB). The De Jong Gierveld Loneliness Scale was used to measure loneliness, and the 21-item Depression Anxiety Stress Scale (DASS-21) was used to measure aspects of mental health. Associations between baseline hearing loss and various cognitive, mental and psychosocial measures were evaluated using logistic regression.A total of 71 (29.6%) of the participants had normal hearing, 70 (29.2%) had mild hearing loss, and 99 (41.2%) had moderate or severe hearing loss at baseline, based on mean hearing thresholds in the better ear. After adjusting for demographic and other factors, baseline moderate/severe audiometric hearing loss was associated with an increased risk of cognitive impairment at follow-up . When pure-tone average (PTA) was modeled continuously, an average difference of 0.24 in HI-MoCA scores for every 10 dB increase in BE4FA existed, and an average difference of 0.07 in the change of HI-MoCA scores in a 12 month period.The results revealed a significant longitudinal relationship between age-related hearing loss and cognitive decline in this cohort of tonal language-speaking older adults. Steps should also be taken to incorporate hearing assessment and cognitive screening in clinical protocols for older adults 60 years and above in both hearing and memory clinics. Hearing loss is considered the fourth greatest cause of disability in the world, according to the measured years lived with disability (YLDs) . In ChinThe state of cognitive impairment covers a wide range of disorders, from subjective memory complaints and mild cognitive impairment to dementia . Those wDifferences between the structure of tonal and non-tonal languages may result in different associations between hearing loss and cognitive decline. Changes in pitch (tone) at the monosyllabic level transmit the different lexical meanings of a word in tonal languages. Psychophysiological data suggests that a tonal language background is associated with enhanced overall cognitive ability . FurtherThe association between untreated age-related hearing loss and cognitive impairment in Mandarin-speaking older adults has been supported by data from cross-sectional  and caseMost of the cross-sectional and longitudinal cohort studies of cognition and hearing loss conducted with Chinese older adults have a few limitations regarding methods used to assess hearing and/or cognitive function. For example, self-reported hearing loss, not the audiometric measures of hearing, was utilized in most of the longitudinal studies to date . EvidencFurthermore, most of the cognitive assessments included verbally loaded scales or questionnaires that rely on the hearing ability of participants, e.g., the Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA). As hearing loss can influence participants’ performance during cognitive assessments, it is essential to adopt non-verbal cognitive test materials when assessing the cognitive functions of elderly participants with hearing loss . FurtherWhen compared to people with normal hearing, those with impaired communication abilities brought on by untreated hearing loss have a higher risk of experiencing negative mental and psychosocial effects. Hearing loss has been linked to depression , anxietyThis study explored the potential links between hearing loss and cognitive decline in a tonal language-speaking adult population based on data from a longitudinal study, utilizing both a non-verbal computer-based assessment battery for the different domains of cognitive functions (CANTAB) and a modified Montreal Cognitive Assessment for hearing impairment (HI-MoCA). We aimed to quantify the association between baseline hearing loss categories and cognitive impairment at follow-up, and also the association between audiometric hearing level and various domain-specific cognitive functions at follow-up.This study’s protocol was previously published as part of a report of a cross-sectional study on hearing loss and cognitive performance in an adult Chinese population . These aParticipants were recruited through social media notices and community activities. Participants were native Mandarin speakers and at least 60 years of age when enrolled. Those who were not in general good health, unable to complete tasks necessary for the cognition evaluation tasks due to an underlying medical or mental illness, or who had previously worn or were using hearing aids or a hearing implant at the time of the study were excluded from the study.The University of Western Australia-Human Research Ethics Committee (RA/4/20/5538) and Beijing Tongren Hospital, Capital Medical University (TRECKY2019-090) approved this study. Permission was also obtained from MoCA officials. All procedures were carried out in compliance with these approvals, and all participants signed informed consent forms.Hearing loss was assessed by pure-tone audiometry with an audiometer . For all participants, bilateral air-conduction thresholds were measured at 0.25, 0.5, 1, 2, 4, 6, and 8 kHz through a standard audiometric assessment conducted by a qualified audiologist in a soundproof booth at the audiology center of the Beijing Institute of Otolaryngology.Two different methods were used to classify the hearing loss: the traditional average of the four mid-frequency hearing thresholds at 0.5, 1, 2, and 4 kHz in the better ear, and the average of the three high-frequency hearing thresholds at 4, 6, and 8 kHz in the better ear, noted respectively, as BE4FA and BE3HFA. Hearing thresholds at the higher frequencies were included because these frequencies contribute to the clarity of speech, whereas hearing in lower frequencies is necessary for speech comprehension. Furthermore, hearing loss in adults usually starts in the higher frequencies which may not be captured by summarizing the mid-frequencies. The hearing thresholds were also classified into a categorical variable, normal hearing (BE4FA ≤ 25 dB HL), mild hearing loss (26 to 40 dB HL), and moderate or above hearing loss (>40 dB HL) .HI-MoCA was used to assess the individuals’ overall cognitive abilities. A Mandarin version of the MoCA (Version 7) was adapted, which was converted into a timed PowerPoint  presentation with all the verbal instructions replaced with visual instructions, here named HI-MoCA . To accoThe evaluation of cognitive function for this study was focused on working and episode memory, processing speed, and special information processing. CANTAB is a neuropsychological test battery that was used to measure four non-verbal cognitive functions : Motor Screening (MOT), delayed matching to sample (DMS), paired associates learning (PAL), and spatial working memory (SWM).Motor screening screens visual, movement, and comprehension issues that could limit the data collection. The DMS test assesses both simultaneous visual matching ability and short-term visual recognition memory for non-verbalisable patterns . The perThe Mandarin version of the 6-item De Jong Gierveld Loneliness Scale (DJGLS) was used to measure loneliness, a validated tool to assess overall, emotional, and social loneliness . In thisThe validated Chinese version  of the 2Demographic information, including age (years), sex, and education , was collected in 2019/2020 using a self-report questionnaire. Lifestyle characteristics, including longest occupation in life, residential arrangements , marital status , and drinking and smoking habits , were obtained.Participants reported their history of diabetes mellitus and cardiovascular-related diseases . These were chosen as covariates because they may increase the risk of hearing loss  and cognLeisure activities, which constitute a major portion of daily living and provide cognitive stimulation for older adults, were classified into recreational, intellectual, physical, and social categories . The parContinuous variables at both baseline and follow-up were described as the mean ± standard deviation, and the categorical variables were described as numbers (percentage). A further series of comparisons of hearing thresholds, cognitive performance, loneliness, and mental health scores were analyzed among these two waves by chi-square test or Wilcoxon rank-sum test.Associations between baseline hearing loss and outcome cognition impairment at follow-up were evaluated using the odds ratio (OR) and its corresponding 95% confidence intervals (95% CI) by multiple logistic regression, adjusting for confounding variables, including age, sex, education level, smoking, drinking, marital status, chronic disease, and leisure activities. Odds ratios (OR) > 1.00 indicated increased odds of cognitive impairment with every unit increase in HL across participants and other variables, whereas OR < 1.00 indicated lower odds of those variables.As a longitudinal study, the linear mixed-effect model (LME) was used, including the covariates listed above, to study the time to incident cognitive decline. The LME model is designed to analyze longitudinal data. This model offers the advantage of considering multiple observations within a subject and intrasubject correlation. It also allows for adjusting numerous potential confounding variables . An intep ≤ 0.05 based on two-sided tests.Multivariate linear regression (forward stepwise) analyses were used to assess the associations between cognition and hearing loss, loneliness and DASS-21 (continuous variables). A regression coefficient and its 95% CI were calculated. The different CANTAB modules  and HI-MoCA scores were entered as dependent variables, respectively. The collinearity tests were examined during each stepwise regression analysis. All statistical analyses were performed using Stata version 17 . The significance level was Of the 293 patients recruited in 2018/2019 at baseline, 39 did not attend the 12 month follow-up and 14 had incomplete covariate information. These 53 were excluded, leaving 240 participants who participated in both baseline and follow-up waves.Z = 6.713, p < 0.001). The mean progression of hearing loss was 0.68 and 1.58 dB/year for BE4FA and BE3HFA, respectively. Regarding the mental health and loneliness scores, we also observed significant changes over the follow-up period. The average change of depression, anxiety and stress scores were 0.83, 1.19, and 0.9, respectively  had normal hearing, 70 (29.2%) had mild hearing loss, and 99 (41.2%) had moderate or greater hearing loss at baseline . Compareectively . Mean chectively .Participants with hearing impairment at baseline had a higher incidence of developing mild cognitive impairment based on HI-MoCA cutoff scores, than those with normal hearing. The 12 month unadjusted OR of developing mild cognitive impairment was 3.23 (95% CI = 1.69−6.17) in subjects with moderate or above hearing loss , but forB = −0.04, P < 0.001) and 12 month follow-up period . Model 2 examined the association between hearing loss and cognitive decline, adjusted for age, sex, and educational level. The strength of the association between HI-MoCA scores and BE4FA and time decreased but was still significant . Finally, Model 3 assessed the same relationship as Model 2, with additional adjustments for several factors . After controlling for these factors, the coefficients of cognitive decline with hearing loss and the follow-up period were still significant . When BE3HFA was used as the independent variable, it was also significantly associated with the coefficients of cognitive decline in the three models.These results were confirmed when HI-MoCA scores were analyzed as a continuous variable. p = 0.041 and 0.037), but not for SWM scores (p = 0.082). However, no significant changes in any of the specific CANTAB cognitive domain scores during the 12 month period were observed to be associated with hearing loss .We conducted additional analyses to investigate the association between hearing loss and specific cognitive domains . When pure-tone average (PTA) was modeled continuously, we estimated an average change of 0.24 in HI-MoCA scores for every 10 dB increase in BE4FA and an average change of 0.07 in the change of HI-MoCA scores in a 12 month period for every 10 dB increase in BE4FA. As shown in Our results demonstrate that baseline hearing loss is associated with an increased risk of cognitive impairment at 12 months, as assessed by specific and general cognitive tests. However, the findings from this tonal language-speaking cohort do not appear to be significantly different from similar studies with non-tonal language speakers. Baseline moderate or severe hearing loss is associated with a greater risk of cognitive impairment after a 12 month follow-up period , compared with participants with normal hearing, after adjusting demographic and other factors, including mental health, loneliness status, behavior factors, and health conditions. Besides the general cognitive performance, an association was also observed between hearing loss and some specific baseline cognitive functions, including simultaneous visual matching ability and short-term visual recognition memory (DMS module in CANTAB) and episodic visuospatial memory (PAL module in CANTAB). This finding is consistent with previous longitudinal studies on the relationship between hearing loss measured by pure tone audiometry and cognitive impairment , and cogBaseline hearing loss was demonstrated to be a predictor of the change in overall cognitive performance (HI-MoCA) over 12 months, regardless of whether the continuous or categorical values were used. Furthermore, an association in the baseline scores of DMS and PAL with every 10 dB change of hearing loss was observed. These findings accord with those of previous studies, suggesting that these participants are at risk of developing dementia . HoweverOur findings are in general agreement with the findings in studies with non-tonal language speakers. Therefore, we provide no evidence to support the notion that speaking a tonal language provides an advantage over non-tonal language speakers over a 12 month period.There is only a limited number of longitudinal studies in this field in tonal language speaking populations . Most ofIn this study, we also observed a significant decrease in HI-MoCA scores over 12 months, with a mean change of 0.35 points in the cognitive impairment group and 0.21 points in the cognitively intact group. A previous study on the changes in MoCA scores over time, reported that a group with mild cognitive impairment at baseline showed a decline of 0.47 points/year over 3.5 years, while the cognitively intact group showed a decline of 0.18 points/year, but there was no significant difference between the two groups . We alsoSignificant changes were observed in the mental health and loneliness scores over the follow-up period. One potential explanation for the significant changes in DASS-21 and loneliness scales, could be related to the impact of COVID-19. China was the first country that identified the coronavirus disease in the world at the end of 2019, and Beijing reported the first cases in February 2020 , just afNon-verbal materials were utilized in this study, both for the general cognitive performance and in specific domains, which may be a better estimation of the association between hearing loss and cognitive impairment than achieved when using verbal materials that are based on verbal materials. It is possible that age-related hearing loss and cognitive impairment share a common etiology, such as vascular disease. Furthermore, this study provides further evidence that the link between hearing loss and cognitive decline may also be mediated by depressive disorders and social isolation. This study attempted to control for these covariates and showed that the associations remained robust.Two limitations have already been noted above. The short follow-up period may underpower the potential association between audiometric hearing loss and cognitive declines at the scale of general and specific domains. Furthermore, the participants experienced the COVID-19 pandemic between the baseline (2019/2020) and the 12 month follow-up session (2020/2021). At this stage, it is difficult to distinguish to what extent the pandemic impacted the mental health and also cognitive function of these older adults.Another limitation is that as a volunteer cohort, older adults with high self-awareness of health concerns may have tended to be enrolled; therefore, extrapolating the findings from this current study must be done with caution. More extensive studies with more representative and community-based participants will be required to confirm the results.Central auditory processing function was not measured in this study. There is evidence that central auditory processing impairment is the primary impairment associated with cognitive impairment and dementia . Future Finally, the recommended cutoff score for the MoCA, 26, was adopted for cognitive impairment in this study, which may result in a higher rate of identification of those at risk of cognitive impairment and dementia, and increase the odds ratio between hearing loss and cognitive impairment . RecentlThis study contributes to the growing but still limited body of evidence that hearing loss and cognitive impairment, and decline are significantly associated in tonal language-speaking older adults in China. Hearing loss may be a modifiable solution for health problems associated with cognitive impairment. As hearing aids are the primary management option for hearing loss, it is important to conduct a clinical trial to investigate whether hearing aids can delay cognitive decline, especially in a randomized controlled trial .Given the high occurrence of dementia, actions to reduce these concerns for seniors may have considerable public health implications. Steps should also be taken to incorporate hearing assessment and cognitive screening in clinical protocols for older adults 60 years and above in both hearing and memory clinics. Clinicians should start thinking about incorporating objective electrophysiological measurements as part of the hearing test battery, considering their advantage in evaluating hearing acuity in older adults with cognitive impairment, who are unable to complete behavioral pure tone audiometry . FurtherIn summary, this study found that moderate or above hearing loss at baseline was associated with cognitive decline during 12 months of follow-up in a Chinese language-speaking population aged 60 years and above. This finding supplied evidence that hearing loss may be a risk factor for cognitive impairment in older adults. Given that more than 50 per cent of adults older than 60 years in China are affected by hearing impairment, hearing intervention may be a target to prevent or at least delay cognitive decline in older adults.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the University of Western Australia-Human Research Ethics Committee (RA/4/20/5538) and Beijing Tongren Hospital, Capital Medical University (TRECKY2019-090). The patients/participants provided their written informed consent to participate in this study.DJ and XF designed the experiments. XF carried out the experiments. XF, RE, DJ, SW, and BL analyzed the experimental data. XF wrote the manuscript. RE and DJ revised the manuscript. RE, DJ, SW, and BL reviewed the manuscript. All authors contributed to the article and approved the submitted version.


The development of drugs that successfully target Bruton tyrosine kinase (BTK) represents a major scientific and clinical advance for the treatment of chronic lymphocytic leukaemia (CLL). This article will begin by reviewing the scientific observations that underpinned the targeting of this kinase in CLL. It will then discuss the evolution of BTK inhibitors, from the initial studies with ibrutinib, to the development of more specific and noncovalently binding BTK inhibitors, focusing on how different agents can be sequenced in patients who are resistant or intolerant to one of these drugs. Finally, this article will also review the concept of BTK degraders and offer insights into the future direction of the field.The development of inhibitors of Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) has resulted in a paradigm shift in the treatment of chronic lymphocytic leukaemia (CLL) over the last decade. Observations regarding the importance of B-cell receptor signalling for the survival and proliferation of CLL cells led to the development of the first-in-class BTK inhibitor (BTKi), ibrutinib, for the treatment of CLL. Despite being better tolerated than chemoimmunotherapy, ibrutinib does have side effects, some of which are due to the off-target inhibition of kinases other than BTK. As a result, more specific inhibitors of BTK were developed, such as acalabrutinib and zanubrutinib, which have demonstrated equivalent/enhanced efficacy and improved tolerability in large randomized clinical trials. Despite the increased specificity for BTK, side effects and treatment resistance remain therapeutic challenges. As these drugs all bind covalently to BTK, an alternative approach was to develop noncovalent inhibitors of BTK, including pirtobrutinib and nemtabrutinib. The alternative mechanisms of BTK-binding of these agents has the potential to overcome resistance mutations, something that has been borne out in early clinical trial data. A further step in the clinical development of BTK inhibition has been the introduction of BTK degraders, which remove BTK by ubiquitination and proteasomal degradation, in marked contrast to BTK inhibition. This article will review the evolution of BTK inhibition for CLL and offer future perspectives on the sequencing of an increasing number of different agents, and how this may be impacted on by mutations in BTK itself and other kinases. IGHV) gene of the CLL BCRs was of prognostic value, with patients with unmutated (>98% homology to germline) IGHV genes (UM-IGHV) having a poorer prognosis than those with mutated (≤98% homology to germline) IGHV genes (M-IGHV) [IGHV CLL cells have higher expression of surface immunoglobulin , which is associated with a retained ability to undergo calcium flux and tyrosine phosphorylation upon BCR ligation [9) of BCRs, meaning that the chances of two patients with CLL having identical or near-identical BCRs should be negligible [IGHV CLL cases are thought to have higher-affinity binding to restricted sets of epitopes, reflecting the fact that the clone has arisen from a B-cell that has undergone somatic hypermutation and affinity maturation in the germinal centre [IGHV CLL cases express polyreactive BCRs that bind with low affinity to environmental and autoantigens such as vimentin, myosin, or rheumatoid factors [The development of inhibitors of B-cell receptor (BCR) signalling, particularly those that inhibit Bruton tyrosine kinase (BTK), has transformed the treatment landscape for chronic lymphocytic leukaemia (CLL) over the last decade. The recognition of the importance of this signalling pathway for CLL was due to a number of important observations over the preceding 10–15 years. One of the most important findings was that the mutational status of the variable region of the immunoglobulin heavy chain  which is bound noncovalently to a CD79a/CD79b heterodimer . When thThe molecular understanding of BCR signalling highlights multiple potential targets. Several drugs that inhibit kinases involved in this pathway entered clinical testing including inhibitors of SYK , pan-SRC kinases (dasatinib), PI3K , and BTK , and tirabrutinib (ONO-4059)) ,13,18. DBTK gene (present on the long arm of the X-chromosome) and an immunodeficiency characterized by the absence of mature B-cells, resulting in severe antibody deficiency and recurrent infections that can manifest as soon as the protective effect of maternal immunoglobulins wanes at around 3–6 months of age. Preclinical observations confirmed the importance of BTK in CLL, demonstrating overexpression of this kinase in the leukemic cells compared with healthy B-cells, with ibrutinib demonstrating preferential, albeit modest, killing of CLL cells in vitro [Ibrutinib, initially known as PCI-32765, was the first BTKi to enter clinical testing. Ibrutinib is an orally bioavailable small molecule which binds irreversibly to a cysteine residue (C481) in the BTK kinase domain to inhibit its enzymatic activity . BTK couin vitro .IGHV genes, a finding replicated in other studies, logically suggesting that BTK inhibition is more effective in cases where the CLL cells have a higher BCR signalling capacity [An initial phase 1b/2 study in 85 patients with relapsed/refractory CLL or small lymphocytic lymphoma (SLL) compared two different doses of ibrutinib, 420 mg versus 840 mg . Interescapacity ,36.Initial studies also demonstrated the efficacy of the PI3K inhibitor, idelalisib, for the treatment of CLL . A randoTP53-intact patients only, particularly in those with UM-IGHV CLL, replicating the earlier observations with ibrutinib [TP53 or del17p also obtained durable disease control with acalabrutinib-based treatment, with a 4-year PFS of 76% and 75%, respectively, for acalabrutinib monotherapy and acalabrutinib–obinutuzumab. Acalabrutinib-treated patients in the ASCEND trial obtained an equivalent PFS whether TP53 mutated/del17p or not.The advent of the second-generation BTKis acalabrutinib and zanubrutinib now provides additional options in the management of front-line and relapsed CLL. Acalabrutinib (dosed at 100 mg twice daily) is a highly selective irreversible covalent BTKi licensed as monotherapy in R/R CLL following the ASCEND trial which demonstrated its superiority over investigator choice of either idelalisib–rituximab or bendamustine–rituximab ,48. Acalbrutinib . PatientTP53 mutation or 11q deletion) [The ELEVATE-RR open-labelled randomized controlled trial directly compared acalabrutinib with ibrutinib in R/R CLL patients and at least one high-risk genetic aberrancy (del17p/eletion) . The stueletion) .IGHV CLL. One hundred and ten patients with del17p/TP53 mutation were enrolled in a separate open label phase II nonrandomized arm of the SEQUOIA trial (Arm C), receiving zanubrutinib monotherapy to progression. At a median follow-up of 30.5 months, the overall response rate (ORR) was 90%, the estimated 24-month PFS was 88.9%, and the estimated 24-month overall survival was 93.6%.Zanubrutinib (dosed at 160 mg twice daily) is another second-generation irreversible covalent BTKi approved as monotherapy for both front-line and relapsed CLL following results of the SEQUOIA trial and the ALPINE trial, respectively ,56. ZanuTP53 mutated/del17p CLL (HR 0.53). Discontinuation rates for reasons other than progression, cardiac sudden deaths, and atrial fibrillation rates were all important findings in favour of zanubrutinib. The toxicity profile between the two agents for other parameters such as hypertension, infection, bleeding, and cytopenia rates were similar. Zanubrutinib also recently demonstrated safety and efficacy in 67 patients previously intolerant to either ibrutinib or acalabrutinib [The recently published ALPINE trial directly compared zanubrutinib monotherapy with ibrutinib monotherapy in a large open-label, phase 3, randomized trial with ORR  the primary end point, with PFS and safety key secondary endpoints . The popbrutinib .As a result, it now seems reasonable to recommend these second-generation molecules with increased specificity for BTK over ibrutinib, due to the improved safety profile with acalabrutinib and the demonstrated improved efficacy and safety with zanubrutinib. Whether zanubrutinib is superior in terms of efficacy compared to acalabrutinib is unknown, and there are no head-to-head clinical trials planned or enrolling. The ALPINE and ELEVATE-RR trials studied different patient risk populations, with different geographies, across different treatment eras, and it is therefore impossible to cross-compare these studies. However, now that the clinical benefits of targeting BTK with improved specificity are proven, the next step in the evolutionary process of inhibiting this kinase in CLL is to test whether altering the mode of binding of drugs to BTK can further enhance the “fitness” of these agents for treating patients.While covalent BTKis have dramatically improved outcomes for patients with CLL/SLL, they are not curative. Long-term continuous usage can be associated with side effects that are difficult for patients to tolerate and also result in resistance due to development of mutations. Several resistance mutations have now been described, including a cysteine-to-serine mutation in BTK at the binding site of ibrutinib (C481S mutation) or gain-of-function mutations in the downstream kinase PLC-γ2 (R665W and L845F mutations) ,60. As aTP53 aberrant patients, pentad-exposed patients , and C481-mutated patients. Perhaps unsurprisingly, response rates in patients with downstream mutations in PLCγ2 were lower (ORR 55.6%). The median PFS for the whole cohort was 19.6 months. The most common all-grade treatment-emergent adverse events (TEAEs) across all 773 B-cell malignancy patients in BRUIN treated with pirtobrutinib were fatigue (29%), neutropenia (24%), and diarrhoea (24%). The rates of BTKi-associated events of special interest were low, including hypertension (9.2%), atrial fibrillation/flutter (2.8%), minor bleeding, and major haemorrhage (2.2%) [Pirtobrutinib  is a highly selective, first-in-class noncovalent (reversible) BTKi evaluated for both safety and efficacy in patients with CLL/SLL previously treated with a covalent BTKi in the first-in-human phase 1–2 BRUIN trial . Pirtobre (2.2%) . Notablye (2.2%) . A numbee (2.2%) . Figure Nemtabrutinib  is another noncovalent BTK in earlier development in the phase I-II 1/2 BELLWAVE-001 study. Recently updated efficacy data for 57 CLL/SLL pts with CLL/SLL treated with nemtabrutinib 65 mg once daily and safety for all 112 patients with B-cell malignancies treated at the 65 mg dose were presented . The medinhibitor treatment may mean that they form an important component of future treatment algorithms for CLL [Another BTK-targeting approach that may prove to be a critical addition to the CLL armamentarium is the strategy of degrading this kinase. In contrast to the agents discussed above which inhibit BTK function, “BTK degraders” essentially remove the BTK protein from the cell by targeting it for degradation by the proteasome. Ubiquitin-dependent proteolysis is a major pathway that degrades intracellular proteins as part of normal cellular maintenance processes . In this for CLL .The last decade has seen great advances in the treatment of CLL, with multiple covalent and noncovalent BTKis demonstrating significant clinical efficacy. However, there remain several questions and challenges. A key question is whether the activity of noncovalent BTKis will be equivalent in patients resistant to different covalent BTKis. The C481S mutations are most commonly seen with ibrutinib and acalabrutinib, with relatively little being known about zanubrutinib. However, recently, the novel Leu528Trp mutation has been described in a small case series of seven zanubrutinib-treated patients . Two of Finally, both covalent and noncovalent BTKis are being studied in combination in numerous ongoing clinical trials. The most common partner agents are anti-CD20 monoclonal antibodies (most commonly obinutuzumab) and BCL2 inhibitors. Treatment strategies in the front-line and relapsed settings have generally been to deliver treatment according to MRD-stopping rules or as fixed duration. The aim for both strategies is to stop therapy in a deep remission after a time-limited duration and therefore limit both toxicity and the induction of resistance mechanisms to both BTK and BCL2 inhibitors. Ibrutinib plus venetoclax as fixed duration in the front-line setting is closest to being broadly approved following the results of the CAPTIVATE and GLOW trials ,76,77. I


Studies show conflicting results on neonatal outcomes following embryo biopsy for PGT, primarily due to small sample sizes and/or heterogeneity in the timing of embryo biopsy  and type of embryo transfer. Even fewer data exist on the impact on children’s health beyond the neonatal period. This study aimed to explore outcomes in children born after EBD3 or EBD5 followed by fresh (FRESH) or frozen-thawed embryo transfer (FET).This single-centre cohort study compared birth data of 630 children after EBD3, of 222 EBD5 and of 1532 after non-biopsied embryo transfers performed between 2014 and 2018. Follow-up data on growth were available for 426, 131 and 662 children, respectively.Embryo biopsy, either at EBD3 or EBD5 in FET and FRESH cycles did not negatively affect anthropometry at birth, infancy or childhood compared to outcomes in non-biopsied FET and FRESH cycles.While there was no adverse effect of the timing of embryo biopsy (EBD3 versus EBD5), children born after EBD3 followed by FET had larger sizes at birth, but not thereafter, than children born after EBD3 followed by FRESH.Reassuringly, weight and height gain, proportions of major congenital malformations, developmental problems, hospital admissions and surgical interventions were similar between comparison groups.Our study indicated that neither EBD3 nor EBD5 followed by FRESH or FET had a negative impact on anthropometry and on health outcomes up to 2 years of age.The online version contains supplementary material available at 10.1186/s12958-023-01140-3. Preimplantation Genetic Testing (PGT) has been instrumental in preventing the transmission of genetic diseases within families. The PGT procedure is characterized by the biopsy of one or more cells from the developing embryo, followed by genetic testing to allow the transfer of non-at-risk embryos into the uterus.PGT has evolved over the years: the practice of blastomere biopsy performed on cleavage-stage embryos (day 3) followed by either a fresh or a frozen-thawed embryo Transfer (FET) has shifted to trophectoderm biopsy on blastocysts (day 5/6) followed by vitrification of the blastocysts .As embryo biopsy is invasive, safety concerns for the health of the offspring exist. One can hypothesize that the removal of embryonic cells has a detrimental effect on the development of the fetus and may affect the pregnancy course and, eventually, the pre- and postnatal growth of the offspring. It is well-known that, in the general population, birth size and inappropriate infant growth are associated with adverse health conditions later in life, including obesity and cardiovascular morbidity . TherefoA few studies have evaluated the health of children born after PGT so far. Due to the relatively small sample sizes, the mix of types of biopsy (at cleavage-stage or blastocyst-stage) and the type of embryo transfer (frozen or fresh) in the available studies, strong conclusions regarding the impact on the offspring are lacking . FurtherOur group previously described outcomes at 2 years of age but in a modest group of children born after PGT using cleavage-stage biopsy . The curThis single-centre study aimed to investigate the impact of embryo biopsy on the health and growth of children up to 2 years of age, taking into account several parental and treatment factors.All singleton deliveries following cleavage- and blastocyst-stage embryo biopsy followed by fresh or frozen-thawed embryo transfers between January 2014 and December 2018 were considered. This resulted in three embryo biopsy groups: cleavage-stage biopsy followed by vitrification on day 5 and frozen-thawed embryo transfer , blastocyst-stage biopsy followed by vitrification on day 5 and frozen-thawed embryo transfer  and cleavage-stage biopsy followed by fresh embryo transfer at day 5 (EBD3 FRESH).The non-biopsy/control study population consisted of two groups of singleton deliveries after transferring a non-biopsied frozen-thawed (non-biopsy FET) and fresh blastocyst (non-biopsy FRESH) during the same study period.Data are limited to single embryo transfer cycles. In both groups, embryos were obtained after ICSI, either with ejaculated or non-ejaculated, fresh or frozen sperm. Pregnancies after frozen embryo manipulation (FrEM), in vitro maturation of oocytes (IVM), oocyte vitrification and after oocyte/embryo donation were excluded.Vitrification was the cryopreservation method used in all frozen-thawed embryo transfer cycles (biopsy and non-biopsy).Patient counselling and genetic testing methods for PGT-M have been described previously . TestingAll children conceived in our centre and living in Belgium are eligible for follow-up. Depending on the mode of conception, all or random samples are approached for follow-up until young adulthood. In this case, all children born after embryo biopsy (study group) and living in Belgium are approached for follow-up. For the comparison group, a random group of children born after ICSI, either after fresh or frozen-thawed embryo transfer, and living in Belgium is approached. This strategy has been in place since 2004 due to the high numbers of ICSI children conceived in our centre. In practice, a computer program randomly selects 1 out of 3 families with children conceived after ICSI. Only these families are invited to our centre for an examination of their child in infancy and childhood. Pregnancy, delivery and birth data are provided by gynecologists and/or pediatricians or parents and are double-checked during the visit.For all children (born after embryo biopsy or without embryo biopsy) in our follow-up program, a morphological assessment focusing on biometry and congenital malformations at 3–6 months, is performed by certified pediatricians and information on the course of infancy is added. The child’s second visit, which takes place at the age of around 2 years, focuses on growth but also includes information regarding psychomotor development, postnatal illnesses, hospital admissions, surgical interventions and medication intake.Regarding congenital malformations, identical guidelines, definitions and classifications have been used for all children conceived in our centre since the introduction of our follow-up program for children born after ART . A widelAll parents gave informed consent for participation in the follow-up program. The study was approved by the Ethics Committee of the UZ Brussel (B.U.N. 1432022000045).Primary outcomes were anthropometric measures of weight, height and head circumference at birth, infancy (3-6 months) and childhood (2 years). Waist circumference and mid-upper arm circumference were additionally measured at childhood. The anthropometric measurements are expressed as standard deviation scores (SDS) to correct for gestational age and sex according to Belgian growth references . AnthropNeonatal outcomes explored were small-for-gestational age , large-for-gestational age , low birthweight , preterm birth (gestation <37 weeks), macrosomia (birthweight >4000g), perinatal death and major congenital malformations.P-value < 0.05).Descriptive statistics are presented as means ± standard deviation (SD) for continuous variables and as frequencies (percentages) for categorical variables. Statistical significance was set at the 5% level  and each neonatal outcomes using logistic regression. Covariates for the final model were selected based on factors known from the literature to affect body size and/or were statistically different among the study groups. For reasons of uniformity, the same covariates were used in all models: treatment characteristics ), maternal characteristics , body mass index , smoking, alcohol, gestational diabetes, pregnancy-induced hypertensive disorder).The impact of embryo biopsy was assessed in frozen and fresh transfer cycles separately: blastocyst-stage embryo biopsy and cleavage-stage embryo biopsy followed by frozen-thawed embryo transfers were compared with outcomes after the transfer of non-biopsied vitrified blastocysts. Outcomes after cleavage-stage embryo biopsy followed by fresh embryo transfer were compared with outcomes after transfer of fresh non-biopsied blastocysts. As secondary and tertiary outcomes, we explored, within the PGT cycles, if the timing of biopsy (at day 3 or day 5/6) and if the vitrification process after embryo biopsy impacted children’s outcomes.A subgroup analysis (biopsy versus non-biopsy groups) was performed in children born to parents with an infertility background. Three categories were distinguished: PGT for a genetic reason but no infertility in the couple, PGT for a non-genetic reason but infertility background  or PGT for a genetic reason and infertility problem in the couple .Statistical analyses were performed in Stata . 95% confidence intervals (95% CI) for the estimates are presented.A power calculation  demonstrated that the current sample was appropriate to detect a mean birthweight difference of 122g, 100g, and 104g for the comparisons of EBD5 FET vs non-Biopsy FET, EBD3 FET vs non-Biopsy FET, and EBD3 FRESH vs non-Biopsy FRESH, respectively.All embryo transfers in the ‘embryo biopsy day 5/6 group’ (EBD5) were frozen-thawed (EBD5 FET) embryo transfers: 250 singleton deliveries resulting in 3 1.2%) stillborn and 247 liveborn children , either frozen-thawed (EBD3 FET) or fresh embryos (EBD3 FRESH) were transferred. In frozen-thawed embryo transfer cycles, 347 singleton deliveries resulted in 2 (0.6%) stillborn and 345 liveborn children. Birth data were available for 322 (92.7%) children and 272 were eligible for follow-up. Of these, 67 (24.6%) were not reached or refused participation. Information on 205 children was available either at infancy and/or childhood. Follow-up data at the first visit were available for 193 (71.0%) children. In fresh embryo transfer cycles, 330 singleton deliveries resulted in 2 (0.6%) stillborn and 328 liveborn children. Birth data were available for 308 (93.3%) children and 274 were eligible for follow-up. Of these, 53 (19.3%) were not reached or refused. Information on 221 children was available at infancy and/or childhood. Follow-up data at the first visit were available for 215 (78.5%) children.In the non-biopsy FET group, 814 singleton deliveries resulted in 6 (0.7%) stillborn and 808 liveborn children. Of the 751 (92.2%) children with birth data recorded, 697 were eligible for follow-up. A random selection for follow-up resulted in data from 362 children either at infancy and/or childhood. Follow-up data at the first visit were available for 345 (49.5%) children.In the non-biopsy FRESH group, 831 singleton deliveries resulted in 9 (1.1%) stillborn and 822 liveborn children. Birth data were collected for 781 (93.9%) children of which 731 were eligible for follow-up. A random selection for follow-up resulted in data from 300 children at infancy and/or childhood. Follow-up data at the first visit were available for 282 (38.5%) children.Treatment and maternal characteristics of the biopsy and non-biopsy groups are presented in Table A comparison of birth parameters, treatment and parental characteristics of the non-participants and participants is provided in Supplementary Table SP=0.78 and P=0.99 respectively. Further, comparable rates of children were admitted to the NCU for >1 week .In frozen-thawed embryo transfer cycles, the rates of premature birth, SGA, LGA, LBW and macrosomia were comparable between the biopsy (either at the blastocyst or cleavage stage) and non-biopsy group Table , even afP=0.36). A similar proportion of children was admitted to the NCU for >1 week .In fresh embryo transfer cycles, the rates of premature birth, SGA, LBW and LGA did not differ between the biopsy and non-biopsy group Table , but macP>0.05).The rate of major congenital malformations in liveborns following embryo biopsy was comparable to that in children born after the transfer of non-biopsied embryos for all comparisons Table . Total mThe timing of embryo biopsy (day 3 or day 5/6) did not affect neonatal outcomes  and non-biopsy groups. Adjustment for treatment and maternal confounders did not change the result .There were no differences in the occurrence of mild and severe developmental  disorders between the different biopsy and non-biopsy groups all P>0.0; Table 5n=150) and children born after the transfer of a non-biopsied embryo (n=1532), no differences were found for any of the anthropometrical measurements at birth, infancy or childhood in the adjusted analyses  did not affect anthropometrics at any age. However, within the embryo biopsy group, vitrification after embryo biopsy resulted in larger-sized babies at birth, but not thereafter. In our limited subgroup of children born to infertile parents, embryo biopsy did not affect anthropometry at any age.The findings of this study on health outcomes at birth after cleavage-stage biopsy are overall in line with previous reports from our group  and otheIn parallel to the findings after cleavage-stage biopsy, our results showed no harmful effect of blastocyst-stage biopsy on anthropometrics at birth, infancy and childhood compared to outcomes after transfer of a non-biopsied blastocyst. This aligns with published data from China and the USA, where no adverse effects of blastocyst biopsy were reported on mean birthweight, rates of prematurity, LBW, SGA, LGA and macrosomia , 8, 22. Given the shift towards blastocyst-stage biopsy rather than cleavage-stage embryo biopsy, it is reassuring that the timing of embryo biopsy does not negatively affect the health of the offspring. Given that the contemporary practice of PGT worldwide now involves blastocyst biopsy  more data regarding long-term health risks are expected to become available.Information on congenital malformations after PGT is important but scarce and often gathered from questionnaires or interviews , 5, 23 oWe additionally conducted a sensitivity analysis taking into account parental infertility status. When restricting the dataset to children born to parents with an infertility background, we did not observe any impact of embryo biopsy on anthropometrics and growth up to childhood. In a subgroup analysis of a large registry-based study of 14 285 cycles with a stated infertility diagnosis , an increased odds of preterm birth was observed in PGT cycles compared to non-PGT cycles . HoweverWhen comparing outcomes across studies, several methodological factors should be considered. Although more recent studies described neonatal outcomes after blastocyst-stage biopsy, most do not express birth parameters as standard deviation scores, SGA or LGA rates are not presented , 7, 8 orThe current findings on health outcomes at 2 years of age were favorable and in line with our previous report describing children born after cleavage stage biopsy . Indeed,One of the main strengths of this study is the inclusion of large and well-defined cohorts in terms of embryo biopsy (day 3 or day 5/6) and type of embryo transfer cycle (fresh or frozen) from a single centre and for which various treatment and parental characteristics were available. As such, our data add to the shortcomings in literature data as extensively described by Alteri et al. .Our study also had some limitations. The number of children born after embryo biopsy to parents with an infertility diagnosis was limited as most of the PGT cycles in our centre were performed in patients with a genetic disorder without concomitant documented infertility. Therefore, the results from the sensitivity analyses should be interpreted cautiously. However, the main limitation of our study was the lack of prenatal growth data, which could have shed light on the findings of higher birth size in the group of children born after cleavage-stage embryo biopsy and frozen-thawed embryo transfer cycles compared with fresh embryo transfer cycles. Indeed, according to a large Nordic register study, the freeze-warming process was associated with excessive fetal growth from the third trimester of pregnancy onwards .In conclusion, our study showed no adverse impact of embryo biopsy, either at the blastocyst or cleavage stage, on child growth and health up to 2 years of age. Although these findings were reassuring, longitudinal studies on long-term outcomes are recommended, as the implications of the current shift towards blastocyst biopsy in combination with freeze-warming protocols are yet to be identified.Additional file 1: Supplementary Table S1. Non-participation analysis. Supplementary Table S2. The impact of the timing of embryo biopsy and the vitrification process after embryo biopsy on neonatal outcomes. Supplementary Table S3. The impact of the timing of the embryo biopsy and the impact of the vitrification process after embryo biopsy on anthropometrics from birth up to 2 years. Supplementary Table S4. Sensitivity analysis: including children whose parents have an infertility background


The adverse health effects of individual-level social isolation  have been well documented in older adults. However, little is known about the impact of collective-level social isolation on health outcomes. We sought to examine the association of group-level segregation with cardiovascular health (CVH) in older adults.From the prospective Korean Social Life, Health, and Aging Project database, we identified 528 community-dwelling older adults who were aged ≥60 years or were married to those aged ≥60 years. Participants who belonged to smaller social groups separate from the major social group were defined as group-level-segregated. The CVH score was calculated as the number of ideal non-dietary CVH metrics (0-6), as modified from the American Heart Association’s Life’s Simple 7. Using ordinal logistic regression models, we assessed cross-sectional and longitudinal associations between group-level segregation and CVH.Of the 528 participants , 108 (20.5%) were segregated at baseline. In the cross-sectional analysis, group-level segregation was significantly associated with lower odds of having a higher CVH score at baseline after adjusting for socio-demographic factors and cognitive function . Among 274 participants who completed an 8-year follow-up, group-level segregation at baseline was marginally associated with lower odds of having a higher CVH score at 8 years .Group-level segregation was associated with worse CVH. These findings imply that the social network structure of a community may influence its members’ health status. As social beings, humans must maintain social relationships for survival and well-being. A growing body of evidence indicates that insufficient social connections lead to higher mortality, suggesting that social relationships are crucial for health and longevity -3. In paA substantial number of studies have focused primarily on individual-level social isolation measures  concerning health outcomes. In contrast, only a few studies have investigated the prognostic implications of group-level segregation -14. In aUsing the prospective Korean Social Life, Health, and Aging Project (KSHAP) database, which includes information on the complete social network structure of a single village in Korea, we examined (1) the cross-sectional association between group-level segregation and CVH at baseline; (2) temporal changes in group-level segregation status and CVH; and (3) the longitudinal association between group-level segregation and CVH at follow-up.The KSHAP is a prospective cohort study designed to examine social activity, health-related factors, and aging in Korean older adults. All inhabitants of Township K in Ganghwa Island, Korea who were aged ≥ 60 years or were married to those aged ≥ 60 years were recruited.Township K is one of the 12 townships of Ganghwa Island, the fourth largest island in Korea. The township is a rural community located in the northernmost part of the island, which has been connected to the mainland by bridges since 1970. Most of the inhabitants engage in farming, and nearly half are aged over 60 . The cohA total of 860 participants were recruited in the KSHAP at baseline (2011). Of the 860 individuals in the target population, 814 (94.7%) completed an enumeration survey in the first wave of the KSHAP between December 2011 and July 2012. Among them, 698 participants underwent additional health examinations and were included in the KSHAP-health examination cohort . After eGroup-level segregation status was assessed using a complete social network analysis of Township K ,17. In s2 and 22.9 kg/m2 was defined as ideal BMI status. BP was measured using an oscillometric sphygmomanometer after 5 minutes of rest in the sitting position. Three BP measurements were obtained at 1-minute intervals, and the average of the 3 measurements was used as each participant’s BP; an untreated BP < 120/80 mmHg was defined as ideal BP status. Fasting glucose and total cholesterol levels were measured from blood samples collected after an 8-hour fasting period; an untreated fasting glucose level < 100 mg/dL and a total cholesterol level < 200 mg/dL were defined as ideal fasting glucose and total cholesterol status, respectively. We assessed participants’ physical function using the TUG test, as we lacked detailed information on their physical activity levels. During the test, a medical staff measured the time it took for the participants to rise from an armchair, walk a distance of 3 m, turn, walk back to the chair, and sit down [Each participant’s CVH score was calculated as the number of ideal non-dietary CVH metrics (0-6), as modified from the American Heart Association’s Life’s Simple 7 . The 6 Csit down ; a TUG tData on participants’ demographics, educational attainment , social network size, marital status (living with a spouse or not), Mini-Mental State Examination for Dementia Screening (MMSE) score, and household income were also collected.Baseline characteristics were presented as mean± standard deviation or number (%) and compared using the independent t-test or chi-square test. In the cross-sectional analysis, we examined the association of group-level segregation with the CVH score at baseline using ordinal logistic regression models, treating the CVH score as an ordinal variable from 0 to 6. The “Polr” function of the MASS package in R was used for the analyses. Potential confounders were adjusted stepwise: model 1 included age, sex, and educational attainment; model 2 was further adjusted for social network size and marital status; and model 3 was further adjusted for the MMSE score.In the longitudinal analysis, we assessed the temporal changes in group-level segregation status and CVH score among 274 participants who completed an 8-year follow-up. We also investigated the association of group-level segregation at baseline with CVH score at 8 years using the same regression models mentioned above, all of which were further adjusted for the baseline CVH score.As sensitivity analyses, we repeated our main regression analyses after further adjusting for household income or depressive symptoms assessed by the Center for Epidemiologic Studies Depression scale in the subset of participants who had available information. All statistical analyses were conducted using R version 4.0.3 .This study complied with the Declaration of Helsinki, and the study protocol was approved by the Institutional Review Board of Yonsei University, Seoul, Korea . Written informed consent was obtained from all participants.Of the 528 participants , 108 (20.5%) displayed social segregation at baseline. The segregated individuals were younger, were more highly educated, had smaller social networks, and lived with their spouses less frequently than those who were integrated .Group-level segregation was significantly associated with reduced odds of having a higher CVH score at baseline after adjusting for demographics and educational attainment . The association remained significant after further adjusting for social network size and marital status , and MMSE score  . The finOf the 274 participants  who completed an 8-year follow-up, 34 (12.4%) showed social segregation at baseline . SimilarOver the follow-up, the proportion of segregated individuals increased from 12.4% to 32.8% p<0.001; , and theGroup-level segregation at baseline was marginally associated with reduced odds of having a higher CVH score at 8 years after adjusting for baseline CVH score, demographics, educational attainment, social network size, marital status, and MMSE score  . The finThis prospective cohort study showed that community-level social isolation was significantly associated with worse CVH among Korean older adults. Segregated participants within small groups whose network did not reach the whole village exhibited worse CVH profiles than those who were integrated. Moreover, this negative association between group-level segregation and CVH persisted after 8 years, implying that socially isolated individuals, in general, remained unhealthy unless they were specially cared for or received an intervention of some sort. The associations of group-level segregation with individual CVH metrics varied to some extent, especially for smoking and total cholesterol . HoweverOur findings are in accordance with previous studies demonstrating the associations of neighborhood-level segregation with cardiovascular diseases and mortality -23. HoweThe present study focused on whether group-level segregation in a homogeneous ethnic group can impact health outcomes. Utilizing a single racial group and complete social network structure of an entire town, we showed that group-level segregation was associated with worse CVH at both baseline and 8 years. Herein, we speculate that 2 possible pathways might link group-level segregation and CVH. First, segregated older adults may be less likely to have access to communication resources disseminated through local community networks, which may restrict their ability to obtain sufficient health information for maintaining ideal CVH. Among racially segregated African Americans and Latinos in the United States, limited access to community-based communication infrastructure was associated with a reduced chance of obtaining knowledge about the detection and prevention of chronic diseases . In thisA growing body of evidence has linked health outcomes with individual-level social disconnection, such as loneliness, which is a subjective experience of social isolation ,31-33. HOur findings should be interpreted in light of several limitations. First, a causal relationship between group-level segregation and worse CVH could not be established due to the observational nature of the study. Second, despite adjusting for major covariables, including demographic characteristics, social factors, and cognitive function, the possibility of residual confounding still exists. In particular, unmeasured confounders, such as nutritional intake, physical activity, and genetic predisposition, may have affected the association between group-level segregation and CVH. Third, given the cohort’s low retention rate (52%) over the follow-up, we cannot exclude the possibility of selection bias in our longitudinal analysis. As a matter of fact, the participants who completed the follow-up were significantly younger and, interestingly, less segregated than those who were lost to follow-up . It is pIn older adults, group-level segregation was associated with worse CVH at both baseline and 8 years. These findings underscore the importance of community-level social isolation as one of the potential determinants of an individual’s health status that should be considered when developing future health promotion interventions for older adults. Further studies are warranted to demonstrate the potential mechanisms by which group-level segregation affects an individual’s health outcomes.


Despite concern about migrant children’s mental health and their access to mental healthcare services during the COVID-19 pandemic, this topic has attracted little research attention. This study aimed to examine the impact of the COVID-19 pandemic on the use primary and specialist healthcare services for mental health problems among children and adolescents with migrant background.Using event study models, we investigated the impact of lockdown and subsequent COVID-19 infection control measures on children’s health service use for mental health problems according to migrant background. Drawing on reimbursement data from Norwegian public healthcare providers we observe consultations in a pre-pandemic (2017–2019) and pandemic cohort (2019–2021) in primary and specialised care.The pre-pandemic cohort included 77 324 migrants, 78 406 descendants of migrants and 746 917 non-migrants and the pandemic cohort included 76 830 migrants, 88 331 descendants and 732 609 non-migrants (age 6–19). The full cohorts were observed for mental healthcare use in primary care while a subsample (age 6–16) was observed for health care use in specialist care. Lockdown resulted in a dip in consultation volumes for mental disorders for all children, but this dip was relatively larger and more persistent for children with migrant background. After lockdown, consultation volumes rose more for non-migrant children than for children with migrant background. Consultations in primary healthcare peaked during January to April 2021 for non-migrants and descendants of migrants, but not for migrants . In specialist care during the same period, consultations dropped by 11% for migrants (95% CI -21 to -1).By October 2021, all mental health consultations in specialist care were up with 8% for non-migrants (95% CI 0 to 15), and down with -18% for migrants and -2% for descendants (95% CIs -31 to -5 and -14 to 10).Migrant males experienced the largest reduction in consultations.Changes in consultation volumes among children with migrant background after lockdown were not as pronounced as for non-migrants, and at times actually decreased. This suggests that an increase in barriers to care emerged during the pandemic for children with a migrant background.The online version contains supplementary material available at 10.1186/s12913-023-09666-3. The psychological burden on children and adolescents has been a returning concern during the COVID-19 pandemic . Non-phaChildren and adolescents with migrant background may have been particularly vulnerable to the psychological burden of the COVID-19 pandemic: compared to the majority population, they were more likely to have an adult relative who was hospitalized with or died from COVID-19  and to lDespite concern for migrant children and adolescents’ welfare during the pandemic, few studies have examined the impact of the COVID-19 pandemic on their mental health . The exiIn this study we aim to examine the impact of the COVID-19 pandemic on the use of healthcare services for mental health problems among children and adolescents with migrant background. To better understand changes in healthcare use for mental disorders among children and adolescents with a migrant background, we compare these changes to the changes in healthcare use observed in non-migrant children and adolescents.We use Norwegian population-wide data to examine changes in primary and specialist healthcare consultations for mental health symptoms and disorders in children aged 6–19 years old. We compare consultation volumes during the pandemic to pre-pandemic years, and we employ an approach that allows us to net out seasonal effects and period changes.We utilize data from the Norwegian national emergency preparedness registry (BeredtC19). The register includes data from the Norwegian Control and Payment of Health Reimbursements Database (KUHR) and the National Patient Registry (NPR), as well as demographic data from Statistics Norway. Data on parents and children were linked through unique (de-identified) personal identifiers. The sample is restricted to all children aged 6–19 in 2018 or 2020.In Norway, primary and specialist healthcare is free for all children aged 18 years and younger, lowering the threshold for seeking care also for low-income families. Data on primary healthcare use was retrieved from KUHR and specialist healthcare data from the NPR. KUHR includes consultation dates and diagnoses according to the International Classification of Primary Care (ICPC-2) with either a symptom or disorder code . PrimaryMonthly dummy variables were constructed for every child in the sample, indicating as least one consultation for (i) all mental symptoms and disorders registered in primary care and specific diagnoses for ADHD, anxiety, depression, and sleep problems and (ii) all mental disorders in specialist care as well as specific diagnoses for ADHD, anxiety, depression and hospitalizations  and 2).Low sample sizes . All observations in the pre-pandemic cohorts fall into the reference category.We first display trends in mental healthcare consultations for the pre-pandemic and the pandemic cohorts. We then fit multivariate event study models with controls for month and time in years to formally test, month by month, whether the change in use of healthcare services differs between the cohorts :X is a vector of control variables, including region, age dummies, sex dummies, and a variable running from 0 to 1 indicating the proportion of Easter falling into that month.We control for calendar month to net out shared seasonal differences, and duration in years to handle shared secular change, by the following term These models are also used to assess whether the assumption of parallel trend before the interruption, alias the pandemic, holds.Finally, we estimate difference-in-difference models, where we group months into six periods for the pandemic cohort : lockdown (March–May 2020), summer’20 (June–August 2020), fall’20 (September-December 2020), winter ‘21 (January-April 2021), summer’21 (June–August 2021) and fall’21 (September-December 2021). These models allows us to assess the effects of the pandemic.p-values in large samples [p-values in our application. However, acknowledging the limited information conveyed by p-values, we are careful to also report the magnitude of effects and their precision using confidence intervals (CIs), in accordance with the recommendation of Wassterstein et al. [While we rely on full population data, our statistical model splits data into several subgroups, reducing the statistical power of our model. Despite the caveats regarding reporting  samples , we thern et al. .The pre-pandemic cohort included 77 324 migrants, 78 406 descendants and 746 917 non-migrants observed for mental healthcare use in primary care (age 6–18) and 56 445 migrants, 67 132 descendants and 582 148 non-migrants observed for mental healthcare use in specialist care (age 6–16). The pandemic cohort included 76 830 migrants, 88 331 descendants and 732 609 non-migrants observed for mental healthcare use in primary care (age 6–18) and 56 493 migrants, 75 708 descendants and 674 687 non-migrants observed for mental healthcare use in specialist care (age 6–16) . We observe an upward trend for all outcomes in both primary and specialist care. Before lockdown, trends are largely similar in the pandemic and pre-pandemic cohorts, fulfilling the assumption of parallel trends. During lockdown, consultations drop in the pandemic cohort, then quickly recuperate to the level of the pre-pandemic cohort and surpass the pre-pandemic level from January to May 2021 and September to December 2021.Non-migrant children displayed the highest consultation volumes across both cohorts and across consultations in primary and specialist care. 16.6% of the pre pandemic cohort, and 18.4% of the pandemic cohort had a consultation in primary care for any mental symptom or disorder during the three years they were observed. The corresponding figures were 12.7% and 11.0% for the pre-pandemic migrant and descendant cohort and 13.3% and 12.0% for the pandemic migrant and descendant cohort .From December 2020, a new increase in consultation volumes is observed in both primary and specialist care, resulting in a peak for consultations in primary care in March 2021, coinciding with reinstated COVID-19 restrictions. Consultation volumes for all psychological disorders in primary care were up with 21% (95% CI 5 to 39) for migrants, 34% for descendants (95 CI 16 to 53) and 35% for non-migrants (95% CI 21 to 50).By July 2021, consultation volumes were again returning to pre-pandemic levels across the board. Autumn 2021 saw an increase in consultations in primary care for all three groups. In specialist care, however, there were signs of divergence between migrants and partly descendants on the one side and non-migrants on the other. In October 2021, all mental health consultations in specialist care were up with 8% for non-migrants (95% CI 0 to 15), and down with -18% for migrants (95% CI -31 to -5) and -2% for descendants (95% CI -14 to 10).Migrant consultation volumes for sleep disorders in primary care were deviating from these general trends during autumn 2020 and 2021 and remained mostly below pre-pandemic levels Tables  and 4.TaThe results from the difference-in-difference analysis confirm that children with migrant background experienced the largest relative dip in consultation volumes during lockdown, although confidence intervals overlap for most outcomes both in primary and specialised care. For any mental health problem in primary care the reduction for migrant children during lockdown was -36% (95% CI -43 to -29), while for non-migrants the reduction was -22% (95% CI -28 to -16) and the reduction for descendants was -24 (95% CI -33 to -15). The reduction was strongest for anxiety/depression. In specialist care the reductions in consultations for any mental disorder was -31% for migrants (95% CI -39 to -23), -13% for non-migrants (95% CI -19 to -7) and -18% for descendants (95% CI -25 to -9).p-values: 0.78 & 0.76). A noticeable exception was ADHD consultations, which saw significant increases for migrant children ranging between 36 and 55% in primary care from fall 2020 to fall 2021. A similar increase in ADHD consultations was seen for descendants of migrants.Winter 2021 consultation levels were significantly higher for mental health consultations in primary healthcare for non-migrants and descendants , while migrant children were on the pre-pandemic trend . Similarly, fall 2021 saw an increase in consultation volumes for any mental symptom or disorder in primary care for non-migrant children of 15% (95% CI 7 to 22) while changes in consultations volumes for migrants and descendants were not statistically significant different from zero  or in the rest of Norway Figure A.Using registry data covering three years of children’s healthcare service use for mental health problems, we were able to illuminate large differences according to migrant background and separate those from changes that arose after the pandemic. The descriptive trends revealed that both before and after the COVID-19 pandemic hit, children with migrant background used services for mental health problems less than children without migrant background.We found that lockdown resulted in a significant and substantial reduction in the use of primary and specialist healthcare services for mental health problems, and that migrants faced the highest relative reduction . After lockdown consultations returned to pre-pandemic levels within a couple of months.In 2021, we observed two periods where consultations were significantly and substantially higher than the pre-pandemic trend: March to May and October to November. Migrant status modified this relationship: For most outcomes, fall 2021 showed a statistically significant and substantial increase in consultation volumes for children without migrant background . Meanwhile, changes to migrant children’s consultation volumes were often not statistically different from zero, or even negative. Consultation volumes for descendants of migrants more closely followed the trend for non-migrants, although also often not statistically different from zero either, except for a similar increase in ADHD consultations .Looking closer at which segments drove the differences observed by migrant background, we found that the non-significant, or negative, trend in consultation volumes in specialist care for migrants were mainly attributed to males and children aged 6–12 years.On the whole, children with migrant background did not experience substantially higher consultation volumes in primary and specialist healthcare after lockdown than non-migrants. To the contrary, the trend was below pre-pandemic levels for migrant males and migrants aged 6–12 years for considerable periods in the fall 2020 and in 2021. This latter finding can be interpreted in at least two ways: On the one hand, there could be a real lack of change in demand for healthcare services for mental health problems for migrant youth after the pandemic, which suggests that the pandemic did not result in deteriorating mental health for this group. For migrants and their descendants, larger families and more dense social networks could have protected against poor mental health outcomes during social distancing. This interpretation contrasts with the finding of no clear differences by migrant background among Swiss adolescents , and sliIt is also possible, however, that our results differ from results based on self-reported health because they reflect increased barriers to access mental healthcare. Like in many other countries, the use of e-consultations increased steeply in the first phase of the pandemic, and some studies have indicated that vulnerable groups including migrants experience challenges in relation to e-consultation due to lack of digital and/or language skills and lack of private space , 29. FurWe found that differences in trends between children with migrant background versus children without such background were most discernible for migrant youth. Descendants of migrants are similar to non-migrants as they are both born and schooled in the Norwegian system and so language is less problematic than an adolescent who moved to Norway. However, much of help-seeking behaviour is likely learned from the home and perceptions of mental health may be very much influenced by their parents’ and others’ perceptions within their own community .A strength of our study is the full population data. Migrants and descendants have lower survey response rate and often reach a highly selected group in terms of language proficiency and socioeconomic status  and therIn the overall population, about 70% with a mental health diagnosis will have a primary care consultation related to mental health over a three year period . As suchAs for the external validity of our results, some important features of the Norwegian context should be highlighted. First, the relatively low rates of COVID-19 death and severe morbidity, and moderate levels of contact reducing non-pharmaceutical interventions in place means that both the overall and any excess strain experienced by the migrant and descendant community, may be lower than in other western contexts. While increased disparities in unmet needs during the pandemic has been found in the US , a publiContrary to our expectation, changes in consultation volumes for mental health problems among children with migrant background during the COVID-19 pandemic were not higher than for non-migrant children and adolescents. During some periods from March 2020 to December 2021, migrant children even faced reductions in consultation volumes compared to the pre-pandemic trend. These findings suggest an increase in barriers to care emerged during the pandemic for children with a migrant background. Our results suggest that national health authorities should address increasing disparities in access to mental health care in a health crisis such as the COVID-19 pandemic. Furthermore, the school and primary care should have a particular focus on children and adolescents with immigrant background and their mental health in the wake of the COVID-19 pandemic.Finally, to get the full picture of how the mental health of migrant youth changed during the pandemic, and whether they receive adequate healthcare support, both data on self-reported health and use of health services is needed. Thus, it is crucial that this evidence is complemented with self-reported measures of mental health from nationally representative surveys that also cover migrant and descendant children and adolescents.Additional file 1: Appendix A. Supplementary results. Table A1. Sample characteristics and sample sizes in the pre-pandemic cohort and pandemic-cohort observed for ages 6-19 (primary care) and 6-16  according to migrant background. Table A2. Top 10 country background for migrants and descendants of migrants. Pre-pandemic cohort (age 6-19) in panel A) and pandemic-cohort (ages 6-19) in panel B). Figure A1. Results from separate event study models by migrant background . Complete lines show coefficients, and shaded areas their 95% confidence intervals. Coefficients and confidence intervals are scaled to the pre-lockdown level in the main sample . Complete lines show coefficients, and shaded areas their 95% confidence intervals. Coefficients and confidence intervals are scaled to the pre-lockdown level in the main sample  and the rest of Norway, by migrant background. Complete lines show coefficients, and shaded areas their 95% confidence intervals. Coefficients and confidence intervals are scaled to the pre-lockdown level in the main sample (see Table


Background: During the COVID-19 pandemic, TB mortality increased while diagnoses decreased, likely due to care disruption. In March, 2020, Uganda—a country with high TB burden, implemented a COVID-19 lockdown with associated decrease in TB diagnoses. This study aims to examine patient level risk factors for disruption in TB care during the COVID-19 pandemic in Uganda. This retrospective cross-sectional cohort study included six TB clinics in Uganda. Clustered sampling included phases of TB care and three time-periods: pre-lockdown, lockdown and post-lockdown. Characteristics of patients with TB care disruption (TBCD), defined as those with > 2 months of symptoms prior to diagnosis or who missed a TB clinic, and those without TB care disruption (non-TBCD) were analyzed between time-periods. 1,624 charts were reviewed; 1322 were contacted, 672 consented and completed phone interview; pre-lockdown (n = 213), lockdown (n = 189) and post-lockdown (n = 270). TBCD occurred in 57% (385/672) of patients. There was an increase in the proportion of urban patients in the TBCD and non-TBCD groups during post-lockdown (p <0.001). There was no difference in demographics, HIV co-infection, socioeconomic status, or distance to TB clinic between TBCD and non-TBCD groups or within TBCD by time-period. There were few differences amongst TBCD and all TB patients by time-period. The increase in urban patients’ post-lockdown may represent a portion of urban patients who delayed care until post-lockdown. Insignificant trends suggesting more TBCD amongst those who lived further from clinics and those without HIV-coinfection require more investigation. The COVID-19 pandemic severely disrupted healthcare globally. This is particularly concerning in low-middle income countries (LMICs), where health resources are limited and where vaccination has lagged . In 2020Disruptions in TB care are significant for several reasons. First, delays in diagnosis and care disruption are associated with a notable increase in all-cause mortality for TB patients –9. Indivth, 2020—May, 18th, 2020, primary school closure March, 20th, 2020 –January, 10th, 2022, suspension of public transport, including motorcycle taxis and buses as well as restriction of private transport March, 25th, 2020 –May, 25th, 2020, strict nationwide curfew from 7pm-6:30am March, 30th, 2020 –May, 28th,2020 [Uganda is an LMIC in East Africa with a high prevalence of TB . In mid-8th,2020 , 13. A s8th,2020 , 15. Cli8th,2020 .Similar measures to control the spread of COVID-19 were common in other LMICs and likely led to disruptions in TB care. In a study of 84 countries with high rates of TB, TB case notifications decreased by 21% after March 2020 with an even larger impact in the ten highest burden countries . While tth, 2020), lockdown  and post-lockdown  was utilized. Dates for lockdown were chosen to focus on transportation lockdown periods with the end date of the 1st of June to coincide with the first Monday following easing of public transport restrictions. Data on date of diagnosis, admission to TB ward, clinic attendance and missing clinic was collected. Only charts with complete data were included in the analysis.To assess factors associated with TB care disruption (TBCD) in Uganda during transportation lockdowns we classified patients into two groups: those that reported a care delay (> 2 months from symptoms onset to diagnosis or admission to TB-wards) or those that missed at least one clinic visit during treatment (> 3 days from scheduled visit) were assigned to the TBCD group. Those who had diagnosis < 2 months prior to symptoms and no missed visits were considered non-TBCD patients. Participants were over the age of 18 and had a diagnosis of TB from chart review at six TB clinics  who received care between September 2019–2020 in Uganda. Rural clinics included: Jinja Regional Referral Hospital, Mubende Regional Referral hospital and Kiboga General Hospital. Urban clinics included: Kiruddu National Referral Hospital-Kampala district, Kisenyi Health Centre IV-Kampala district and Mulago National Referral Hospital-Kampala district.  In attemSociodemographic data, time from symptom onset to TB care, comorbid conditions, smoking and exposure history, medication and clinic adherence and perceived barriers to care were collected by phone. Quality of life was also measured via phone interview using the EQ-5D-3L, a well validated tool which has been used frequently in TB research and measures quality of life in five dimensions; the St. George Respiratory Questionnaire (SGRQ), a respiratory quality of life questionnaire consisting of 76 items in three categories has been validated for use in Uganda and is also validated in TB patients –21. To mTo determine factors associated with TBCD, we compared those who reported > 2 months of symptoms prior to TB diagnosis or a missed clinic visit during phone interview with those with no missed visit or care delays (non-TBCD). Potential risk factors for TBCD were compared amongst groups and time-periods and included: Demographics, distance from residence to clinic (measured as distance from patient’s parish to TB clinic), co-morbidities (including co-infection with HIV), socioeconomic status (SES), employment status, urban or rural TB clinic and time of TB care .Socioeconomic status was determined utilizing a modified WAMI score. The WAMI score was computed based on ownership of household assets, water source/sanitation facilities, and household income . This SECategorical variables were summarized using frequencies and percentages. Continuous variables were summarized using median and interquartile ranges (IQR). The chi-square and Fisher’s exact test were used to assess the association between the categorical variables and the outcomes (i.e care disruption as well as comparisons across the three time-periods). Kruskal Wallis test was used to compare medians for continuous variables by the outcome variable. Additionally, using a causal approach, univariable and multivariable logistic regression models were fitted to estimate the effect of each explanatory variable and the outcome. From the fitted models, odds ratios and 95% confidence intervals were then reported. All tests were done at 5% level of significance and analysis was done using Stata version 17.We calculated that 346 participants would be needed in our reference group (pre-lockdown) and 173 in our lockdown and post lockdown groups to obtain 80% power to detect a difference of 15% with .05 alpha.Regulatory approval was obtained from the Makerere University School of Medicine Research and Ethics Committee of the College of Health Sciences . All subjects who completed phone interviews provided verbal witnessed consent via phone in accordance with local regulations regarding human subject interviews.1,624 charts were reviewed from patients at six TB clinics throughout Uganda who obtained care from September 2019 to September 2021; the median age for all charts reviewed was 34 (IQR 26–44) and a majority were male 63% (1023/1624); Phone numbers were available for 1322 individuals and 1320 were contacted, 2 individuals phone numbers were not in service and family member numbers were not answered after 3 attempts. A total of 54% (710/1320) of TB patients consented and underwent phone interview and 672 completed interviews  which diThere was a high rate of TBCD in our phone interview sample 57.2% (385/672). There were no differences in gender, age or comorbid conditions, including HIV co-infection amongst the aggregated TBCD group when compared to the non-disruption group . There was no difference in the distance of patient residence from TB clinic in those with TBCD vs. those without TBCD (4.5km (IQR 2.3-9km) vs. 6 . There was a weak evidence suggesting fewer subjects with HIV-coinfection experiencing TBCD compared to those without HIV-coinfection overall, 51.6% vs. 58.6% (p = 0.12), however this was not significant. Socioeconomic status also did not differ significantly among all patients with TBCD and those without TBCD. Results were similar in the logistic regression model.There was no difference in the number of people who experienced TBCD by time-period (pre-lockdown 128/213 (60.1%), lockdown 109/189 (57.7%) and post-lockdown 98/170 (57.6%) (p = 0.84) . We alsoOur sample had more patients from urban settings than rural settings for all time-periods Figs  and 4. TIn this retrospective clustered cross-sectional study, we were able to collect a large sample of patients who had received care for TB before, during and after the initial COVID-19 lockdown in Uganda. While previous reports have utilized TB registrar data to describe the reduction in TB case notifications, this study is one of the first to use interviews to identify patient level risk factors for TBCD during the pandemic , 23. DesResearch prior to 2020 has shown clinical and system-related factors associated with TB diagnostic delay –28. The While the present study did not identify a significant increase in those reporting delays in diagnosis in the lockdown period, there were higher numbers of urban patients seeking care post-lockdown. The COVID-19 lockdowns were likely to be more strictly enforced in urban areas where police presence is greater; this may have led to a “backlog” of urban patients who sought care after the initial COVID-19 lockdown was lifted. The lack of other differences between time-periods for those with TBCD was surprising and but was not entirely inconsistent with other work in countries outside of Africa that examined TB care during the COVID-19 pandemic. A retrospective Chinese study examining medical records of TB patients from a national database from TB patients during the 10 weeks prior to COVID-19 lockdown, 10 weeks during COVID-19 lockdown and 10 weeks following lifting of lockdown found that TB notifications dropped by 60% during lockdown and individuals presented with more severe disease on chest x-ray during lockdown compared to pre and post-lockdown. However, there was no difference in time to diagnosis when comparing the 10-week periods pre, during or post-lockdown although there was a longer delay in care for all time-periods in 2020 when compared to historical control periods .We hypothesized that patients with TBCD would live further from TB clinics than those who did not have TBCD. We also believed that all subjects, regardless of TBCD, who did engage in care during lockdown would have a shorter distance to care than those who received care prior to lockdown. While our analysis demonstrated weak evidence that TB patients after the COVID-19 lockdown lived a greater distance from TB care, this was not statistically significant; furthermore, there was no change in distance by time-period for the TBCD group. Our data showed weak evidence towards less care disruption overall in TB-HIV coinfection but this was not significant and not affected by time-period. Further investigation into these groups may be reasonable to evaluate if better engagement in care and robust systems to deliver care to HIV patients during the COVID-19 pandemic improved TB care in those with coinfection.Strengths of the study included a relatively large sample of charts at six TB clinics representing a range of settings, a high phone contact rate (approximately 80%) and obtaining interview data in 710 subjects. Uganda has a well-established TB screening and treatment infrastructure. The selected clinics represent a large study catchment area with active community surveillance and referral programs in place . We addiUltimately this study did not identify patient level characteristics associated with TBCD during the COVID-19 lockdown in Uganda. Furthermore, there were no statistically significant differences in the demographics, SES, distance or comorbid conditions of patients who obtained care before, during or after the COVID-19 lockdown. It is important to note that there were likely disruptions in TB care, evidenced by decreased TB case notifications during the COVID-19 pandemic within Uganda and most of Africa. However, in this study none of the patient level variables investigated were associated with higher risk of TBCD or having a delay in TB diagnosis. While this is surprising it may suggest that the effect of COVID-19 mitigation measures was widespread and affected a broad range of TB patients in Uganda. It is possible that additional variables that we did not investigate may be associated with TBCD during the COVID-19 pandemic. Lastly, the fact that this study relied on patient interviews for those who had disruptions in care and may not have reliable phone access raises a concern for selection bias that excludes more subjects who experienced care disruption and we may have underestimated the overall rates of TBCD; however, policies aimed to limit infectious risk during the study period precluded other methods for patient recruitment. Further work is necessary to determine if some of the weak evidence seen in this data may represent meaningful associations with TBCD and studies with in person case finding, larger sample sizes and a focus on comparison such TBCD in those without HIV coinfection and those that live further from care may be warranted.S1 Data(CSV)Click here for additional data file.